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author:("Zhao, chunan")
1.  Effect of interleukin 21 and its receptor on CD8+ T cells in the pathogenesis of diffuse large B-cell lymphoma 
Oncology Letters  2014;8(1):421-425.
Interleukin 21 (IL-21) and its receptor, IL-21R, play a key role in innate and adaptive immunity. In the present study, the effect of IL-21 and IL-21R on the pathogenesis of diffuse large B-cell lymphoma (DLBCL) was investigated. The serum levels of IL-21 were detected by enzyme-linked immunosorbent assay, and the expression of IL-21R on CD8+ T cells was examined through flow cytometry. The data showed that the serum level of IL-21 was significantly decreased in the patients with DLBCL compared with the healthy controls (P<0.001), whereas the expression of IL-21R was clearly elevated on the CD8+ T cells in the patients with DLBCL. Further analyses revealed that the downregulation of the IL-21 serum level was correlated with an increased tumor stage of DLBCL, while the expression of IL-21R on the CD8+ T cells was positively correlated with the tumor stage. Also, the serum level of IL-21 and the proportion of IL-21R on the CD8+ T cells were negatively correlated in the patients. Notably, it was identified that the proportion of IL-21R on the CD8+ T cells, but not the serum level of IL-21, was significantly upregulated in the patients with bone-marrow involvement and B symptoms. These results indicate that IL-21 and IL-21R may be involved in the pathogenesis of DLBCL, in which IL-21R may reflect the progression of the disease more accurately than the serum level of IL-21.
doi:10.3892/ol.2014.2062
PMCID: PMC4063596  PMID: 24959288
interleukin-21; serum; interleukin-21 receptor; cluster of differentiation 8; diffuse large B-cell lymphoma
2.  Expression of activator protein-1 (AP-1) family members in breast cancer 
BMC Cancer  2013;13:441.
Background
The activator protein-1 (AP-1) transcription factor is believed to be important in tumorigenesis and altered AP-1 activity was associated with cell transformation. We aimed to assess the potential role of AP-1 family members as novel biomarkers in breast cancer.
Methods
We studied the expression of AP-1 members at the mRNA level in 72 primary breast tumors and 37 adjacent non-tumor tissues and evaluated its correlation with clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR) and HER2/neu status. Expression levels of Ubiquitin C (UBC) were used for normalization. Protein expression of AP-1 members was assessed using Western blot analysis in a subset of tumors. We used student’s t-test, one-way ANOVA, logistic regression and Pearson’s correlation coefficient for statistical analyses.
Results
We found significant differences in the expression of AP-1 family members between tumor and adjacent non-tumor tissues for all AP-1 family members except Fos B. Fra-1, Fra-2, Jun-B and Jun-D mRNA levels were significantly higher in tumors compared to adjacent non-tumor tissues (p < 0.001), whilst c-Fos and c-Jun mRNA levels were significantly lower in tumors compared with adjacent non-tumor tissues (p < 0.001). In addition, Jun-B overexpression had outstanding discrimination ability to differentiate tumor tissues from adjacent non-tumor tissues as determined by ROC curve analysis. Moreover, Fra-1 was significantly overexpressed in the tumors biochemically classified as ERα negative (p = 0.012) and PR negative (p = 0.037). Interestingly, Fra-1 expression was significantly higher in triple-negative tumors compared with luminal carcinomas (p = 0.01).
Conclusions
Expression levels of Fra-1 and Jun-B might be possible biomarkers for prognosis of breast cancer.
doi:10.1186/1471-2407-13-441
PMCID: PMC3849565  PMID: 24073962
AP-1 family members; Breast cancer; Estrogen receptor; Progesterone receptor
3.  Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum 
PLoS ONE  2012;7(8):e43389.
Background
Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics.
Methodology/Principal Findings
Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide.
