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1.  The prion protein regulates beta-amyloid-mediated self-renewal of neural stem cells in vitro 
The beta-amyloid (Aβ) peptide and the Aβ-oligomer receptor, prion protein (PrP), both influence neurogenesis. Using in vitro murine neural stem cells (NSCs), we investigated whether Aβ and PrP interact to modify neurogenesis. Aβ imparted PrP-dependent changes on NSC self-renewal, with PrP-ablated and wild-type NSCs displaying increased and decreased cell growth, respectively. In contrast, differentiation of Aβ-treated NSCs into mature cells was unaffected by PrP expression. Such marked PrP-dependent differences in NSC growth responses to Aβ provides further evidence of biologically significant interactions between these two factors and an important new insight into regulation of NSC self-renewal in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-015-0067-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4435829  PMID: 25884827
2.  Investigating the cellular fate of a DNA-targeted platinum-based anticancer agent by orthogonal double-click chemistry 
Confocal fluorescence microscopy was used to study a platinum-based anticancer agent in intact NCI-H460 lung cancer cells. Orthogonal copper-catalyzed azide–alkyne cycloaddition (click) reactions were used to simultaneously determine the cell-cycle-specific localization of the azide-functionalized platinum–acridine agent 1 and monitor its effects on nucleic acid metabolism. Copper-catalyzed postlabeling showed advantages over copper-free click chemistry using a dibenzocyclooctyne (DIBO)-modified reporter dye, which produced high background levels in microscopic images and failed to efficiently label platinum adducts in chromatin. Compound 1 was successfully labeled with the fluorophore DIBO to yield 1* (characterized by in-line high-performance liquid chromatography/electrospray mass spectrometry). 1 and 1* show a high degree of colocalization in the confocal images, but the ability of 1* to target the (compacted) chromatin was markedly reduced, most likely owing to the steric bulk introduced by the DIBO tag. Nuclear platinum levels correlated inversely with the ability of the cells to synthesize DNA and cause cell cycle arrest, as confirmed by bivariate flow cytometry analysis. In addition, a decrease in the level of cellular transcription, shrinkage of the nucleolar regions, and redistribution of RNA into the cytosol were observed. Postlabeling in conjunction with colocalization experiments is a useful tool for studying the cell killing mechanism of this type of DNA-targeted agent.
PMCID: PMC4060739  PMID: 24407462
Click chemistry; Confocal fluorescence microscopy; DNA synthesis; Platinum agents; Transcription
3.  Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine 
British Journal of Pharmacology  2014;171(4):1054-1067.
Background and purpose
Voltage-activated Na+ channels contain one distinct α-subunit. In the brain NaV1.1, NaV1.2, NaV1.3 and NaV1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na+ channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine.
Experimental approach
Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits.
Key results
NaV1.2 and NaV1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin.
Conclusions and implications
The four Na+ channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na+ channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development.
PMCID: PMC3925043  PMID: 24283699
sodium channel; epilepsy; carbamazepine; phenytoin; lamotrigine; antiepileptic drug
4.  Genome-wide identification and comparative analysis of the heat shock transcription factor family in Chinese white pear (Pyrus bretschneideri) and five other Rosaceae species 
BMC Plant Biology  2015;15:12.
Heat shock transcription factors (Hsfs), which act as important transcriptional regulatory proteins in eukaryotes, play a central role in controlling the expression of heat-responsive genes. At present, the genomes of Chinese white pear (‘Dangshansuli’) and five other Rosaceae fruit crops have been fully sequenced. However, information about the Hsfs gene family in these Rosaceae species is limited, and the evolutionary history of the Hsfs gene family also remains unresolved.
In this study, 137 Hsf genes were identified from six Rosaceae species (Pyrus bretschneideri, Malus × domestica, Prunus persica, Fragaria vesca, Prunus mume, and Pyrus communis), 29 of which came from Chinese white pear, designated as PbHsf. Based on the structural characteristics and phylogenetic analysis of these sequences, the Hsf family genes could be classified into three main groups (classes A, B, and C). Segmental and dispersed duplications were the primary forces underlying Hsf gene family expansion in the Rosaceae. Most of the PbHsf duplicated gene pairs were dated back to the recent whole-genome duplication (WGD, 30–45 million years ago (MYA)). Purifying selection also played a critical role in the evolution of Hsf genes. Transcriptome data demonstrated that the expression levels of the PbHsf genes were widely different. Six PbHsf genes were upregulated in fruit under naturally increased temperature.
