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Find video protocols related to scientific articles indexed in Pubmed.
Dietary compound isoliquiritigenin targets GRP78 to chemosensitize breast cancer stem cells via ?-catenin/ABCG2 signaling.
Carcinogenesis
PUBLISHED: 09-06-2014
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Accumulating evidence suggests that ?-catenin signaling in breast cancer stem cells (CSCs) is closely correlated to chemoresistance and adenosine triphosphate (ATP)-binding cassette subfamily G2 (ABCG2) expression. Targeting the aberrant ?-catenin signaling in CSCs has become a promising strategy to improve chemosensitivity in cancer treatment. In a pilot screening study, we found that the natural compound isoliquiritigenin (ISL) blocked ?-catenin transcription activity with the highest inhibition ratio. Here, we investigated the chemosensitizing effects of ISL on breast CSCs and the underlying mechanisms regulating the ?-catenin pathway. ISL could have synergistic effects with chemotherapeutic drugs to inhibit breast cancer cell proliferation and colony formation. In addition, ISL could significantly limit the side population and CSC ratios in breast cancer cells, accompanied by inhibited self-renewal and multidifferentiation abilities. A mechanistic study revealed that ISL could inhibit ?-catenin/ABCG2 signaling by activating the proteasome degradation pathway. The drug affinity responsive target stability strategy further identified GRP78 as the direct target of ISL. Subsequent molecular docking analysis and functional studies demonstrated that ISL could dock into the ATP domain of GRP78 and thereby inhibit its ATPase activity, resulting in its dissociation from ?-catenin. An in vivo study also suggested that ISL could chemosensitize breast CSCs via the GRP78/?-catenin/ABCG2 pathway, with little toxicity in normal tissues and mammary stem cells. Taken together, the data from this study not only suggest ISL as a natural candidate to enhance breast CSC chemosensitivity but also highlight the significance of GRP78 in mediating cancer drug resistance and ?-catenin signaling in CSCs.
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Experimental study of the vortex-induced vibration of drilling risers under the shear flow with the same shear parameter at the different Reynolds numbers.
PLoS ONE
PUBLISHED: 08-13-2014
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A considerable number of studies for VIV under the uniform flow have been performed. However, research on VIV under shear flow is scarce. An experiment for VIV under the shear flow with the same shear parameter at the two different Reynolds numbers was conducted in a deep-water offshore basin. Various measurements were obtained by the fiber bragg grating strain sensors. Experimental data were analyzed by modal analysis method. Results show several valuable features. First, the corresponding maximum order mode of the natural frequency for shedding frequency is the maximum dominant vibration mode and multi-modal phenomenon is appeared in VIV under the shear flow, and multi-modal phenomenon is more apparent at the same shear parameter with an increasing Reynolds number under the shear flow effect. Secondly, the riser vibrates at the natural frequency and the dominant vibration frequency increases for the effect of the real-time tension amplitude under the shear flow and the IL vibration frequency is the similar with the CF vibration frequency at the Reynolds number of 1105 in our experimental condition and the IL dominant frequency is twice the CF dominant frequency with an increasing Reynolds number. In addition, the displacement trajectories at the different locations of the riser appear the same shape and the shape is changed at the same shear parameter with an increasing Reynolds number under the shear flow. The diagonal displacement trajectories are observed at the low Reynolds number and the crescent-shaped displacement trajectories appear with an increasing Reynolds number under shear flow in the experiment.
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Genome-wide transcriptional changes of ramie (Boehmeria nivea L. Gaud) in response to root-lesion nematode infection.
Gene
PUBLISHED: 07-11-2014
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Ramie fiber extracted from stem bark is one of the most important natural fibers. The root-lesion nematode (RLN) Pratylenchus coffeae is a major ramie pest and causes large fiber yield losses in China annually. The response mechanism of ramie to RLN infection is poorly understood. In this study, we identified genes that are potentially involved in the RLN-resistance in ramie using Illumina pair-end sequencing in two RLN-infected plants (Inf1 and Inf2) and two control plants (CO1 and CO2). Approximately 56.3, 51.7, 43.4, and 45.0 million sequencing reads were generated from the libraries of CO1, CO2, Inf1, and Inf2, respectively. De novo assembly for these 196 million reads yielded 50,486 unigenes with an average length of 853.3bp. A total of 24,820 (49.2%) genes were annotated for their function. Comparison of gene expression levels between CO and Inf ramie revealed 777 differentially expressed genes (DEGs). The expression levels of 12 DEGs were further confirmed by real-time quantitative PCR (qRT-PCR). Pathway enrichment analysis showed that three pathways (phenylalanine metabolism, carotenoid biosynthesis, and phenylpropanoid biosynthesis) were strongly influenced by RLN infection. A series of candidate genes and pathways that may contribute to the defense response against RLN in ramie will be helpful for further improving resistance to RLN infection.
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Transcriptome comparison reveals the patterns of selection in domesticated and wild ramie (Boehmeria nivea L. Gaud).
Plant Mol. Biol.
PUBLISHED: 05-02-2014
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Ramie is an old fiber crop, cultivated for thousands of years in China. The cultivar ramie evolved from the wild species Qingyezhuma (QYZM, Boehmeria nivea var. tenacissima). However, the mechanism of domestication of this old fiber crop is poorly understood. In order to characterize the selective pattern in ramie domestication, orthologous genes between the transcriptomes of domesticated ramie variety Zhongzhu 1 (ZZ1) and wild QYZM were assessed using bidirectional best-hit method and ratio of non-synonymous (Ka) to synonymous (Ks) nucleotide substitutions was estimated. Sequence comparison of 56,932 and 59,246 unigenes from the wild QYZM and domesticated ZZ1, respectively, helped identify 10,745 orthologous unigene pairs with a total orthologous length of 10.18 Mb. Among these unigenes, 85 and 13 genes were found to undergo significant purifying and positive selection, respectively. Most of the selected genes were homologs of those involved in abiotic stress tolerance or disease resistance in other plants, suggesting that abiotic and biotic stresses were important selective pressures in ramie domestication. Two genes probably related to the fiber yield of ramie were subjected to positive selection, which may be caused by human manipulation. Thus, our results show the pervasive effects of artificial and natural selections on the accelerated domestication of ramie from its wild relative.
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Finite-time master-slave synchronization and parameter identification for uncertain Lurie systems.