Conclusions/Significance
These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate individualized drug therapy.
doi:10.1371/journal.pone.0043389
PMCID: PMC3422234  PMID: 22912866
4.  The Transcription Factor Encyclopedia 
Yusuf, Dimas | Butland, Stefanie L | Swanson, Magdalena I | Bolotin, Eugene | Ticoll, Amy | Cheung, Warren A | Cindy Zhang, Xiao Yu | Dickman, Christopher TD | Fulton, Debra L | Lim, Jonathan S | Schnabl, Jake M | Ramos, Oscar HP | Vasseur-Cognet, Mireille | de Leeuw, Charles N | Simpson, Elizabeth M | Ryffel, Gerhart U | Lam, Eric W-F | Kist, Ralf | Wilson, Miranda SC | Marco-Ferreres, Raquel | Brosens, Jan J | Beccari, Leonardo L | Bovolenta, Paola | Benayoun, Bérénice A | Monteiro, Lara J | Schwenen, Helma DC | Grontved, Lars | Wederell, Elizabeth | Mandrup, Susanne | Veitia, Reiner A | Chakravarthy, Harini | Hoodless, Pamela A | Mancarelli, M Michela | Torbett, Bruce E | Banham, Alison H | Reddy, Sekhar P | Cullum, Rebecca L | Liedtke, Michaela | Tschan, Mario P | Vaz, Michelle | Rizzino, Angie | Zannini, Mariastella | Frietze, Seth | Farnham, Peggy J | Eijkelenboom, Astrid | Brown, Philip J | Laperrière, David | Leprince, Dominique | de Cristofaro, Tiziana | Prince, Kelly L | Putker, Marrit | del Peso, Luis | Camenisch, Gieri | Wenger, Roland H | Mikula, Michal | Rozendaal, Marieke | Mader, Sylvie | Ostrowski, Jerzy | Rhodes, Simon J | Van Rechem, Capucine | Boulay, Gaylor | Olechnowicz, Sam WZ | Breslin, Mary B | Lan, Michael S | Nanan, Kyster K | Wegner, Michael | Hou, Juan | Mullen, Rachel D | Colvin, Stephanie C | Noy, Peter John | Webb, Carol F | Witek, Matthew E | Ferrell, Scott | Daniel, Juliet M | Park, Jason | Waldman, Scott A | Peet, Daniel J | Taggart, Michael | Jayaraman, Padma-Sheela | Karrich, Julien J | Blom, Bianca | Vesuna, Farhad | O'Geen, Henriette | Sun, Yunfu | Gronostajski, Richard M | Woodcroft, Mark W | Hough, Margaret R | Chen, Edwin | Europe-Finner, G Nicholas | Karolczak-Bayatti, Magdalena | Bailey, Jarrod | Hankinson, Oliver | Raman, Venu | LeBrun, David P | Biswal, Shyam | Harvey, Christopher J | DeBruyne, Jason P | Hogenesch, John B | Hevner, Robert F | Héligon, Christophe | Luo, Xin M | Blank, Marissa Cathleen | Millen, Kathleen Joyce | Sharlin, David S | Forrest, Douglas | Dahlman-Wright, Karin | Zhao, Chunyan | Mishima, Yuriko | Sinha, Satrajit | Chakrabarti, Rumela | Portales-Casamar, Elodie | Sladek, Frances M | Bradley, Philip H | Wasserman, Wyeth W
Genome Biology  2012;13(3):R24.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
doi:10.1186/gb-2012-13-3-r24
PMCID: PMC3439975  PMID: 22458515
5.  Rapid identification of Mycobacterium tuberculosis complex by a novel hybridization signal amplification method based on self-assembly of DNA-streptavidin nanoparticles 
Brazilian Journal of Microbiology  2011;42(3):964-972.
Rapid detection of Mycobacterium tuberculosis complex (MTBC) is a critical step in controlling tuberculosis (TB). In this study, we used IS6110 as the specific identification target to develop a novel hybridization signal amplification method (HSAM) for the rapid and direct detection of MTBC from clinical sputum specimens. This system consists of magnetic bead-linked capture probes for target isolation, dextran-based nanoparticles for amplifying the reporter molecule (biotinylated-FITC), and detection probes (2B-DNA) for binding the nanoparticles. Both the capture and detection probes were specific to the IS6110 target sequence. Our results determined that as few as 10 copies of the IS6110 sequence or 10 M. tuberculosis bacteria could be detected, indicating that the HSAM assay is as sensitive as conventional PCR, and the assay was specific enough to distinguish MTBC from nontuberculosis mycobacteria (NTM). A total of 176 clinical sputum specimens were collected for HSAM evaluation, and the results were compared to those from traditional culture and biochemical identification techniques. This assay had a sensitivity of 88.3%, a specificity of 91.8%, a positive predictive value of 93.8% and a negative predictive value of 84.8% for the detection of MTBC. This technique is highly sensitive and specific, is easy to perform, and does not require any sophisticated detection equipment; thus, this approach has great potential in clinical TB detection and diagnostic applications.
doi:10.1590/S1517-838220110003000016
PMCID: PMC3768757  PMID: 24031713
Mycobacterium tuberculosis; complex (MTBC); Detection; Diagnosis; Rapid methods; Identification
6.  Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions 
PLoS ONE  2010;5(12):e15594.
Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E2), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ERβ but not ERα, while in presence of E2 FAs modulated both ERβ and ERα. Moreover, in presence of FAs, the E2-induced recruitment of the EAB1 co-activator peptide to ERα is masked and the E2-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E2, FAs inhibited the ERE-mediated transactivation by ERβ but not ERα, while in presence of E2, FAs inhibited ERE-activity by both ERβ and ERα. Molecular modeling revealed favorable binding of FAs to ERα at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ERα or ERβ. In KS483 osteoblasts, FAs, like E2, induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E2, mediate estrogen signaling, at least in part, by modulating the recruitment of ERα, ERβ and co-activators to target genes.
doi:10.1371/journal.pone.0015594
PMCID: PMC3008742  PMID: 21203528
7.  Gene Expression Profiling and Chromatin Immunoprecipitation Identify DBN1, SETMAR and HIG2 as Direct Targets of SOX11 in Mantle Cell Lymphoma 
PLoS ONE  2010;5(11):e14085.
The SRY (sex determining region Y)-box 11 (SOX11) gene, located on chromosome 2p25, encodes for a transcription factor that is involved in tissue remodeling during embryogenesis and is crucial for neurogenesis. The role for SOX11 in hematopoiesis has not yet been defined. Two genes under direct control of SOX11 are the class- III β-tubulin gene (TUBB3) in neural cells and the transcription factor TEA domain family member 2 (TEAD2) in neural and mesenchymal progenitor cells. Normal, mature lymphocytes lack SOX11 but express SOX4, another member of the same group of SOX transcription factors. We and others recently identified SOX11 as aberrantly expressed in mantle cell lymphoma (MCL). Since SOX11 is variably expressed in MCL it may not be essential for tumorigenesis, but may carry prognostic information. Currently, no specific functional effects have been linked to SOX11 expression in MCL and it is not known which genes are under influence of SOX11 in lymphoma. In this study we found variable expression of SOX11, SOX4 and SOX12 mRNA in mantle cell lymphoma cell lines. Downregulation of SOX11 expression by siRNA verified that SOX11 controlled the expression of the gene TUBB3 in the MCL cell line Granta 519. Furthermore we identified, by global gene expression analysis, 26 new target genes influenced by siRNA SOX11 downmodulation. Among these genes, DBN1, SETMAR and HIG2 were found to be significantly correlated to SOX11 expression in two cohorts of primary mantle cell lymphomas. Chromatin immunoprecipitation (ChIP) analysis showed that these genes are direct targets of the SOX11 protein. In spite of almost complete downregulation of the SOX11 protein no significant effects on Granta 519 cell proliferation or survival in short term in vitro experiments was found. In summary we have identified a number of genes influenced by SOX11 expression in MCL cell lines and primary MCL. Among these genes, DBN1, SETMAR and HIG2 are direct transcriptional targets of the SOX11 protein.
doi:10.1371/journal.pone.0014085
PMCID: PMC2989913  PMID: 21124928
8.  Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability 
BMC Genetics  2009;10:55.
Background
The present study represents the first attempt to functionally characterize two common single nucleotide polymorphisms (SNPs) in the 3'untranslated regions (3'UTRs) of estrogen receptor β (ERβ), focusing on the differences between alleles with regard to mRNA stability and translatability. These two ERβ SNPs have been investigated for association with disease in a large number of reports.
Results
Here we examined allelic expression in breast tumor samples from heterozygous individuals. A significant difference in mRNA levels of the two alleles was observed for one of the SNPs. A cell model system was employed to further investigate potential molecular effects of the two SNPs. We used a modified plasmid, containing the ERβ promoter and ERβ 3'UTRs which include the different alleles of investigated SNPs. Quantitative Real-Time PCR was used to determine mRNA levels after inhibition of transcription by actinomycin D, and a luciferase assay was used to determine protein levels. The obtained results suggested that there was no difference in mRNA stability or translatability between the alleles of investigated SNPs.
