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1.  4-[(Z)-(2-Fur­yl)(2-naphthyl­amino)methyl­ene)]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one. Corrigendum 
Corrigendum to Acta Cryst. (2009), E65, o1824.
The title of the paper by Li, Li, Li, Zhang & Li [Acta Cryst. (2009), E65, o1824] is corrected.
PMCID: PMC2979883  PMID: 21579582
2.  4-[(Z)-(2-Fur­yl)(2-naphthyl­amino)methyl­ene)]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 
The title compound, C25H19N3O2, crystallizes as discrete mol­ecules which are well ordered through one intra­molecular N—H⋯O hydrogen bond. Structural analysis indicates that the mol­ecules exist as the amine–one form.
PMCID: PMC2977223  PMID: 21583526
3.  Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics 
Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment).
Experimental Design
Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent–metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics.
In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 μL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to >2-fold increase in veliparib exposure.
Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure.
PMCID: PMC4151156  PMID: 24947923
4.  Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts 
Diabetes  2014;63(8):2676-2689.
Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.
PMCID: PMC4113065  PMID: 24677713
5.  Computational Prediction and Validation of BAHD1 as a Novel Molecule for Ulcerative Colitis 
Scientific Reports  2015;5:12227.
Ulcerative colitis (UC) is a common inflammatory bowel disease (IBD) producing intestinal inflammation and tissue damage. The precise aetiology of UC remains unknown. In this study, we applied a rank-based expression profile comparative algorithm, gene set enrichment analysis (GSEA), to evaluate the expression profiles of UC patients and small interfering RNA (siRNA)-perturbed cells to predict proteins that might be essential in UC from publicly available expression profiles. We used quantitative PCR (qPCR) to characterize the expression levels of those genes predicted to be the most important for UC in dextran sodium sulphate (DSS)-induced colitic mice. We found that bromo-adjacent homology domain (BAHD1), a novel heterochromatinization factor in vertebrates, was the most downregulated gene. We further validated a potential role of BAHD1 as a regulatory factor for inflammation through the TNF signalling pathway in vitro. Our findings indicate that computational approaches leveraging public gene expression data can be used to infer potential genes or proteins for diseases, and BAHD1 might act as an indispensable factor in regulating the cellular inflammatory response in UC.
PMCID: PMC4505333  PMID: 26183847
6.  Associations between NBS1 Polymorphisms and Colorectal Cancer in Chinese Population 
PLoS ONE  2015;10(7):e0132332.
As the central protein of the double strand breaks (DSB)-induced DNA repair pathway, NBS1 participates in detecting the DSBs and plays an essential role in maintaining genomic stability. Single nucleotide polymorphisms (SNPs) in NBS1 gene were commonly tested that associated with the susceptibility to multiple cancers, but the results remained controversial. Thus, we conducted two independent hospital-based case–control studies comprising 1,072 colorectal cancer patients and 1,263 controls to evaluate the association between four NBS1 SNPs and colorectal cancer risk. The result showed that rs2735383C/G polymorphism in the 3’-untranslated region (UTR) of NBS1 was significantly associated with risk of colorectal cancer using logistic regression (P<10-4). Furthermore, we observed that rs2735383CC genotype was associated with substantially increased risk of colorectal cancer (odds ratio=1.55, 95% confidence interval=1.27–1.94), compared with the rs2735383GC+GG genotypes. Further functional experiments demonstrated that the rs2735383C allele in the NBS1 disrupted the binding affinity of has-miR-509-5p to the NBS1 3’-UTR in colorectal cancer cells, affecting the NBS1 transcriptional activity and expression level. In conclusion, current evidence suggests that the rs2735383C/G polymorphism might contribute to the risk for colorectal cancer.
PMCID: PMC4505902  PMID: 26186548
7.  Association between MEFV Mutations M694V and M680I and Behçet’s Disease: A Meta-Analysis 
PLoS ONE  2015;10(7):e0132704.