ISA Trans
PUBLISHED: 03-26-2014
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This paper investigates the finite-time master-slave synchronization and parameter identification problem for uncertain Lurie systems based on the finite-time stability theory and the adaptive control method. The finite-time master-slave synchronization means that the state of a slave system follows with that of a master system in finite time, which is more reasonable than the asymptotical synchronization in applications. The uncertainties include the unknown parameters and noise disturbances. An adaptive controller and update laws which ensures the synchronization and parameter identification to be realized in finite time are constructed. Finally, two numerical examples are given to show the effectiveness of the proposed method.
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Identification of 32 full-length NAC transcription factors in ramie (Boehmeria nivea L. Gaud) and characterization of the expression pattern of these genes.
Mol. Genet. Genomics
PUBLISHED: 03-18-2014
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NAM, ATAF, and CUC (NAC) genes are plant-specific transcription factors (TFs) that play key roles in plant growth, development, and stress tolerance. To date, none of the ramie NAC (BnNAC) genes had been identified, even though ramie is one of the most important natural fiber crops. In order to mine the BnNAC TFs and identify their potential function, the search for BnNAC genes against two pools of unigenes de novo assembled from the RNA-seq in our two previous studies was performed, and a total of 32 full-length BnNAC genes were identified in this study. Forty-seven function-known NAC proteins published in other species, in concert with these 32 BnNAC proteins were subjected to phylogenetic analysis, and the result showed that all the 79 NAC proteins can be divided into eight groups (NAC-I-VIII). Among the 32 BnNAC genes, 24, 2, and 1 gene showed higher expression in stem xylem, leaf, and flower, respectively. Furthermore, the expression of 14, 11 and 4 BnNAC genes was regulated by drought, cadmium stress, and infection by root lesion nematode, respectively. Interestingly, there were five BnNAC TFs which showed high homology with the NAC TFs of other species involved in regulating the secondary wall synthesis, and their expressions were not regulated by drought and cadmium stress. These results suggested that the BnNAC family might have a functional diversity. The identification of these 32 full-length BnNAC genes and the characterization of their expression pattern provide a basis for future clarification of their functions in ramie growth and development.
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Polymer nanodots of graphitic carbon nitride as effective fluorescent probes for the detection of Fe³? and Cu²? ions.
Nanoscale
PUBLISHED: 03-08-2014
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A simple and green route was developed for the first time to produce fluorescent graphitic carbon nitride (F-g-C?N?) by hydrothermal treatment of bulk g-C?N?. The produced F-g-C?N? dots have blue emission and a high quantum yield, and were applied as a very effective fluorescent probe for label-free selective and sensitive detection of Cu(2+) and Fe(3+) ions; the limits of detection were as low as 0.5 nM and 1.0 nM, respectively. By using sodium hexametaphosphate (SHPP) as a masking agent of Fe(3+), Cu(2+) was exclusively detected in the presence of Fe(3+) ions. Cu(2+) and Fe(3+) ions in real water samples were also detected successfully. This exceptional fluorescent performance makes the probes based on F-g-C?N? dots attractive for highly sensitive detection of Cu(2+) and Fe(3+) ions in real water.
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Critical evaluation of adsorption-desorption hysteresis of heavy metal ions from carbon nanotubes: influence of wall number and surface functionalization.
Chem Asian J
PUBLISHED: 02-02-2014
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Single-, double-, and multi-walled carbon nanotubes (SWCNTs, DWCNTs, and MWCNTs), and two oxidized MWCNTs with different oxygen contents (2.51?wt % and 3.5?wt %) were used to study the effect of the wall number and surface functionalization of CNTs on their adsorption capacity and adsorption-desorption hysteresis for heavy metal ions (Ni(II), Cd(II), and Pb(II)). Metal ions adsorbed on CNTs could be desorbed by lowering the solution pH. Adsoprtion of heavy metal ions was not completely reversible when the supernatant was replaced with metal ion-free electrolyte solution. With increasing wall number and amount of surface functional groups, CNTs had more surface defects and exhibited higher adsorption capacity and higher adsorption-desorption hysteresis index (HI) values. The coverage of heavy metal ions on the surface of CNTs, solution pH, and temperature affect the metal ion adsorption-desorption hysteresis. A possible shift in the adsorption mechanism from mainly irreversible to largely reversible processes may take place, as the amount of metal ions adsorbed on CNTs increases. Heavy metal ions may be irreversibly adsorbed on defect sites.
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Robust master-slave synchronization for general uncertain delayed dynamical model based on adaptive control scheme.
ISA Trans
PUBLISHED: 01-21-2014
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In this paper, the robust exponential synchronization problem for a class of uncertain delayed master-slave dynamical system is investigated by using the adaptive control method. Different from some existing master-slave models, the considered master-slave system includes bounded unmodeled dynamics. In order to compensate the effect of unmodeled dynamics and effectively achieve synchronization, a novel adaptive controller with simple updated laws is proposed. Moreover, the results are given in terms of LMIs, which can be easily solved by LMI Toolbox in Matlab. A numerical example is given to illustrate the effectiveness of the method.
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Bandgap engineering and mechanism study of nonmetal and metal ion codoped carbon nitride: C+Fe as an example.
Chemistry
PUBLISHED: 01-07-2014
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Bandgap narrowing and a more positive valence band (VB) potential are generally considered to be effective methods for improving visible-light-driven photocatalysts because of the significant enhancement of visible-light absorption and oxidation ability. Herein, an approach is reported for the synthesis of a novel visible-light-driven high performance polymer photocatalyst based on band structure control and nonmetal and metal ion codoping, that is, C and Fe-codoped as a model, by a simple thermal conversion method. The results indicate that compared to pristine graphitic carbon nitride (g-C3 N4 ), C+Fe-codoped g-C3 N4 shows a narrower bandgap and remarkable positively shifted VB; as a result the light-absorption range was expanded and the oxidation capability was increased. Experimental results show that the catalytic efficiency of C+Fe-codoped g-C3 N4 for photodegradation of rhodamine?B (RhB) increased 14 times, compared with pristine g-C3 N4 under visible-light absorption at ?>420?nm. The synergistic enhancement in C+Fe-codoped g-C3 N4 photocatalyst could be attributed to the following features: 1)?C+Fe-codoping of g-C3 N4 tuned the bandgap and improved visible-light absorption; 2)?the porous lamellar structure and decreased particle size could provide a high surface area and greatly improve photogenerated charge separation and electron transfer; and 3)?both increased electrical conductivity and a more positive VB ensured the superior electron-transport property and high oxidation capability. The results imply that a high-performance photocatalyst can be obtained by combining bandgap control and doping modification; this may provide a basic concept for the rational design of high performance polymer photocatalysts with reasonable electronic structures for unique photochemical reaction.