Conclusion
Our results indicate that observed associations between ERβ 3'UTR SNPs and disease susceptibility are due to linkage disequilibrium with another gene variant, rather than the variant itself being the susceptibility factor.
doi:10.1186/1471-2156-10-55
PMCID: PMC2759954  PMID: 19754929
9.  Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms 
Experimental & Molecular Medicine  2009;41(8):538-547.
Total aralosides of Aralia elata (Miq) Seem (TASAES) from Chinese traditional herb Longya Aralia chinensis L was found to improve cardiac function. The present study was to determine the protective effects of TASAES on diabetic cardiomyopathy, and the possible mechanisms. Therefore, a single dose of streptozotocin was used to induce diabetes in Wister rats. Diabetic rats were immediately treated with low, medium and high doses of TASAES at 4.9, 9.8 mg/kg and 19.6 mg/kg body weight by gavage, respectively, for eight weeks. Cardiac function was evaluated by in situ hemodynamic measurements, and patch clamp for the L-type Ca2+ channel current (ICa2+-L) and transient outward K+ channel current (Ito). Histopathological changes were observed under light and electron microscope. The expression of pro-fibrotic factor, connective tissue growth factor (CTGF) was monitored using immunohistochemistry staining. Compared with diabetic group, medium and high doses, but not low dose, of TASAES showed a significant protection against diabetes-induced cardiac dysfunction, shown by increased absolute value of left ventricular systolic pressure (LVSP) and maximum rates of pressure development (±dp/dtmax), and enhanced amplitude of ICa2+-L (P < 0.05). Histological staining indicated a significant inhibition of diabetes-caused pathological changes and up-regulation of CTGF expression (P < 0.05). The results suggest that TASAES prevents diabetes-induced cardiac dysfunction and pathological damage through up-regulating ICa2+-L in cardiac cells and decreasing CTGF expression.
doi:10.3858/emm.2009.41.8.059
PMCID: PMC2739893  PMID: 19381071
araloside; calcium channels, L-type; cardiomyopathies; connective tissue growth factor; diabetes mellitus; heart; hemodynamics; myocardium
10.  Estrogen receptor β: an overview and update  
The discovery of a second estrogen receptor (ER), designated ERβ (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by estrogens and has broad implications for our understanding of regulation of estrogen-responsive tissues. Highly variable and even contrasting effects of estrogens in different tissues seem to be at least partially explained by different estrogen signaling pathways, involving ERα (NR3A1) and/or ERβ. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two receptor subtypes in diverse estrogen target tissues. First, ERα and ERβ have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERα and ERβ knockout (αERKO and βERKO) mice. Second, ERα and ERβ appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERα and ERβ have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for βERKO mice have suggested certain therapeutic areas to be further explored. The development of ERβ-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERβ agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERβ targeted drugs will prove to be efficient in enhancing human health.
doi:10.1621/nrs.06003
PMCID: PMC2254331  PMID: 18301783
11.  Use of Ramification Amplification Assay for Detection of Escherichia coli O157:H7 and Other E. coli Shiga Toxin-Producing Strains 
Journal of Clinical Microbiology  2005;43(12):6086-6090.
Escherichia coli O157:H7 and other Shiga toxin-producing E. coli (STEC) strains are important human pathogens that are mainly transmitted through the food chain. These pathogens have a low infectious dose and may cause life-threatening illnesses. However, detection of this microorganism in contaminated food or a patient's stool specimens presents a diagnostic challenge because of the low copy number in the sample. Often, a more sensitive nucleic acid amplification method, such as PCR, is required for rapid detection of this microorganism. Ramification amplification (RAM) is a recently introduced isothermal DNA amplification technique that utilizes a circular probe for target detection and achieves exponential amplification through the mechanism of primer extension, strand displacement, and ramification. In this study, we synthesized a circular probe specific for the Shiga toxin 2 gene (stx2). Our results showed that as few as 10 copies of stx2 could be detected, indicating that the RAM assay was as sensitive as conventional PCR. We further tested 33 isolates of E coli O157:H7, STEC, Shigella dysenteriae, and nonpathogenic E. coli by RAM assay. Results showed that all 27 STEC isolates containing the stx2 gene were identified by RAM assay, while S. dysenteriae and nonpathogenic E. coli isolates were undetected. The RAM results were 100% in concordance with those of PCR. Because of its simplicity and isothermal amplification, the RAM assay could be a useful method for detecting STEC in food and human specimens.
doi:10.1128/JCM.43.12.6086-6090.2005
PMCID: PMC1317159  PMID: 16333102

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