Several studies have identified an association between Behçet’s disease (BD) and mutations in the Mediterranean fever (MEFV) gene, which was originally linked to the autosomal recessive disease, Familial Mediterranean fever. However, no consensus has been reached. Here, a meta-analysis was conducted on published data to comprehensively evaluate this relationship.
Literature searches were performed in Pubmed, Embase, the Web of Science, and HuGE Navigator databases, in order to identify studies pertaining to the association between MEFV mutations and BD. Two investigators independently extracted and evaluated the data from eligible studies. The association between MEFV mutations (M694V, M680I, and E148Q) and BD was estimated overall by the odds ratio (OR) and 95% confidence intervals (95% CI). Further analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX).
Eligible studies (n=8) included genotyping data obtained from 2538 BD patients and 2792 healthy controls. Of the three mutations, M694V (pooled OR: 2.60, 95% CI: 2.02-3.34) and M680I (pooled OR: 1.74, 95% CI: 1.23-2.46) were found to be associated with BD in the overall analysis. The third mutation, E148Q, however, was not found to be linked with BD (pooled OR: 1.26, 95% CI: 0.69-2.31). Subgroup analysis furthermore revealed that M694V and M680I were risk loci for BD specifically in Turkish patients.
The meta-analysis confirmed that MEFV mutations M694V and M680I were associated with BD. Additional studies from other ethnic populations and functional experiments are necessary to determine the extent to which the MEFV gene underlies the development of BD.
PMCID: PMC4503748  PMID: 26176758
8.  Genetic Variants of IκB Kinase β (IKBKB) and Polymerase β (POLB) Were Not Associated with Systemic Lupus Erythematosus Risk in a Chinese Han Population 
PLoS ONE  2015;10(7):e0132556.
A previous large-scale replication study validation of a genome wide association study (GWAS) identified IκB kinase β (IKBKB) single nucleotide polymorphisms (SNPs) as a risk factor associated with systemic lupus erythematosus (SLE) in a Chinese Han population. IKBKB SNPs were associated with polymerase β (POLB) SNPs and reduced POLB expression, and this was proposed to be an underlying cause of human SLE development. In the current case-control study, we evaluated IKBKB (rs12676482 and rs2272733) and POLB (rs3136717 and rs3136744) SNPs in 946 SLE patients and 961 healthy controls. We investigated the possible association of these four SNPs with SLE in a Chinese Han population using the polymerase chain reaction-ligation detection reaction (PCR-LDR) technique. The differences in the frequencies of the four SNP alleles and the genotypes and haplotypes of the POLB polymorphisms were statistically insignificant when the SLE patients were compared with the controls in the Chinese Han population enrolled in this study (all, p ˃ 0.05). Furthermore, no associations were detected using different genetic models (additive, dominant, and recessive; all, p ˃ 0.05). Our findings indicate that the IKBKB (rs12676482 and rs2272733) and POLB (rs3136717, rs3136744) SNPs confer no genetic predisposition to SLE risk in this Chinese Han population.
PMCID: PMC4500405  PMID: 26167925
9.  BSPAT: a fast online tool for DNA methylation co-occurrence pattern analysis based on high-throughput bisulfite sequencing data 
BMC Bioinformatics  2015;16(1):220.
Bisulfite sequencing is one of the most widely used technologies in analyzing DNA methylation patterns, which are important in understanding and characterizing the mechanism of DNA methylation and its functions in disease development. Efficient and user-friendly tools are critical in carrying out such analysis on high-throughput bisulfite sequencing data. However, existing tools are either not scalable well, or inadequate in providing visualization and other desirable functionalities.