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Role of colchicine-induced microtubule depolymerization in hyperalgesia via TRPV4 in rats with chronic compression of the dorsal root ganglion.
Neurol. Res.
PUBLISHED: 12-06-2013
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The aim of this study is to investigate the effect of microtubule depolymerization by colchicine on hyperalgesia mediated by transient receptor potential vanilloid 4 (TRPV4) in a neuropathic pain model of chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) in rat. Intrathecal administration of microtubule-depolymerizing agent, colchicine, attenuated the activated effect of 4alphaphorbol 12, 13-didecanoate (4alpha-PDD, TRPV4 specific agonist) on mechanical and thermal hyperalgesia in CCD rats. This observation is in agreement with our in vitro experiments with DRG cells that showed a significant attenuation of 4alpha-PDD-activated Ca(2+)-influx and substance P (SP) release with the colchicine treatment. We conclude that microtubule depolymerization by colchicine can regulate pain sensitivity by depressing the hyperalgesia mediated by TRPV4.
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In situ synthesis of water-soluble magnetic graphitic carbon nitride photocatalyst and its synergistic catalytic performance.
ACS Appl Mater Interfaces
PUBLISHED: 11-22-2013
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Water-soluble magnetic-functionalized graphitic carbon nitride (g-C3N4) composites were synthesized successfully by in situ decorating spinel ZnFe2O4 nanoparticles on g-C3N4 sheets (CN-ZnFe) through a one-step solvothermal method. The magnetic properties of CN-ZnFe can be effectively controlled via tuning the coverage density and the size of ZnFe2O4 nanoparticles. The results indicate that the CN-ZnFe exhibits excellent photocatalytic efficiency for methyl orange (MO) and fast separation from aqueous solution by magnet. Interestingly, the catalytic performance of the CN-ZnFe is strongly dependent on the loading of ZnFe2O4. The optimum activity of 160CN-ZnFe photocatalyst is almost 6.4 and 5.6 times higher than those of individual g-C3N4 and ZnFe2O4 toward MO degradation, respectively. By carefully investigating the influence factors, a possible mechanism is proposed and it is believed that the synergistic effect of g-C3N4 and ZnFe2O4, the smaller particle size, and the high solubility in water contribute to the effective electron-hole pairs separation and excellent photocatalytic efficiency. This work could provide new insights that g-C3N4 sheets function as good support to develop highly efficient g-C3N4-based magnetic photocatalysts in environmental pollution cleanup.
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Stability and antimicrobial property of soy protein/chitosan mixed emulsion at acidic condition.
Food Funct
PUBLISHED: 07-27-2013
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To fabricate a soy protein emulsion with good storage stability against microorganisms, we investigated the stability and antimicrobial activity of a ?-conglycinin (7S) and chitosan (CS) mixed emulsion at acidic pHs. Results of droplet size and microstructure showed that 7S/CS mixed emulsions were stable at acidic pHs while the 7S emulsion was not. As for the storage test, results showed that the 7S/CS mixed emulsion displayed an significantly (p < 0.05) improved storage stability than the control both under un-inoculated and inoculated conditions at 20 °C because of the presence of chitosan. A well diffusion assay showed that the 7S/CS mixed emulsion provided better inhibition against Escherichia coli and the minimum mixing ratio of the chitosan content, of 0.25 mg mL(-1), adequately inhibited the bacteria used in this research. Moreover, the aerobic plate count analysis indicated that the 7S/CS mixed emulsion, compared to the control, effectively inhibited the growth of microorganisms. This inhibition was believed to be independent of the CS/7S mixing ratio. The results in this paper demonstrate that the growth of microorganisms dramatically accelerated the destabilization of the stable 7S emulsion and the fabrication of 7S/CS mixed emulsion could increase the acidic stability and antimicrobial activity in order to extend shelf-life.
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Hierarchically grown CdS/?-Fe2O3 heterojunction nanocomposites with enhanced visible-light-driven photocatalytic performance.
Dalton Trans
PUBLISHED: 07-26-2013
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Wide spectral responsive 3D hierarchical CdS/?-Fe2O3 heterojunction nanocomposites were synthesized through a facile chemical bath method under mild conditions, and used for the reduction of Cr(VI) into Cr(III) under visible light irradiation. The effects of CdS/?-Fe2O3 molar ratio in the nanocomposites on the crystal phases, microstructures, optical absorption properties, and photocatalytic reduction of Cr(VI) were investigated comparatively. It was found that the as-synthesized CdS/?-Fe2O3 nanocomposites with a suitable CdS content (e.g., the molar ratio of Fe?:?Cd = 1.25?:?3) had not only high visible-light-driven photocatalytic activity in the Cr(VI) reduction, but also good photocatalytic stability. The enhanced photocatalytic activity can be ascribed to some CdS nanoparticles closely contacting the ?-Fe2O3 microflowers to form a heterojunction structure. These tight heterojunctions of the photocatalysts result in an efficient electron-hole pairs separation at the interface, followed by fast diffusion of photogenerated charge between CdS and ?-Fe2O3, which is beneficial for separating the photogenerated carriers in space and improving the photocatalytic activity.
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Comparison of the clinical efficacy of temozolomide (TMZ) versus nimustine (ACNU)-based chemotherapy in newly diagnosed glioblastoma.