A comprehensive analysis of Hsf genes was performed in six Rosaceae species, and 137 full length Hsf genes were identified. The results presented here will undoubtedly be useful for better understanding the complexity of the Hsf gene family and will facilitate functional characterization in future studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0401-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4310194  PMID: 25604453
Hsf; Stress-response; Evolution; Transcriptome sequencing; Pear; Rosaceae
5.  Database screening of herbal monomers regulating autophagy by constructing a "disease-gene-drug" network 
Studies suggest an important role of autophagy as a target for cancer therapy. We constructed a "disease-gene-drug" network using the modular approach of bioinformatics and screened herbal monomers demonstrating functions related to autophagy regulation.
Based on the microarray results of the gene expression omnibus (GEO) database (GSE2435 and GSE31040, starvation-induced autophagy model), we used the human protein reference database (HPRD) to obtain the protein-protein interaction (PPI) network. In addition, we used the CFinder software to identify several functional modules, performed gene ontology-biological process (GO-BP) functional enrichment analysis using the DAVID software, constructed a herbal monomer-module gene regulatory network using literature search and the Cytoscape software, and then analyzed the relationships between autophagy, genes, and herbal monomers.
We screened 544 differentially expressed genes related to autophagy, 375 pairs of differentially expressed genes, and 7 gene modules, wherein the functions of module 3 (composed of 7 genes) were enriched in "cell death". Using the constructed herbal monomer-module gene regulatory network, we found that 30 herbal monomers can simultaneously regulate these 7 genes, indicating a potential regulatory role in autophagy.
Database screening using the disease-gene-drug network can provide new strategies and ideas for the application of herbal medicines in cancer therapy.
PMCID: PMC4295301  PMID: 25475428
Herbal monomer; Autophagy; Genomics; Bioinformatics
6.  Effective Removal of Cadmium Ions from a Simulated Gastrointestinal Fluid by Lentinus edodes 
Lentinus edodes, a functional food, was evaluated as a potential antidote for adsorption/removal of cadmium ion from simulated gastrointestinal fluids. An adsorption/removal capacity of 65.12 mg/g was achieved by L. edodes in solutions with a pH ranging from 2.5 to 6.0, while little if any adsorption was observed in solutions with a pH under 2.5. In solutions with pH 6.0, 84% of the cadmium adsorption by L. edodes occurred in the first minute. Scanning electronic microscopic examination showed that the cell wall polysaccharides of L. edodes provided a rough sponge-like surface for effective cadmium adsorption. FTIR indicated that the carboxyl, hydroxyl and –NH groups of the cell wall polysaccharides and proteins were the primary functional groups that chemically bind with cadmium ions. The energy dispersive spectrometry further revealed that cation exchange might be attributed to cadmium biosorption. These results suggested that L. edodes was effective for cadmium detoxication, especially in low concentration.
PMCID: PMC4276626  PMID: 25469921
adsorption; antidote; cadmium; heavy metal; L. edodes; simulated gastrointestinal fluid
7.  Identification of miRNAs involved in pear fruit development and quality 
BMC Genomics  2014;15(1):953.
MicroRNAs (miRNAs) are a class of small, endogenous RNAs that take part in regulating genes through mediating gene expressions at the post-transcriptional level in plants. Previous studies have reported miRNA identification in various plants ranging from model plants to perennial fruit trees. However, the role of miRNAs in pear (Pyrus bretschneideri) fruit development is not clear. Here, we investigated the miRNA profiles of pear fruits from different time stages during development with Illumina HiSeq 2000 platform and bioinformatics analysis. Quantitative real-time PCR was used to validate the expression levels of miRNAs.