In order to handle ultra large sequencing data and to provide additional functions and features, we have developed BSPAT, a fast online tool for bisulfite sequencing pattern analysis. With a user-friendly web interface, BSPAT seamlessly integrates read mapping/quality control/methylation calling with methylation pattern generation and visualization. BSPAT has the following important features: 1) instead of using multiple/pairwise sequence alignment methods, BSPAT adopts an efficient and widely used sequence mapping tool to provide fast alignment of sequence reads; 2) BSPAT summarizes and visualizes DNA methylation co-occurrence patterns at a single nucleotide level, which provide valuable information in understanding the mechanism and regulation of DNA methylation; 3) based on methylation co-occurrence patterns, BSPAT can automatically detect potential allele-specific methylation (ASM) patterns, which can greatly enhance the detection and analysis of ASM patterns; 4) by linking directly with other popular databases and tools, BSPAT allows users to perform integrative analysis of methylation patterns with other genomic features together within regions of interest.
By utilizing a real bisulfite sequencing dataset generated from prostate cancer cell lines, we have shown that BSPAT is highly efficient. It has also reported some interesting methylation co-occurrence patterns and a potential allele-specific methylation case. In conclusion, BSPAT is an efficient and convenient tool for high-throughput bisulfite sequencing data analysis that can be broadly used.
PMCID: PMC4499179  PMID: 26163275
DNA methylation; Bisulfite sequencing analysis; Methylation co-occurrence patterns; Allele-specific methylation
10.  Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats 
AIM: To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.
METHODS: The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups (n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine (156 mg/kg per day) (berberine group) or metformin (184 mg/kg per day) (metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) (0.5 mg/kg per day) (AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested. The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator (TORC)2 was observed by immunohistochemical staining.
RESULTS: Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Berberine upregulated protein expression of liver kinase (LK)B1, AMP-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK). The level of phophorylated TORC2 (p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues.
CONCLUSION: Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2 signaling pathway.
PMCID: PMC4491964  PMID: 26167077
Berberine; Diabetes; AMPK; LKB1; Hepatic gluconeogenesis; TORC2
11.  Effect of biodegradability on CXCR4 antagonism, transfection efficacy and antimetastatic activity of polymeric Plerixafor 
Biomaterials  2014;35(21):5572-5579.
Chemokine receptor CXCR4 and its sole ligand SDF-1 are key players in regulating cancer cell invasion and metastasis. Plerixafor (AMD3100) is a small-molecule CXCR4 antagonist that prevents binding of SDF-1 to CXCR4 and has potential in prevention of cancer metastasis. This study investigates the influence of biodegradability of a recently reported polymeric Plerixafor (PAMD) on CXCR4 antagonism, antimetastatic activity, and transfection efficacy of PAMD polyplexes with plasmid DNA. We show that PAMD exhibits CXCR4 antagonism and inhibition of cancer cell invasion in vitro regardless of its biodegradability. Biodegradable PAMD showed considerably enhanced transfection efficiency and decreased cytotoxicity when compared with the non-degradable PAMD. Despite similar CXCR4 antagonism in vitro, only biodegradable PAMD displayed antimetastatic activity in experimental lung metastasis model in vivo.
PMCID: PMC4038967  PMID: 24726746
12.  let-7 Enhances Osteogenesis and Bone Formation While Repressing Adipogenesis of Human Stromal/Mesenchymal Stem Cells by Regulating HMGA2 
Stem Cells and Development  2014;23(13):1452-1463.
Bone and fat cells share a common progenitor, stromal/mesenchymal stem cells (MSCs), that can differentiate into osteoblasts or adipocytes. Osteogenesis and adipogenesis of MSCs maintain homeostasis under physiological conditions. The disruption of this homeostasis leads to bone-related metabolic diseases. For instance, reduction in bone formation, which is usually accompanied by an increase in bone marrow adipogenesis, occurs with aging, immobility, or osteoporosis. Thus, it is crucial to gain an understanding of how osteogenic and adipogenic lineages of MSCs are regulated. Here, we present evidence that let-7 is a positive regulator of bone development. Using gain- and loss-of-function approaches, we demonstrate that let-7 markedly promotes osteogenesis and suppresses adipogenesis of MSCs in vitro. Moreover, let-7 could promote ectopic bone formation of MSCs in vivo. Subsequent studies further demonstrated that let-7's effects are mediated through the repression of high-mobility group AT-hook 2 (HMGA2) expression. RNAi depletion of HMGA2 could also enhance osteogenesis and repress adipogenesis. Overall, we found a novel role of let-7/HMGA2 axis in regulating the balance of osteogenesis and adipogenesis of MSCs. Thus, let-7 can be used as a novel therapeutic target for disorders that are associated with bone loss and adipocyte accumulation.