Neurosurg Rev
PUBLISHED: 05-05-2013
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Although temozolomide (TMZ) replaced nitrosoureas as the standard initial chemotherapy for glioblastoma (GBM), no studies have compared TMZ with nimustine (ACNU), a nitrosourea agent widely used in central Europe and most Asian regions. One hundred thirty-five patients with GBM who underwent extensive tumor resection in our institution received both radiation and chemotherapy as initial treatment, 34 received TMZ and 101 ACNU-based (ACNU plus teniposide or cisplatin) chemotherapy. Efficacy analysis included overall survival (OS) and progression-free survival (PFS). The following prognostic factors were taken into account: age, performance status, extent of resection, and O(6)-methylguanine-DNA-methyltransferase (MGMT) gene status. The median OS was superior in the TMZ versus the ACNU group (p?=?0.011), although MGMT gene silencing, which is associated with a striking survival benefit from alkylating agents, was more frequent in the ACNU group. In multivariate Cox analysis adjusting for the common prognostic factors, TMZ chemotherapy independently predicted a favorable outcome (p?=?0.002 for OS, hazard ratio [HR], 0.45; p?=?0.011 for PFS, HR, 0.56). Given that >40 % of patients in ACNU group did not receive the intensive chemotherapy cycles because of severe hematological and nonhematological toxicity, we performed a further subanalysis for patients who received at least 4 cycles of chemotherapy. Although a modest improvement in survival occurred in this ACNU subgroup, the efficacy was still inferior to that in the TMZ cohort. Our data suggest that the survival benefit of TMZ therapy is superior to that of an ACNU-based regimen in patients with extensive tumor resection, also shows greater tolerability.
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Polyaniline nanorods dotted on graphene oxide nanosheets as a novel super adsorbent for Cr(VI).
Dalton Trans
PUBLISHED: 04-23-2013
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Hierarchical nanocomposites of polyaniline (PANI) nanorods array on graphene oxide (GO) nanosheets are successfully obtained by dilute polymerization under -20 °C. They exhibit excellent water treatment performance with a superb removal capacity of 1149.4 mg g(-1) for Cr(VI).
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[Histone acetylation modulates influenza virus replicative intermediate dsRNA-induced interleukin-6 expression in A549 cells].
Nan Fang Yi Ke Da Xue Xue Bao
PUBLISHED: 02-28-2013
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To investigate the role of histone acetylation in regulating influenza virus replicative intermediate double-stranded RNA (dsRNA)-induced interleukin-6 (IL-6) expression in A549 cells.
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Development and characterization of 1,827 expressed sequence tag-derived simple sequence repeat markers for ramie (Boehmeria nivea L. Gaud).
PLoS ONE
PUBLISHED: 02-25-2013
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Ramie (Boehmeria nivea L. Gaud) is one of the most important natural fiber crops, and improvement of fiber yield and quality is the main goal in efforts to breed superior cultivars. However, efforts aimed at enhancing the understanding of ramie genetics and developing more effective breeding strategies have been hampered by the shortage of simple sequence repeat (SSR) markers. In our previous study, we had assembled de novo 43,990 expressed sequence tags (ESTs). In the present study, we searched these previously assembled ESTs for SSRs and identified 1,685 ESTs (3.83%) containing 1,878 SSRs. Next, we designed 1,827 primer pairs complementary to regions flanking these SSRs, and these regions were designated as SSR markers. Among these markers, dinucleotide and trinucleotide repeat motifs were the most abundant types (36.4% and 36.3%, respectively), whereas tetranucleotide, pentanucleotide, and hexanucleotide motifs represented <10% of the markers. The motif AG/CT was the most abundant, accounting for 28.74% of the markers. One hundred EST-SSR markers (97 SSRs located in genes encoding transcription factors and 3 SSRs in genes encoding cellulose synthases) were amplified using polymerase chain reaction for detecting 24 ramie varieties. Of these 100 markers, 98 markers were successfully amplified and 81 markers were polymorphic, with 2-6 alleles among the 24 varieties. Analysis of the genetic diversity of all 24 varieties revealed similarity coefficients that ranged from 0.51 to 0.80. The EST-SSRs developed in this study represent the first large-scale development of SSR markers for ramie. These SSR markers could be used for development of genetic and physical maps, quantitative trait loci mapping, genetic diversity studies, association mapping, and cultivar fingerprinting.
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De novo assembly and characterization of transcriptome using Illumina paired-end sequencing and identification of CesA gene in ramie (Boehmeria nivea L. Gaud).
BMC Genomics
PUBLISHED: 02-18-2013
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Ramie fiber, extracted from vegetative organ stem bast, is one of the most important natural fibers. Understanding the molecular mechanisms of the vegetative growth of the ramie and the formation and development of bast fiber is essential for improving the yield and quality of the ramie fiber. However, only 418 expressed tag sequences (ESTs) of ramie deposited in public databases are far from sufficient to understand the molecular mechanisms. Thus, high-throughput transcriptome sequencing is essential to generate enormous ramie transcript sequences for the purpose of gene discovery, especially genes such as the cellulose synthase (CesA) gene.
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Identification of drought stress-responsive transcription factors in ramie (Boehmeria nivea L. Gaud).
BMC Plant Biol.
PUBLISHED: 02-01-2013
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Ramie fiber extracted from stem bark is one of the most important natural fibers. Drought is a main environment stress which severely inhibits the stem growth of ramie and leads to a decrease of the fiber yield. The drought stress-regulatory mechanism of ramie is poorly understood.
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Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer.
PLoS ONE
PUBLISHED: 01-11-2013
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Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. Spatholobus suberectus (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds. We found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. Bioactivity-guided fractionation finally identified epigallocatechin as a key compound in SS inhibiting LDH-A activity. Further studies revealed that LDH-A plays a critical role in mediating the apoptosis-induction effects of epigallocatechin. The inhibited LDH-A activities by epigallocatechin is attributed to disassociation of Hsp90 from HIF-1? and subsequent accelerated HIF-1? proteasome degradation. In vivo study also demonstrated that epigallocatechin could significantly inhibit breast cancer growth, HIF-1?/LDH-A expression and trigger apoptosis without bringing toxic effects. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH-A activity and the possibility to consider epigallocatechin as a lead compound to develop LDH-A inhibitors. Future studies of SS for chemoprevention or chemosensitization against breast cancer are thus warranted.
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Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway.
PLoS ONE
PUBLISHED: 01-01-2013
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Angiogenesis is crucial for cancer initiation, development and metastasis. Identifying natural botanicals targeting angiogenesis has been paid much attention for drug discovery in recent years, with the advantage of increased safety. Isoliquiritigenin (ISL) is a dietary chalcone-type flavonoid with various anti-cancer activities. However, little is known about the anti-angiogenic activity of isoliquiritigenin and its underlying mechanisms. Herein, we found that ISL significantly inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) at non-toxic concentration. A series of angiogenesis processes including tube formation, invasion and migration abilities of HUVECs were also interrupted by ISL in vitro. Furthermore, ISL suppressed sprout formation from VEGF-treated aortic rings in an ex-vivo model. Molecular mechanisms study demonstrated that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting HIF-1? (Hypoxia inducible factor-1?) proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies further showed that ISL administration could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling, elevated apoptosis ratio and little toxicity effects. Molecular docking simulation indicated that ISL could stably form hydrogen bonds and aromatic interactions within the ATP-binding region of VEGFR-2. Taken together, our study shed light on the potential application of ISL as a novel natural inhibitor for cancer angiogenesis via the VEGF/VEGFR-2 pathway. Future studies of ISL for chemoprevention or chemosensitization against breast cancer are thus warranted.