Both conserved and species-specific miRNAs in pear have been identified in this study. Total reads, ranging from 19,030,925 to 25,576,773, were obtained from six small RNA libraries constructed for different stages of fruit development after flowering. Comparative profiling showed that an average of 90 miRNAs was expressed with significant differences between various developmental stages. KEGG pathway analysis on 2,216 target genes of 188 known miRNAs and 1,127 target genes of 184 novel miRNAs showed that miRNAs are widely involved in the regulation of fruit development. Among these, a total of eleven miRNAs putatively participate in the pathway of lignin biosynthesis, nine miRNAs were identified to take part in sugar and acid metabolism, and MiR160 was identified to regulate auxin response factor.
Comparative analysis of miRNAomes during pear fruit development is presented, and miRNAs were proved to be widely involved in the regulation of fruit development and formation of fruit quality, for example through lignin synthesis, sugar and acid metabolism, and hormone signaling. Combined with computational analysis and experimental confirmation, the research contributes valuable information for further functional research of microRNA in fruit development for pear and other species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-953) contains supplementary material, which is available to authorized users.
PMCID: PMC4233070  PMID: 25366381
Pear; Fruit development; High-throughput sequencing; miRNA; Lignin synthesis; Sugar and acid
8.  Genetic variations of the ADIPOQ gene and risk of prostate cancer in Chinese Han men 
Asian Journal of Andrology  2014;16(6):878-883.
Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQ are thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital-based case-control study of 917 prostate cancer (PCa) cases and 1036 cancer-free controls, we evaluated the association of single nucleotide polymorphisms in ADIPOQ with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of cases and controls. We found that the ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk [adjusted odds ratio (OR): 0.66, 95% confidence interval (CI) =0.48–0.92] and increased plasma adiponectin levels (P = 0.036 and 0.043), with significant difference by tumor grade, clinical stage, and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index was observed in modifying the risk of PCa (P = 6.7 × 10−3). ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support that ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa.
PMCID: PMC4236333  PMID: 25038177
adiponectin; ADIPOQ; polymorphism; prostate cancer
9.  Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas 
Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas.
Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining.
Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10−9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25–164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39–94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27–9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA.
CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.
PMCID: PMC4130880  PMID: 25099181
10.  On the Open Problem Related to Rank Equalities for the Sum of Finitely Many Idempotent Matrices and Its Applications 
The Scientific World Journal  2014;2014:702413.
Tian and Styan have shown many rank equalities for the sum of two and three idempotent matrices and pointed out that rank equalities for the sum P1 + ⋯+Pk with P1,…, Pk be idempotent (k > 3) are still open. In this paper, by using block Gaussian elimination, we obtained rank equalities for the sum of finitely many idempotent matrices and then solved the open problem mentioned above. Extensions to scalar-potent matrices and some related matrices are also included.
PMCID: PMC4121197  PMID: 25121133
11.  Characterization of the lipoxygenase (LOX) gene family in the Chinese white pear (Pyrus bretschneideri) and comparison with other members of the Rosaceae 
BMC Genomics  2014;15(1):444.
Lipoxygenases (LOXs), a type of non-haem iron-containing dioxygenase, are ubiquitous enzymes in plants and participate in the formation of fruit aroma which is a very important aspect of fruit quality. Amongst the various aroma volatiles, saturated and unsaturated alcohols and aldehydes provide the characteristic aroma of the fruit. These compounds are formed from unsaturated fatty acids through oxidation, pyrolysis and reduction steps. This biosynthetic pathway involves at least four enzymes, including LOX, the enzyme responsible for lipid oxidation. Although some studies have been conducted on the LOX gene family in several species including Arabidopsis, soybean, cucumber and apple, there is no information from pear; and the evolutionary history of this gene family in the Rosaceae is still not resolved.
In this study we identified 107 LOX homologous genes from five Rosaceous species (Pyrus bretschneideri, Malus × domestica, Fragaria vesca, Prunus mume and Prunus persica); 23 of these sequences were from pear. By using structure analysis, phylogenic analysis and collinearity analysis, we identified variation in gene structure and revealed the phylogenetic evolutionary relationship of this gene family. Expression of certain pear LOX genes during fruit development was verified by analysis of transcriptome data.