PMCID: PMC4066225  PMID: 24617339
13.  Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy 
Cardiovascular Research  2014;103(1):60-71.
To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.
Methods and results
Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca2+]i, and sarcoplasmic reticulum (SR) Ca2+ content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and the Na+/Ca2+ exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.
In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.
PMCID: PMC4133593  PMID: 24812281
Duchenne muscular dystrophy; Heart; Beta-adrenergic response; Myocyte contraction; Calcium
14.  Bioreducible Polycations in Nucleic Acid Delivery: Past, Present, and Future Trends 
Macromolecular bioscience  2014;14(7):908-922.
Polycations that are degradable by reduction of disulfide bonds are developed for applications in delivery of nucleic acids. This paper surveys methods of synthesis of bioreducible polycations and discusses current understanding of the mechanism of action of bioreducible polyplexes. Emphasis is placed on the relationship between the biological redox environment and toxicity, trafficking, transfection activity, and in vivo behavior of bioreducible polycations and polyplexes.
PMCID: PMC4410047  PMID: 24678057
polycations; disulfides; gene delivery; polyplexes; bioreducible
15.  The Heterogeneous Effects of Cigarette Prices on Brand Choice in China: Implications for Tobacco Control Policy 
Tobacco control  2015;24(0 3):iii25-iii32.
China has long kept its tobacco taxes below international standards. The Chinese government has cited as two rationales against raising tobacco tax, namely the unfair burden it places on low-income smokers and the ability of consumers to switch to cheaper brands.
This study examines how different socioeconomic subgroups of Chinese smokers switch brands in response to cigarette price changes.
We model smokers’ choice of cigarette tier as a function of tier-specific prices. We examine heterogeneous responses to prices by estimating mixed logit models for different income and education subgroups that allow for random variation in smokers’ preferences. We use data from three waves of the longitudinal ITC China Survey, collected in six large Chinese cities between 2006 and 2009.
Low-income and less educated smokers are considerably more likely to switch tiers (including both up-trading and down-trading) than are their high-socioeconomic status (SES) counterparts. For those in the second-to-lowest tier, a ¥1 ($0.16, or roughly 25%) rise in prices increases the likelihood of switching tiers by 5.6% points for low-income smokers and 7.2% points for less educated smokers, compared to 1.6% and 3.0% points for the corresponding high-SES groups. Low-income and less educated groups are also more likely to trade down compared to their high-SES counterparts.
Only a small percentage of low-income and less educated Chinese smokers switched to cheaper brands in response to price increases. Hence, the concern of the Chinese government that a cigarette tax increase will lead to large-scale brand switching is not supported by this study.
PMCID: PMC4480158  PMID: 25855642
brand choice; socioeconomic status; cigarette price; China; discrete choice analysis
16.  Pure total flavonoids from Citrus paradisi Macfadyen actmsynergistically with arsenic trioxide in inducingmapoptosis of Kasumi-1 leukemia cells in vitro *  
To investigate the potential effects of pure total flavonoid compounds (PTFCs) from Citrus paradisi Macfadyen separately or combined with arsenic trioxide on the proliferation of human myeloid leukemia cells and the mechanisms underlying the action of PTFCs. The effects of PTFCs separately or combined with arsenic trioxide on the proliferation and apoptosis of leukemia cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fluorescence microscopy, and flow cytometry. Their effects on the expression levels of apoptosis-related regulators were determined by Western blot assay. PTFCs combined with arsenic trioxide significantly inhibited the growth of Kasumi-1 cells, and apoptosis was confirmed by flow cytometry analysis. Hoechst 33258 staining showed more significant morphological changes and more apoptosis following the combined treatment. Western blots showed changes in the expression of genes for poly ADP-ribose polymerase (PARP), caspase 3/9, and P65. The results indicated that PTFCs separately or combined with arsenic trioxide inhibited proliferation of leukemia cells in vitro and induced their apoptosis by modulating the expression of apoptosis-related regulator genes.
