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Find video protocols related to scientific articles indexed in Pubmed.
Structure-Function Analysis of the Conserved Tyrosine and Diverse ?-Stacking among Class I Histone Deacetylases: A QM (DFT)/MM MD Study.
J Chem Inf Model
PUBLISHED: 11-06-2014
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Discovery of the isoform-selective histone deacetylases (HDACs) inhibitors is of great medical importance and still a challenge. The comparison studies on the structure-function relationship of the conserved residues, which are located in the linker binding channel among class I HDACs (including 4 isoforms: HDAC1/2/3/8), have been carried out by using ab initio QM/MM MD simulations, a state-of-the-art approach to simulate metallo-enzymes. We found that the conserved tyrosine (Y303/308/286/306 in HDAC1/2/3/8, respectively) could modulate the zinc-inhibitor chelation among all class I HDACs with different regulatory mechanisms. For HDAC1/2/3 selective-inhibitor benzamide, the conserved tyrosine could modulate the coordinative ability of the central atom (Zn(2+)), while for pan-inhibitor SAHA, the conserved tyrosine could increase the chelating ability of the ligand (SAHA). Moreover, it is first found that the conserved tyrosine is correlated with the intertransformation of ?-? stacking styles (parallel shift vs T-shaped) by the aromatic ring in benzamide and the two conserved phenylalanine residues of HDACs. In addition, the catalytic roles of the conserved tyrosine in stabilizing the transition state and intermediate are further revealed. These findings provide useful molecular basis knowledge for further isoform-selective inhibitor design among class I HDACs.
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Palladium-catalyzed oxidative C-H bond acylation of N-nitrosoanilines with toluene derivatives: a traceless approach to synthesize N-alkyl-2-aminobenzophenones.
Chem. Commun. (Camb.)
PUBLISHED: 10-28-2014
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A palladium-catalyzed cascade cross-coupling of N-nitroso-anilines and toluene derivatives for the direct synthesis of N-alkyl-2-aminobenzophenones is described. N-nitroso groups in anilines can act as the traceless directing groups while toluene derivatives can serve as effective acyl precursors under mild reaction conditions.
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Molecular dynamics-based discovery of novel phosphodiesterase-9A inhibitors with non-pyrazolopyrimidinone scaffolds.
Mol Biosyst
PUBLISHED: 10-21-2014
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Phosphodiesterase-9A (PDE9A) is a promising therapeutic target for the treatment of diabetes and Alzheimer's disease (AD). The Pfizer PDE9A inhibitor PF-04447943 has completed Phase II clinical trials in subjects with mild to moderate AD in 2013. However, most of the reported PDE9A inhibitors share the same scaffold as pyrazolopyrimidinone, which lacks structural diversity and is unfavorable for the development of novel PDE9A inhibitors. In the present study, a combinatorial method including pharmacophores, molecular docking, molecular dynamics simulations, binding free energy calculations, and bioassay was used to discover novel PDE9A inhibitors with new scaffolds rather than pyrazolopyrimidinones from the SPECS database containing about 200?000 compounds. As a result, 15 hits out of 29 molecules (a hit rate of 52%) with five novel scaffolds were identified to be PDE9A inhibitors with inhibitory affinities no more than 50 ?M to enrich the structural diversity, different from the pyrazolopyrimidinone-derived family. The high hit ratio of 52% for this virtual screening method indicated that the combinatorial method is a good compromise between computational cost and accuracy. Binding pattern analyses indicate that those hits with non-pyrazolopyrimidinone scaffolds can bind the same active site pocket of PDE9A as classical PDE9A inhibitors. In addition, structural modification of compound AG-690/40135604 (IC50 = 8.0 ?M) led to a new one, , with an improved inhibitory affinity of 2.1 ?M as expected. The five novel scaffolds discovered in the present study can be used for the rational design of PDE9A inhibitors with higher affinities.
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Functional expression of chloride channels and their roles in the cell cycle and cell proliferation in highly differentiated nasopharyngeal carcinoma cells.