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Hybrid impulsive control for closed quantum systems.
ScientificWorldJournal
PUBLISHED: 01-01-2013
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The state transfer problem of a class of nonideal quantum systems is investigated. It is known that traditional Lyapunov methods may fail to guarantee convergence for the nonideal case. Hence, a hybrid impulsive control is proposed to accomplish a more accurate convergence. In particular, the largest invariant sets are explicitly characterized, and the convergence of quantum impulsive control systems is analyzed accordingly. Numerical simulation is also presented to demonstrate the improvement of the control performance.
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Molecular prognostic factors of anaplastic oligodendroglial tumors and its relationship: a single institutional review of 77 patients from China.
Neuro-oncology
PUBLISHED: 10-27-2011
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The increased chemosensitivity of oligodendroglial tumors has been associated with loss of heterozygosity (LOH) on chromosomes 1p and 19q. Other clinical and molecular factors have also been identified as being prognostic and predictive for treatment outcome. Seventy-seven patients with anaplastic oligodendroglioma (AO) or anaplastic oligoastrocytoma (AOA), treated in Beijing Tiantan Hospital from 2006 through 2008, were reviewed. LOH 1p, LOH 19q, IDH1 mutation, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and protein expression level of MGMT, P53, EGFR, and Ki-67 were evaluated. Age at diagnosis, LOH 1p and 19q, IDH1 mutation, P53 expression level, reoperation when progression, and adjuvant chemotherapy were statistically significant factors for overall survival (OS) in univariate analysis. Further multivariate analysis showed that age at diagnosis (P = .010), LOH 1p and 19q (P = .016), IDH1 mutation (P = .011), and reoperation after progression (P = .048) were independent predictors for longer survival in these patients. Nonrandom associations were found between LOH 1p and LOH 19q, MGMT promoter methylation and LOH 1p or 19q, IDH1 mutation and LOH 1p and 19q, IDH1 mutation and MGMT promoter methylation, whereas mutual exclusion was found between MGMT promoter methylation and MGMT expression level. The present study confirmed that age at diagnosis, LOH 1p and 19q, IDH1 mutation, and reoperation after progression were independent significant prognostic factors for patients with anaplastic oligodendroglial tumors. Inter-relationship between LOH 1p, LOH 19q, IDH1 mutation, MGMT promoter methylation, and MGMT expression level were also revealed. Future clinical trials for AO and AOA should consider the molecular alterations of patients.
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A Lie algebraic condition for exponential stability of discrete hybrid systems and application to hybrid synchronization.
Chaos
PUBLISHED: 07-05-2011
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A Lie algebraic condition for global exponential stability of linear discrete switched impulsive systems is presented in this paper. By considering a Lie algebra generated by all subsystem matrices and impulsive matrices, when not all of these matrices are Schur stable, we derive new criteria for global exponential stability of linear discrete switched impulsive systems. Moreover, simple sufficient conditions in terms of Lie algebra are established for the synchronization of nonlinear discrete systems using a hybrid switching and impulsive control. As an application, discrete chaotic systems synchronization is investigated by the proposed method.
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Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and ?-catenin signaling pathways.
Oncol. Rep.
PUBLISHED: 06-01-2011
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Activation of signal transducer and activator of transcription 3 (STAT3) is associated with poor clinical outcome of glioblastoma (GBM). However, the role of STAT3 in resistance to alkylator-based chemotherapy remains unknown. Here, we retrospectively analyzed the phosphorylated STAT3 (p-STAT3) profile of 68 GBM patients receiving alkylator therapy, identifying p-STAT3 as an independent unfavorable prognostic factor for progression-free and overall survival. Additionally, elevated p-STAT3 expression correlated with resistance to alkylator therapy. In vitro analysis revealed that U251 and U87 human glioma cells were refractory to treatment with the common alkylating agent temozolomide (TMZ), with only a modest impact on AKT and ?-catenin activation in the context of high p-STAT3. Inhibition of STAT3 in these cells significantly enhanced the effect of TMZ. Inhibition of STAT3 dramatically decreased the IC50 of TMZ, increasing TMZ-induced apoptosis while up-regulating expression of Bcl-2 and down-regulating expression of Bax. Furthermore, inhibition of STAT3 increased TMZ-induced G?-G? arrest and decreased Cyclin D1 expression compared to TMZ alone. Together, these results indicate that inhibition of STAT3 sensitizes glioma cells to TMZ, at least in part, by blocking the p-AKT and ?-catenin pathways. These findings strongly support the hypothesis that STAT3 inhibition significantly improves the clinical efficacy of alkylating agents.
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Enhanced sorption of radiocobalt from water by Bi(III) modified montmorillonite: a novel adsorbent.
J. Hazard. Mater.
PUBLISHED: 01-10-2011
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In this study, Ca-montmorillonite (Ca-Mt) modified with Bi(3+) was used as a novel adsorbent for the sorption of Co(II) from aqueous solutions. The sorption of Co(II) on Bi-montmorillonite (Bi-Mt) was investigated as a function of contact time, pH, ionic strength, adsorbent content, Co(II) concentrations, fulvic acid (FA) and temperature. Compared to Ca-Mt, Bi-Mt showed a higher affinity to bind Co(II) ions. The sorption percentage of Co(II) on Bi-Mt increased with increasing pH at pH 3.0-8.5, and then maintained the high level at pH 8.5-12. The sorption of Co(II) on Bi-Mt was dependent on ionic strength at low pH, and independent of ionic strength at high pH. The presence of FA enhanced Co(II) sorption at low pH, but suppressed Co(II) sorption at high pH. The thermodynamic data derived from temperature dependent sorption isotherms suggested that the sorption of Co(II) on Bi-Mt was spontaneous and endothermic process. Outer-sphere surface complexation and/or ion exchange were the main mechanisms of Co(II) sorption on Bi-Mt at low pH, whereas inner-sphere surface complexation was the main sorption mechanism at high pH. From the experimental results, it is possible to conclude that Bi-Mt is suitable for application of Co(II) removal from aqueous solutions.