PMCID: PMC4506948  PMID: 26160715
Pure total flavonoid compounds; Human myeloid leukemia cells; Growth inhibition; Synergistic effect; Apoptosis
17.  Correlation analysis of gene polymorphisms and β-lactam allergy*  
A total of 64 patients with β-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between β-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4Rα, high-affinity immunoglobulin E-receptor β chain (FcεRIβ), interferon γ receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY®platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032–0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with β-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and β-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.
PMCID: PMC4506954  PMID: 26160721
Allergy; β-Lactam; Interleukin (IL); Pharmacogenomics; Single nucleotide polymorphism (SNP)
18.  A novel biphenyl urea derivate inhibits the invasion of breast cancer through the modulation of CXCR4 
The increased migration and invasion of breast carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis and invasion. In this study, we investigated a novel biphenyl urea derivate, TPD7 for its ability to affect CXCR4 expression as well as function in breast cancer cells. We demonstrated that TPD7 inhibited the breast cancer proliferation and down-regulated the CXCR4 expression on breast cancer cells both over-expressing and low-expressing HER2, an oncogene known to induce the chemokine receptor. Treatments with pharmacological proteasome inhibitors partial suppressed TPD7-induced decrease in CXCR4 expression. Real-time PCR analysis revealed that down-regulation of CXCR4 by TPD7 also occurred at the translational level. Inhibition of CXCR4 expression by TPD7 further correlated with the suppression of SDF-1α-induced migration and invasion in breast tumour cells, knockdown of CXCR4 attenuated TPD7-inhibitory effects. In addition, TPD7 treatment significantly suppressed matrix metalloproteinase (MMP)-2 and MMP-9 expression, the downstream targets of CXCR4, perhaps via inactivation of the ERK signaling pathway. Overall, our results showed that TPD7 exerted its anti-invasive effect through the down-regulation of CXCR4 expression and thus had the potential for the treatment of breast cancer.
PMCID: PMC4511359  PMID: 25753200
breast cancer; biphenyl urea derivate; invasion; CXCR4
19.  Speciation and Degrees of Contamination of Metals in Sediments from Upstream and Downstream Reaches along the Catchment of the Southern Bohai Sea, China 
Environmental processes and biological community structures change along fluvial gradients within coastal river basins; the accumulation and associated risk of metal contamination would also be expected to change from upstream to downstream reaches. Speciation and degrees of contamination of metals in sediments from the upstream and downstream of river catchments of the southern Bohai Sea were investigated. The mean concentrations of Cu, Zn, Cr, Ni, Cd and Pb from upstream reaches were 82.6, 157, 63.6, 26.6, 0.18 and 24.9 mg/kg, respectively. The mean concentrations of Cu, Zn, Cr, Ni, Cd and Pb from downstream reaches were 38.0, 66.0, 38.9, 18.1, 0.16 and 24.0 mg/kg, respectively. Most of the Cu, Zn, Cr, Ni and Pb in sediments from both the upstream and downstream reaches was mainly associated with the residual fraction. However, Cd was preferentially bound to the exchangeable phase. A cluster analysis was used to study the degree of association between sites, and three distinct clusters were identified in both upstream and downstream sediments. A correlation analysis was conducted to determine the extent of association among metals and showed that metals in sediments from the upstream reaches have more affinity than those in the downstream area. Sediment quality guidelines were used to evaluate potential risks. The risks from Zn, Cr and Ni in the upstream reaches were higher than those from downstream reaches; however, the other three metals (Cu, Pb and Cd) showed opposite results.