Physiol Rep
PUBLISHED: 09-01-2014
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We previously demonstrated that the growth of the poorly differentiated nasopharyngeal carcinoma cells (CNE-2Z) was more dependent on the activities of volume-activated chloride channels than that of the normal nasopharyngeal epithelial cells (NP69-SV40T). However, the activities and roles of such volume-activated chloride channels in highly differentiated nasopharyngeal carcinoma cells (CNE-1) are not clarified. In this study, it was found that a volume-activated chloride current and a regulatory volume decrease (RVD) were induced by 47% hypotonic challenges. The current density and the capacity of RVD in the highly differentiated CNE-1 cells were lower than those in the poorly differentiated CNE-2Z cells, and higher than those in the normal cells (NP69-SV40T). The chloride channel blockers, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and tamoxifen inhibited the current and RVD. Depletion of intracellular Cl(-) abolished the RVD. The chloride channel blockers reversibly inhibited cell proliferation in a concentration- and time-dependent manner, and arrested cells at the G0/G1 phases, but did not change cell viability. The sensitivity of the three cell lines to the chloride channel blockers was different, with the highest in poorly differentiated cells (CNE-2Z) and the lowest in the normal cells (NP69-SV40T). ClC-3 proteins were expressed in the three cells and distributed inside the cells as well as on the cell membrane. In conclusion, the highly differentiated nasopharyngeal carcinoma CNE-1 cells functionally expressed the volume-activated chloride channels, which may play important roles in controlling cell proliferation through modulating the cell cycle, and may be associated with cell differentiation. Chloride channels may be a potential target of anticancer therapy.
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Prostaglandin Derivatives: Nonaromatic Phosphodiesterase-4 Inhibitors from the Soft Coral Sarcophyton ehrenbergi.
J. Nat. Prod.
PUBLISHED: 07-31-2014
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Ten new prostaglandin derivatives (PGs), sarcoehrendins A-J (1-10), together with five known analogues (11-15) were isolated from the soft coral Sarcophyton ehrenbergi. Compounds 4-8 represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (3a, 3b, 4a, and 11a-11c) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 2, 10, 11a, 11b, and 13-15 exhibited inhibition with IC50 values less than 10 ?M, and compound 15 (IC50 = 1.4 ?M) showed comparable activity to the positive control rolipram (IC50 = 0.60 ?M). The active natural PGs (2, 10, and 13-15) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure-activity relationship is also proposed.
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A label-free double-amplification system for sensitive detection of single-stranded DNA and thrombin by liquid chromatography-mass spectrometry.
Chem. Commun. (Camb.)
PUBLISHED: 07-16-2014
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A label-free double amplification system has been developed by using a ternary DNA probe containing the poly(adenine-thymine) sequence assisted by exonuclease III degradation. The method achieved more than 600-fold signal amplification and allowed sensitive detection of single-stranded DNA and thrombin at the pM level by using liquid chromatography/mass spectrometry.
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EGCG decreases the expression of HIF-1? and VEGF and cell growth in MCF-7 breast cancer cells.
J BUON
PUBLISHED: 06-27-2014
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To investigate the effects of epigallocatechin-3-gallate (EGCG) on the expression of HIF-1? and vascular endothelial growth factor (VEGF) and cell growth in MCF-7 breast cancer cells.
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Ubiquitin?specific protease 22?induced autophagy is correlated with poor prognosis of pancreatic cancer.
Oncol. Rep.
PUBLISHED: 06-26-2014
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Ubiquitin?specific protease 22 (USP22) is a component of the transcription regulatory histone acetylation complex SAGA, which broadly regulates gene transcription and correlates with cancer progression, metastasis and prognosis. Autophagy is a cell pathway with dual functions that promotes cell survival or death. However, it is not known whether USP22 can regulate autophagy in pancreatic cancer. In the present study, we first identified that USP22 was overexpressed in a large number of pancreatic cancer patient samples, concomitant with the increased expression of LC3, a marker of autophagy. Statistical analysis revealed that the increase in USP22 and autophagy was positively correlated with poor prognosis of pancreatic cancer patients. Further investigation using a human pancreatic cancer cell (Panc?1) identified that the overexpression of USP22 increased the processing of LC3 into the active form LC3?II and the number of autophagosomes, thus leading to enhanced autophagy. Activation of ERK1/2 kinase rather than AKT1 by USP22 was found to be one of the mechanisms promoting LC3 processing. USP22?induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc?1 cells, therefore expressing an overall effect that promotes cell survival. Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer.
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Signal enhancement of carboxylic acids by inclusion with ?-cyclodextrin in negative high-voltage-assisted laser desorption ionization mass spectrometry.
Rapid Commun. Mass Spectrom.
PUBLISHED: 06-24-2014
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It is difficult to directly analyze carboxylic acids in complex mixtures by ambient high-voltage-assisted laser desorption ionization mass spectrometry (HALDI-MS) in negative ion mode due to the low ionization efficiency of carboxylic acids.
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Reaction and detection click in high-voltage assisted laser desorption ionization mass spectrometry.