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Correlation between tumor-related seizures and molecular genetic profile in 103 Chinese patients with low-grade gliomas: a preliminary study.
J. Neurol. Sci.
PUBLISHED: 06-11-2010
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Tumor-related seizures are a well-known presenting symptom of primary brain tumors, particularly low-grade gliomas (LGGs). The objective of the present study was to investigate the possible correlation between tumor-related seizures and molecular genetic profile in Chinese patients with LGGs. A series of 103 LGGs, including 27 oligodendrogliomas, 41 oligoastrocytomas and 35 astrocytomas, was analyzed by denaturing high-performance liquid chromatography (DHPLC) for 1p and 19q status, with particular emphasis on correlations with tumor-related seizures. Most oligodendrogliomas and oligoastrocytomas had LOH 1p and LOH 19q, which were rarely seen in combination in astrocytomas (p<0.001). LOH 1p and LOH 19q were also closely associated (p=0.022). The majority of patients with LGGs presented with seizures at disease onset (68.9% of all patients). The most common seizure type was secondary generalized seizures (81.7% of patients with seizures). Patients without LOH 19q were more likely to present with seizures (p=0.033), particularly secondary generalized seizures (p=0.005), than those with this alteration. The current study presented an update on studies on tumor-related seizures and molecular genetic profile, and brought forward putative candidate genes for secondary generalized seizures on chromosome 19q, based on the assumption that common molecular genetic pathways may exist for glioma development and tumor-related seizures.
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alpha5beta1-integrin expression is essential for tumor progression in experimental lung cancer.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 01-15-2010
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The matrix glycoprotein, fibronectin, stimulates the proliferation of non-small cell lung carcinoma in vitro through ?5?1 integrin receptor-mediated signals. However, the true role of fibronectin and its receptor in lung carcinogenesis in vivo remains unclear. To test this, we generated mouse Lewis lung carcinoma cells stably transfected with short hairpin RNA shRNA targeting the ?5 integrin subunit. These cells were characterized and tested in proliferation, cell adhesion, migration, and soft agar colony formation assays in vitro. In addition, their growth and metastatic potential was tested in vivo in a murine model of lung cancer. We found that transfected Lewis lung carcinoma cells showed decreased expression of the ?5 gene, which was associated with decreased adhesion to fibronectin and reduced cell migration, proliferation, and colony formation when compared with control cells and cells stably transfected with ?2 integrin subunit in vitro. C57BL/6 mice injected with ?5-silenced cells showed lower burden of implanted tumors, and a dramatic decrease in lung metastases resulting in higher survival as compared with mice injected with wild-type or ?2 integrin-silenced cells. These observations reveal that recognition of host- and/or tumor-derived fibronectin via ?5?1 is important for tumor growth both in vitro and in vivo, and unveil ?5?1 as a potential target for the development of anti-lung cancer therapies.
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Prognostic and predictive value of p53 in low MGMT expressing glioblastoma treated with surgery, radiation and adjuvant temozolomide chemotherapy.
Neurol. Res.
PUBLISHED: 08-21-2009
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To assess the prognostic and predictive significance of p53 protein expression in low O6-methylguanine-DNA methyltransferase (MGMT) expressing glioblastoma multiform (GBM) treated with combined therapy.
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Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha.
Cancer Res.
PUBLISHED: 08-04-2009
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We previously showed that nicotine stimulates non-small cell lung carcinoma (NSCLC) cell proliferation through nicotinic acetylcholine receptor (nAChR)-mediated signals. Activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) has also been shown to induce NSCLC cell growth. Here, we explore the potential link between nicotine and PPARbeta/delta and report that nicotine increases the expression of PPARbeta/delta protein; this effect was blocked by an alpha7 nAChR antagonist (alpha-bungarotoxin), by alpha7 nAChR short interfering RNA, and by inhibitors of phosphatidylinositol 3-kinase (PI3K; wortmannin and LY294002) and mammalian target of rapamycin (mTOR; rapamycin). In contrast, this effect was enhanced by PUN282987, an alpha7 nAChR agonist. Silencing of PPARbeta/delta attenuated the stimulatory effect of nicotine on cell growth, which was overcome by transfection of an exogenous PPARbeta/delta expression vector. Of note, nicotine induced complex formation between alpha7 nAChR and PPARbeta/delta protein and increased PPARbeta/delta gene promoter activity through inhibition of AP-2alpha as shown by reduced AP-2alpha binding using electrophoretic gel mobility shift and chromatin immunoprecipitation assays. In addition, silencing of Sp1 attenuated the effect of nicotine on PPARbeta/delta. Collectively, our results show that nicotine increases PPARbeta/delta gene expression through alpha7 nAChR-mediated activation of PI3K/mTOR signals that inhibit AP-2alpha protein expression and DNA binding activity to the PPARbeta/delta gene promoter. Sp1 seems to modulate this process. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell growth.
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PPARbeta/delta agonist increases the expression of PGE2 receptor subtype EP4 in human lung carcinoma cells.
Methods Mol. Biol.
PUBLISHED: 04-07-2009
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Lung carcinoma remains one of the most common malignant tumors in the world despite recent advancements in the development of new chemotherapeutic agents for its treatment. Therefore, novel approaches for drug target discovery play an important role in the effort to help extend its dismal 5-year survival rate (<15%). Many mechanisms contribute to oncogenic transformation in carcinoma cells in the lung and recent evidence indicates that the overproduction of prostaglandin E(2) (PGE(2)), and the prostag-landin E(2) receptor subtype, EP4, promote the growth and progression of human nonsmall cell lung carcinoma (NSCLC), the most common lung carcinoma. Peroxisome proliferator-activated receptor beta/ delta (PPARbeta/delta), one of the nuclear hormone ligand-dependent transcription factors, has recently been reported to be involved in tumorigeniCity. We have shown that NSCLC cells express PPARbeta/delta protein and that treatment with a selective PPARbeta/delta agonist, GW501516, stimulated the expression of EP4 and induced NSCLC cell proliferation. In addition, this PPARbeta/delta agonist also induced EP4 promoter activity through the binding of C/EBP to the NF-IL6 site in the EP4 promoter. Therefore, PPARbeta/delta activation represents a novel molecular mechanism for regulating human cancer cell growth.