PMCID: PMC4515703  PMID: 26184267
Community Bureau of Reference (BCR); sediment quality guidelines; salinity; cluster analysis; correlation analysis
20.  Identification of Personalized Chemoresistance Genes in Subtypes of Basal-Like Breast Cancer Based on Functional Differences Using Pathway Analysis 
PLoS ONE  2015;10(6):e0131183.
Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC), and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of these pathways. Therefore, these nine differentially expressed genes and their associated functional pathways should provide the basis for novel personalized clinical treatments of basal-like breast cancer.
PMCID: PMC4488356  PMID: 26126114
21.  Global Transcriptome Profiles of 'Meyer' Zoysiagrass in Response to Cold Stress 
PLoS ONE  2015;10(6):e0131153.
A long green period is essential for a turfgrass species with high ornamental value and a wide area of use. Zoysiagrasses (Zoysia spp. Willd.) are perennial turfgrass species popular in tropical, subtropical and temperate zones, possessing many properties necessary to be economically useful turfgrass. They do not have a long green period because of cold sensitivity. A main focus in zoysiagrass research is to develop cold tolerant cultivars. Understanding the cold response in zoysiagrass is a fundamental area of research. In the present study, ‘Meyer’ zoysiagrass (Zoysia japonica), a widely cultivated variety in the genus, is used. We employed RNA-Seq to investigate genome-wide gene expression profiles in leaves under cold stress (4°C). Using the Illumina sequencing platform, we obtained approximately 206 million high-quality paired-end reads from three libraries (0 h, 2 h, and 72 h cold treatment at 4°C). After de novo assembly and quantitative assessment, 46,412 unigenes were generated with an average length of 998 bp and an N50 of 1,522 bp. A total of 25,644 (55.2%) unigenes were annotated by alignment with public protein databases including NR, SwissProt, KEGG and KOG. Differentially expressed genes (DEGs) were investigated using the RPKM method. A total of 756 DEGs were identified between 0h and 2h-cold treatment, with 522 up-regulated and 234 down-regulated; and 5327 DEGs were identified between 0h and 72h-cold treatment, with 2453 up-regulated and 2874 down-regulated. The expression profile of 15 DEGs selected randomly was confirmed with qRT-PCR. The results suggest that cold stress can induce desiccation and oxidative stress, inhibit photosynthesis and substance transport. In response to the stress, genes involved in proline synthesis, in starch hydrolysis, in methionine and ascorbic acid metabolism, in SOD activity, and in DREBs response pathway were up-regulated. GA metabolism, ABA and JA stimulus response were affected under cold exposure. This is the first transcriptome sequencing of Z. japonica, providing a large set of sequence data as well as gene expression profiles under cold stress. It will improve our current understanding of the cold response of zoysiagrass and be beneficial in breeding research.
PMCID: PMC4482698  PMID: 26115186
22.  Synthetic Reactions with Rare Taccalonolides Reveal the Value of C-22,23 Epoxidation for Microtubule Stabilizing Potency 
Journal of Medicinal Chemistry  2014;57(14):6141-6149.
The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC50 values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers.
PMCID: PMC4216226  PMID: 24959756
23.  Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment 
Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer’s disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS+/- mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels.
Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS+/- mice as early as 3–6 months of age but not in eNOS+/+ mice at any age. Remarkably, vascular occlusions in eNOS+/- mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS+/- mice.
These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS+/- mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-015-0020-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4479241  PMID: 26104027
Endothelial nitric oxide synthase (eNOS); Cerebral chronic hypoperfusion; Cerebral dysfunction; Thrombosis; Microvessel occlusion; Cerebral microinfarction; Vascular dementia; Cerebral amyloid angiopathy (CAA)
24.  Effects of electroacupuncture on corticotropin-releasing hormone in rats with chronic visceral hypersensitivity 
AIM: To investigate the effect of electroacupuncture on corticotropin-releasing hormone (CRH) in the colon, spinal cord, and hypothalamus of rats with chronic visceral hypersensitivity.