23 LOX genes were identified in pear and these genes were found to have undergone a duplication 30–45 MYA; most of these 23 genes are functional. Specific gene duplication was found on chromosome4 in the pear genome. Useful information was provided for future research on the evolutionary history and transgenic research on LOX genes.
Electronic supplementary material
The online version of this article (doi: 10.1186/1471-2164-15-444) contains supplementary material, which is available to authorized users.
PMCID: PMC4072886  PMID: 24906560
Pear; LOX; Fruit flavor; Gene family; Rosaceae
12.  Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study 
Journal of neuro-oncology  2012;108(3):491-498.
We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI’s from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan–Meier method with log-rank test. Mean ADC-L was 1,209 × 10−6mm2/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L<1,209 and LCP>0.71 versus ADC-L>1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
PMCID: PMC3997502  PMID: 22426926
Apparent diffusion coefficient; Glioblastoma multiforme; Progression-free survival
13.  Design of a Platinum–Acridine–Endoxifen Conjugate Targeted at Hormone-Dependent Breast Cancer 
The synthesis of a novel pharmacophore comprising a DNA-targeted platinum–acridine hybrid agent and estrogen receptor-targeted 4-hydroxy-N-desmethyltamoxifen (endoxifen) using carbamate coupling chemistry and its evaluation if breast cancer cell lines are described.
PMCID: PMC3606895  PMID: 23416453
14.  Using Fluorescent Post-Labeling to Probe the Subcellular Localization of DNA-Targeted Platinum** 
Angewandte Chemie (International ed. in English)  2013;52(12):10.1002/anie.201210079.
PMCID: PMC3852910  PMID: 23427109
click chemistry; platinum drugs; post-labeling; confocal microscopy; cancer cells
15.  Increased metal content in the TDP-43A315T transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis 
Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43) is associated with the development of frontotemporal lobar degeneration and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43 A315T mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but zinc, copper, and manganese levels were all increased in the spinal cords of TDP-43 A315T mice when compared to wild-type littermates. Performance of the TDP-43 A315T mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43 A315T in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43 A315T mice show symptoms of locomotive decline and not cognitive decline.
PMCID: PMC3920072  PMID: 24575040
amyotrophic lateral sclerosis (ALS); frontotemporal lobar degeneration (FTLD); TAR DNA binding protein-43 (TDP-43); copper (Cu); zinc (Zn); manganese (Mn); neurodegenerative disease
16.  β-amyloid in biological samples: not all Aβ detection methods are created equal 
PMCID: PMC4131196  PMID: 25165449
amyloid; detection; ELISA; western blot; mass spectrometry
17.  Perfusion Deficits Detected by Arterial Spin Labeling (ASL) in TIA Patients with negative diffusion and vascular imaging 
AJNR. American journal of neuroradiology  2013;34(11):10.3174/ajnr.A3551.
Background and Purpose
A substantial portion of clinically diagnosed TIA cases is imaging-negative. The purpose of the current study is to determine if arterial spin-labeling (ASL) is helpful in detecting perfusion abnormalities in patients presenting clinically with TIA.
Materials and Methods
Pseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 49 patients suspected of TIA within 24 hours of symptom onset. All patients were free of prior stroke history and had no lesion-specific findings on general MR, DWI and MRA sequences. The calculated ASL CBF maps were scored from 1 to 3 based on the presence and severity of perfusion disturbance by three independent observers blinded to patient history. An age-matched cohort of 36 patients diagnosed with no cerebrovascular events was evaluated as a control. Inter-observer agreement was assessed using Kendall concordance test.
Scoring of perfusion abnormalities on ASL scans of TIA cohort was highly concordant among the 3 observers (w=0.812). The sensitivity and specificity of ASL in diagnosing perfusion abnormalities in TIA was 55.8% and 90.7%, respectively. In 93.3% (70 out of 75) of the ASL CBF map readings with positive scores (≥2), the brain regions where perfusion abnormalities were identified by 3 observers matched with the neurological deficits at TIA onset.
In this preliminary study, ASL showed promise in detecting perfusion abnormalities that correlated with clinically diagnosed TIA in patients with otherwise normal neuro-imaging.