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Activation of peroxisome proliferator-activated receptor beta/delta induces lung cancer growth via peroxisome proliferator-activated receptor coactivator gamma-1alpha.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 03-06-2009
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We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), GW501516, stimulated human non-small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha), a major regulator of energy metabolism. This was mediated through specific activation of PPARbeta/delta, as a PPARbeta/delta small interfering RNA inhibited the effect. However, AMPKalpha did not mediate the growth-promoting effects of GW501516, as silencing of AMPKalpha did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator-activated receptor coactivator gamma (PGC)-1alpha, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1alpha, consistent with PGC-1alpha being upstream of PI3-K/Akt. Of note, an activator of AMPKalpha, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPKalpha is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPARbeta/delta stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPKalpha may oppose this effect.
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Prostaglandin E2 stimulates human lung carcinoma cell growth through induction of integrin-linked kinase: the involvement of EP4 and Sp1.
Cancer Res.
PUBLISHED: 01-27-2009
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Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) stimulates tumor cell growth and progression. However, the mechanisms by which PGE(2) increases tumor growth remain incompletely understood. In studies performed in non-small cell lung carcinoma (NSCLC) cells, we found that PGE(2) stimulates the expression of integrin-linked kinase (ILK). ILK small interfering RNA (siRNA) inhibited the mitogenic effects of PGE(2). In view of its perceived importance, we turned our attention to the mechanisms involved in PGE(2)-induced ILK expression and found that this effect was blocked by an antagonist of the PGE(2) receptor subtype EP4 and by EP4 siRNA. Furthermore, we showed that PGE(2) induction of ILK was associated with phosphorylation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt, which were abrogated by ILK siRNA. Transient transfection, gel mobility shift assays, and chromatin immunoprecipitation experiments showed that PGE(2) induced ILK promoter activity and increased Sp1, although it had no effect on nuclear factor-kappaB and AP-2 DNA-binding activity. Blockade of Sp1 abrogated the effect of PGE(2) on expression of ILK and promoter activity and on cell growth. In summary, our observations show that PGE(2) increases NSCLC cell growth through increased ILK expression, which is dependent on EP4 signaling and on induction of Sp1 protein and Sp1 DNA-binding activity in the ILK promoter. These studies suggest a novel molecular mechanism by which PGE(2) stimulates NSCLC cell growth and unveils a new molecular target for the development of therapies against NSCLC.
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Fish oil inhibits human lung carcinoma cell growth by suppressing integrin-linked kinase.
Mol. Cancer Res.
PUBLISHED: 01-17-2009
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We previously showed that synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligands inhibit non-small cell lung carcinoma (NSCLC) cell growth through multiple signaling pathways. Here, we show that dietary compounds, such as fish oil (which contains certain kinds of fatty acids like omega3 and omega6 polyunsaturated fatty acids), also inhibit NSCLC cell growth by affecting PPARgamma and by inhibiting the expression of integrin-linked kinase (ILK). Exogenous expression of ILK overcame, whereas silencing ILK enhanced the inhibitory effect of fish oil on cell growth. The inhibitor of p38 mitogen-activated protein kinase, SB239023, abrogated the inhibitory effect of fish oil on ILK expression, whereas the inhibitor of extracellular signal-regulated kinase, PD98059, had no effect. Transient transfection experiments showed that fish oil reduced ILK promoter activity, and this effect was abolished by AP-2alpha small interfering RNA and SB239023 and by deletion of a specific portion of the ILK gene promoter. Western blot analysis and gel mobility shift assay showed that fish oil significantly induced AP-2alpha protein expression and AP-2 DNA-binding activity in the ILK gene promoter and that this was dependent on PPARgamma activation. Blockade of AP-2alpha abrogated the effect of fish oil on ILK expression and on cell growth, whereas exogenous expression of AP-2alpha enhanced cell growth in the setting of fish oil exposure. Taken together, these findings show that fish oil inhibits ILK expression through activation of PPARgamma-mediated and p38 mitogen-activated protein kinase-mediated induction of AP-2alpha. In turn, this leads to inhibition of NSCLC cell proliferation. This study unveils a novel mechanism by which fish oil inhibits human lung cancer cell growth.
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Rosiglitazone inhibits alpha4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor gamma-independent signals.
Mol. Cancer Ther.
PUBLISHED: 01-14-2009
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We and others have shown previously that nicotine, a major component of tobacco, stimulates non-small cell lung carcinoma (NSCLC) proliferation through nicotinic acetylcholine receptor (nAChR)-mediated signals. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit NSCLC cell growth, but the exact mechanisms responsible for this effect remain incompletely defined. Herein, we show that nicotine induces NSCLC cell proliferation in part through alpha4 nAChR, prompting us to explore the effects of rosiglitazone, a synthetic PPARgamma ligand, on the expression of this receptor. Rosiglitazone inhibited the expression of alpha4 nAChR, but this effect was through a PPARgamma-independent pathway, because GW9662, an antagonist of PPARgamma, and the transfection of cells with PPARgamma small interfering RNA failed to abolish the response. The inhibitory effect of rosiglitazone on alpha4 nAChR expression was accompanied by phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 and down-regulation of Akt phosphorylation. These signals mediated the inhibitory effects of rosiglitazone on alpha4 nAChR expression because chemical inhibitors prevented the effect. Rosiglitazone was also found to stimulate p53, a tumor suppressor known to mediate some of the effects of nicotine. Interestingly, p53 up-regulation was needed for rosiglitazone-induced inhibition of alpha4 nAChR. Thus, rosiglitazone inhibits alpha4 nAChR expression in NSCLC cells through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which triggers induction of p53. Finally, like others, we found that nicotine stimulated the expression of alpha4 nAChR. This process was also inhibited by rosiglitazone through similar pathways.
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Significance of miR-196b in tumor-related epilepsy of patients with gliomas.
PLoS ONE
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Seizure is a common presenting symptom of primary brain tumors. There are no published studies regarding the roles of MicroRNA (miRNA) in tumor-related epilepsy. The authors set out to correlate miR-196b expression in low-grade glioma patients with pre-operative seizures and post-operative seizure control.
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Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme.
Cancer
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More reliable clinical outcome prediction is required to better guide more personalized treatment for patients with primary glioblastoma multiforme (GBM). The objective of this study was to identify a microRNA expression signature to improve outcome prediction for patients with primary GBM.