METHODS: A rat model of chronic visceral hypersensitivity was generated according to the internationally accepted method of colorectal balloon dilatation. In the 7th week after the procedure, rats were randomly divided into a model group (MG), electroacupuncture group (EA), and sham electroacupuncture group (S-EA). After treatment, the abdominal withdrawal reflex (AWR) score was used to assess the behavioral response of visceral hyperalgesia. Immunohistochemistry (EnVision method), ELISA, and fluorescence quantitative PCR methods were applied to detect the expression of CRH protein and mRNA in the colon, spinal cord, and hypothalamus.
RESULTS: The sensitivity of the rats to the colorectal distension stimulus applied at different strengths (20-80 mmHg) increased with increasing stimulus strength, resulting in increasing AWR scores in each group. Compared with NG, the AWR score of MG was significantly increased (P < 0.01). After conducting EA, the AWR scores of the rats were decreased compared with MG rats. The relative expression of CRH mRNA in the colon, spinal cord, and hypothalamus of MG rats was significantly increased compared with NG rats (P < 0.01). CRH mRNA in the colon and spinal cord of EA and S-EA rats was decreased to varying degrees (P > 0.05) compared with normal rats (NG). However, the decrease in EA compared with MG rats was statistically significant (P < 0.01). The average optical density of CRH expression in the colon of the MG rats was significantly enhanced compared with NG (P < 0.05), while the average optical density of CRH expression in the EA and S-EA rats was significantly decreased compared with MG rats (P < 0.01, P < 0.05, respectively). Compared with MG rats, the CRH concentration in the spinal cord of EA rats was significantly reduced (P < 0.01), but there was no significant change in S-EA rats (P > 0.05).
CONCLUSION: Electroacupuncture at the Shangjuxu acupoint was able to significantly reduce the visceral hypersensitivity in rats, and regulated the expression of CRH protein and mRNA in the colon, spinal cord and hypothalamus at different levels, playing a therapeutic role in this model of irritable bowel syndrome.
PMCID: PMC4476879  PMID: 26109804
Corticotropin-releasing hormone; Electroacupuncture; Irritable bowel syndrome; Visceral pain; Shangjuxu
25.  Sleep Quality of Patients with Differentiated Thyroid Cancer 
PLoS ONE  2015;10(6):e0130634.
We aimed to measure prevalence of sleep disturbance in patients with differentiated thyroid cancer (DTC) by calculating Pittsburgh Sleep Quality Index (PSQI), and compare these data with patients with benign thyroid nodules or normal participants.
Three groups of patients participated in this cross-sectional study. In the first group, 162 patients with DTC received total thyroidectomy, and then 131I therapy. The second group consisted of 84 patients with benign thyroid nodules, who received partial thyroidectomy. The third group was 78 normal healthy control cases. PSQI was used to assess the sleep quality. Inter-group differences were analyzed by Kruskal-Wallis test or independent samples T test. χ2 test was also used to check prevalence differences of poor sleep quality among the groups. Differences of PSQI score and poor sleep quality prevalence before and after 131I therapy in the same group of DTC participants were analyzed by paired T test and Mcnemar's test.
Higher PSQI score (7.59 ± 4.21) and higher rate of poor sleep quality (54.32%) were shown in DTC patients than in any other group. After 131I therapy, PSQI score and prevalence of poor sleep quality in DTC patients increased significantly to 8.78 ± 4.72 and 70.99%. Then DTC patients were divided into two subgroups based on their metastatic status. DTC patients with metastasis (87/162 cases, 53.70%) had significantly higher PSQI score (10.87 ± 5.18) and higher prevalence of poor sleep quality (79.31%).
DTC patients suffer from sleep disturbance, 131I therapy and awareness of metastatic status could worsen sleep problem. Psychological fear of cancer, nuclear medicine therapy and metastasis could be one major underlying reason. Longitude and interventional studies are necessary for further investigations.
PMCID: PMC4471198  PMID: 26083787

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