PMCID: PMC3864013  PMID: 23721895
18.  Nitroglycerine-Induced Nitrate Tolerance Compromises Propofol Protection of the Endothelial Cells against TNF-α: The Role of PKC-β2 and NADPH Oxidase 
Continuous treatment with organic nitrates causes nitrate tolerance and endothelial dysfunction, which is involved with protein kinase C (PKC) signal pathway and NADPH oxidase activation. We determined whether chronic administration with nitroglycerine compromises the protective effects of propofol against tumor necrosis factor (TNF-) induced toxicity in endothelial cells by PKC-β2 dependent NADPH oxidase activation. Primary cultured human umbilical vein endothelial cells were either treated or untreated with TNF-α (40 ng/mL) alone or in the presence of the specific PKC-β2 inhibitor CGP53353 (1 μM)), nitroglycerine (10 μM), propofol (100 μM), propofol plus nitroglycerin, or CGP53353 plus nitroglycerine, respectively, for 24 hours. TNF-α increased the levels of superoxide, Nox (nitrate and nitrite), malondialdehyde, and nitrotyrosine production, accompanied by increased protein expression of p-PKC-β2, gP91phox, and endothelial cell apoptosis, whereas all these changes were further enhanced by nitroglycerine. CGP53353 and propofol, respectively, reduced TNF-α induced oxidative stress and cell toxicity. CGP53353 completely prevented TNF-α induced oxidative stress and cell toxicity in the presence or absence of nitroglycerine, while the protective effects of propofol were neutralized by nitroglycerine. It is concluded that nitroglycerine comprises the protective effects of propofol against TNF-α stimulation in endothelial cells, primarily through PKC-β2 dependent NADPH oxidase activation.
PMCID: PMC3874952  PMID: 24396568
19.  Using a Build-and-Click Approach for Producing Structural and Functional Diversity in DNA-Targeted Hybrid Anticancer Agents 
Journal of medicinal chemistry  2012;55(22):10198-10203.
An efficient screening method was developed for functionalized DNA-targeted platinum-containing hybrid anticancer agents based on metal-mediated amine-to-nitrile addition, a form of “click” chemistry. The goal of the study was to generate platinum–acridine agents for their use as cytotoxic “warheads” in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to platinum. The assay, which was based on microscale reactions between 6 platinum–nitrile complexes and 10 acridine derivatives, yielded a small library of 60 platinum–acridines. Reactions were monitored and product mixtures were quantitatively analyzed by automated in-line high-performance liquid chromatography– electrospray mass spectrometry (LC-ESMS) analysis and subjected to cell viability screening using a non-radioactive cell proliferation assay. The new prescreening methodology proves to be a powerful tool for establishing structure–activity relationships and for identifying target compounds.
PMCID: PMC3508136  PMID: 23074987
20.  Transient Acidosis during Early Reperfusion Attenuates Myocardium Ischemia Reperfusion Injury via PI3k-Akt-eNOS Signaling Pathway 
In this paper, we concluded that transient acidosis reperfusion conferred cardioprotection against myocardial ischemia reperfusion injury in isolated rat hearts through activating PI3K-Akt-eNOS pathway.
PMCID: PMC3839119  PMID: 24312696
21.  Association of LEP G2548A and LEPR Q223R Polymorphisms with Cancer Susceptibility: Evidence from a Meta-Analysis 
PLoS ONE  2013;8(10):e75135.
Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site) and LEPR (Q223R, nonsynonymous SNP in exon 6) with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations.
We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A) and rs1137101 (Q223R) in normal cell lines derived from 270 subjects with different ethnicities.
The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41). Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51) but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity.
Despite some limitations, this meta-analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies.
PMCID: PMC3798550  PMID: 24146750
23.  No Association between TGFB1 Polymorphisms and Late Radiotherapy Toxicity: A Meta-Analysis 
PLoS ONE  2013;8(10):e76964.
Transforming growth factor-beta 1 (TGF-β1) protein may be multifunctional and related to the development of fibrosis, induction of apoptosis, extracellular signaling and inhibition of proliferation in response to radiation-induced DNA damage. Several studies have investigated associations between single nucleotide polymorphisms (SNPs) in the TGFB1 gene and risk of late radiation-induced injury of normal tissue, but the conclusions remain controversial.