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Removal of Cu(II) and fulvic acid by graphene oxide nanosheets decorated with Fe3O4 nanoparticles.
ACS Appl Mater Interfaces
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Graphene oxide/Fe(3)O(4) (GO/Fe(3)O(4)) composites were synthesized and characterized by scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy. The removal of Cu(II) and a natural organic macromolecule (fulvic acid (FA)) by GO/Fe(3)O(4) was investigated. The mutual effects of FA/Cu(II) on Cu(II) and FA sorption onto GO/Fe(3)O(4), as well as the effect of pH, ionic strength, FA/Cu(II) concentrations, and the addition sequences of FA/Cu(II) were examined. The results indicated that Cu(II) sorption on GO/Fe(3)O(4) were strongly dependent on pH and independent of ionic strength, indicating that the sorption was mainly dominated by inner-sphere surface complexation rather than outer-sphere surface complexation or ion exchange. The presence of FA leads to a strong increase in Cu(II) sorption at low pH and a decrease at high pH, whereas the presence of Cu(II) led to an increase in FA sorption. The adsorbed FA contributes to the modification of sorbent surface properties and partial complexation of Cu(II) with FA adsorbed. Different effects of FA/Cu(II) concentrations and addition sequences on Cu(II) and FA sorption were observed, indicating the difference in sorption mechanisms. After GO/Fe(3)O(4) adsorbed FA, the sorption capacity for Cu(II) was enhanced at pH 5.3, and the sorption capacity for FA was also enhanced after Cu(II) sorption on GO/Fe(3)O(4). These results are important for estimating and optimizing the removal of metal ions and organic substances by GO/Fe(3)O(4) composites.
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Functional interaction of TRPV4 channel protein with annexin A2 in DRG.
Neurol. Res.
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Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable, non-selective cation channel that is involved in the transmission of pain signals mediated by dorsal root ganglion (DRG). Annexin A2 belongs to a class of membrane-binding proteins that plays an important role in the regulation of ion channels. Nevertheless, little is known about the interaction between them in DRG. In this paper, we evaluated the functional interaction of TRPV4 with annexin A2 in DRG.
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Ethylene signaling negatively regulates freezing tolerance by repressing expression of CBF and type-A ARR genes in Arabidopsis.
Plant Cell
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The phytohormone ethylene regulates multiple aspects of plant growth and development and responses to environmental stress. However, the exact role of ethylene in freezing stress remains unclear. Here, we report that ethylene negatively regulates plant responses to freezing stress in Arabidopsis thaliana. Freezing tolerance was decreased in ethylene overproducer1 and by the application of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid but increased by the addition of the ethylene biosynthesis inhibitor aminoethoxyvinyl glycine or the perception antagonist Ag+. Furthermore, ethylene-insensitive mutants, including etr1-1, ein4-1, ein2-5, ein3-1, and ein3 eil1, displayed enhanced freezing tolerance. By contrast, the constitutive ethylene response mutant ctr1-1 and EIN3-overexpressing plants exhibited reduced freezing tolerance. Genetic and biochemical analyses revealed that EIN3 negatively regulates the expression of CBFs and type-A Arabidopsis response regulator5 (ARR5), ARR7, and ARR15 by binding to specific elements in their promoters. Overexpression of these ARR genes enhanced the freezing tolerance of plants. Thus, our study demonstrates that ethylene negatively regulates cold signaling at least partially through the direct transcriptional control of cold-regulated CBFs and type-A ARR genes by EIN3. Our study also provides evidence that type-A ARRs function as key nodes to integrate ethylene and cytokinin signaling in regulation of plant responses to environmental stress.
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miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression.
Neuro-oncology
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Genome-wide microRNA (miRNA) profiling of 82 glioblastomas demonstrated that miR-181d was inversely associated with patient overall survival after correcting for age, Karnofsky performance status, extent of resection, and temozolomide (TMZ) treatment. This association was validated using the Cancer Genome Atlas (TCGA) dataset (n= 424) and an independent cohort (n= 35). In these independent cohorts, an association of miR-181d with survival was evident in patients who underwent TMZ treatment but was not observed in patients without TMZ therapy. Bioinformatic analysis of potential genes regulated by miR-181d revealed methyl-guanine-methyl-transferase (MGMT) as a downstream target. Indeed, transfection of miR-181d downregulated MGMT mRNA and protein expression. Furthermore, luciferase reporter assays and coprecipitation studies showed a direct interaction between miR-181d and MGMT 3UTR. The suppressive effect of miR-181d on MGMT expression was rescued by the introduction of an MGMT cDNA. Finally, MGMT expression inversely correlated with miR-181d expression in independent glioblastoma cohorts. Together, these results suggest that miR-181d is a predictive biomarker for TMZ response and that its role is mediated, in part, by posttranscriptional regulation of MGMT.
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Glioblastoma with an oligodendroglioma component: distinct clinical behavior, genetic alterations, and outcome.
Neuro-oncology
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Glioblastomas (GBMs) containing foci that resemble oligodendroglioma are de?ned as GBM with oligodendroglioma component (GBMO). However, whether GBMO is a distinct clinicopathological variant of GBM or merely represents a divergent pattern of differentiation remains controversial. We investigated 219 consecutive primary GBMs, of which 40 (18.3%) were confirmed as GBMOs. The clinical features and genetic pro?les of the GBMOs were analyzed and compared with the conventional GBMs. The GBMO group showed more frequent tumor-related seizures (P= .027), higher frequency of IDH1 mutation (31% vs. <5%, P= .015), lower MGMT expression (P= .016), and longer survival (19.0 vs. 13.2 months; P= .022). In multivariate Cox regression analyses, presence of an oligodendroglioma component was predictive of longer survival (P= .001), but the extent of the oligodendroglial component appeared not to be linked to prognosis (P= .664). The codeletions of 1p/19q, somewhat surprisingly, were infrequent (<5%) in both GBMO and conventional GBM. In addition, the response to aggressive therapy differed: the GBMO group had no survival advantage associated with aggressive treatment protocols, whereas a clear treatment effect was observed in the conventional GBM group. Collectively, the clinical behavior and genetic alterations of GBMO thus differs from those of conventional GBM. Presence of an oligodendroglial component may therefore be a useful classification and stratification variable in therapeutic trials of GBMs.
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