We searched three electronic databases (i.e., MEDLINE, EMBASE and EBSCO) for eligible publications and performed a meta-analysis assessing the association of three commonly studied SNPs in TGFB1 (i.e., rs1800469, rs1800470 and rs1800471) with risk of late radiation-induced injury of normal tissue.
We finally included 28 case-only studies from 16 publications on aforementioned SNPs in TGFB1. However, we did not find statistical evidence of any significant association with overall risk of late radiotherapy toxicity in the pooled analysis or in further stratified analysis by cancer type, endpoint, ethnicity and sample size.
This meta-analysis did not find statistical evidence for an association between SNPs in TGFB1 and risk of late radiation-induced injury of normal tissue, but this finding needs further confirmation by a single large study.
PMCID: PMC3793936  PMID: 24130819
24.  Potentially Functional Polymorphisms in the CASP7 Gene Contribute to Gastric Adenocarcinoma Susceptibility in an Eastern Chinese Population 
PLoS ONE  2013;8(9):e74041.
Caspase 7 (CASP7) is an important regulator and executioner in the apoptosis pathway and plays a crucial role in cancer development and progression. However, few studies have evaluated associations between functional single nucleotide polymorphisms (SNPs) in the 3′ untranslational region (UTR) of CASP7 and risk of gastric cancer.
In a case-control study of 1117 patients with gastric cancer and 1146 cancer-free controls with frequency matching on age and sex, we genotyped four potentially functional SNPs (rs4353229T>C, rs10787498T>G, rs1127687G>A and rs12247479G>A) located in the microRNA binding sites of the CASP7 3′ UTR by using Taqman assays and evaluated their associations with risk of gastric cancer by using logistic regression analyses as well as multifactorial dimension reduction (MDR) analysis.
In the single-locus analysis, only the CASP7 rs4353229 TT genotype was associated with 0.83-fold decreased risk (95% confidence interval [CI] = 0.70–0.98) of gastric cancer under a recessive model, compared with the CT/CC genotypes. In the combined analysis of all four SNPs, we found that the risk of gastric cancer decreased by 19% in those carrying any of the risk genotypes (adjusted odds ratio = 0.81, 95% CI = 0.68–0.96), compared with those carrying zero risk genotypes, and this risk was more evident in subgroups of younger age (<59 years), females, non-smokers, non-drinkers and patients with non-gastric cardia adenocarcinoma. Further MDR analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer.
Potentially functional CASP7 variants may contribute to risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.
PMCID: PMC3769357  PMID: 24040159
25.  Analysis of the DNA damage produced by a platinum–acridine antitumor agent and its effects in NCI-H460 lung cancer cells 
Metallomics  2012;4(7):645-652.
High-performance liquid chromatography in conjunction with electrospray mass spectrometry (LC-ESMS) was used to structurally characterize the adducts formed by the platinum–acridine agent [PtCl(en)(N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide)](NO3)2 (compound 1) in cell-free DNA. Compound 1 forms monofunctional adducts exclusively with guanine, based on the fragments identified in enzymatic digests (dG*, dGMP*, dApG*, and dTpG*, where the asterisk denotes bound drug). The time course of accumulation and DNA adduct formation of compound 1 and the clinical drug cisplatin in NCI-H460 lung cancer cells at physiologically relevant drug concentrations (0.1 μM) was studied by inductively-coupled plasma mass spectrometry (ICP-MS). Compound 1 accumulates rapidly in cells and reaches intracellular levels of up to 60-fold higher than those determined for cisplatin. The hybrid agent shows unusually high DNA binding levels: while cisplatin adducts form at a maximum frequency of 5 adducts per 106 nucleotides, compound 1 produces 25 adducts per 106 nucleotides after only 3 h of continuous incubation with the lung cancer cells. The high overall levels of compound 1 in the cells and in cellular DNA over the entire 12-h treatment period translate into a rapid decrease in cell viability. Possible implications of these findings for the mechanism of action of compound 1 and the agent’s potential to overcome tumor resistance to cisplatin are discussed.
PMCID: PMC3389219  PMID: 22456976

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