Analyst
PUBLISHED: 06-07-2014
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A click reaction (copper-catalyzed azide-alkyne cycloaddition) catalyzed by "naked" copper ions (without ligands) generated in situ from a copper substrate by laser ablation in a high-voltage assisted laser desorption/ionization (HALDI) ion source is demonstrated.
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2,3,5,6-Tetra-fluoro-1,4-bis-({[(thio-phen-2-yl)methyl-idene]amino}-meth-yl)benzene.
Acta Crystallogr Sect E Struct Rep Online
PUBLISHED: 06-04-2014
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In the title compound, C18H12F4N2S2, a bis-thio-phenyl Schiff base ligand with a perifluorinated aromatic core, the complete molecule is generated by crystallographic inversion symmetry. The thio-phene and tetra-fluorinated benzene rings are oriented at a dihedral angle of 77.38?(4)°. The crystal structure exhibits C-H?F hydrogen bonds, resulting in supra-molecular chains along the c-axis direction.
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2,3,5,6-Tetra-fluoro-1,4-bis-({[(5-methyl-thio-phen-2-yl)methyl-idene]amino}-meth-yl)benzene.
Acta Crystallogr Sect E Struct Rep Online
PUBLISHED: 06-01-2014
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The title compound, C20H16F4N2S2, is a flexible bis-thio-phene-type Schiff base ligand with a perfluorinated backbone. The terminal thio-phene rings are almost normal to one another with a dihedral angle of 83.8?(2)°, and they are tilted to the central tetra-fluorinated benzene ring with dihedral angles of 61.2?(2) and 77.7?(1)°. In the crystal, there are ?-? inter-actions involving the benzene ring and the thiophene ring of a symmetry-related molecule with a centroid-centroid separation of 3.699?(3)?Å.
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[Characterization of biocatalysed sulfate reduction in a cathode of microbial electrolysis system].
Huan Jing Ke Xue
PUBLISHED: 05-13-2014
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In order to improve H2 utilization efficiency and to reduce energy consumption during the hydrogenotrophic sulfate reduction process, a two-chambered microbial electrolysis system (MES) with a biocathode was constructed. The performance of MES in terms of sulfate removal and the electron utilization was studied. With an applied voltage of 0.8 V, biocathode removed about 109.8 mg x L(-1) of SO4(2-) from the wastewater within 36 h of operation, and average reductive rate reached 73.2 mg x (L x d)(-1). The highest current density obtained from the MES was 50-60 A x m(-3). The total coulomb efficiency achieved in a cycle was (43.3 +/- 10.7)%, and around 90% of the effective electrons were used by the cathode bacteria for SO4(2-) reduction. During the operation of MES, the major products of SO4(2-) bio-reduction are sulfide and hydrogen sulfide. With an applied voltage of 0.4 V, both the SO4(2-) removal rate and electron output decreased compared with that of 0.8 V; however, the electric charge efficiency obtained by the MES increased and reached 70% when 0.4 V was applied. Meanwhile, ignorable H2 gas was detected at the end of the cycle, indicating bacteria might directly use cathode as the electron donor thus enhanced energy efficiency. The bacteria could use cathode of the MES as electron donor to reduce SO4(2-) effectively, which may provide a new method to lower energy consumption of the hydrogenotrophic sulfate reduction process, making advanced treatment for sulfate containing wastewater more affordable for practical applications.
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Highly sensitive and specific detection of histamine via the formation of a self-assembled magic number cluster with thymine by mass spectrometry.
Analyst
PUBLISHED: 05-07-2014
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A novel method for the detection of histamine (HIM) via the formation of a self-assembled magic number cluster with thymine (T) by electrospray ionization tandem mass spectrometry (ESI-MS/MS) is described. The formation of the magic number cluster [T17 + HIM + 2H](2+) shifts the MS signal of histamine to the interference-free higher mass range and the signal intensity is increased by four orders of magnitude. In addition, the formation of [T17 + HIM + 2H](2+) is highly specific to histamine compared with its metabolite and other similar biogenic amines, which may be attributed to both of its amino and imidazole groups. The linear dynamic range of the method is in the range of 1 nM-20 ?M, and the limit of detection can be as low as 0.1 nM. The feasibility of this method is further demonstrated by the quantitative analysis of histamine in a red wine sample. Since little sample preparation or separation is required before the analysis, this method provides a rapid new way for the sensitive and specific detection of histamine by MS.
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Cisplatin Activates Volume-Sensitive Like Chloride Channels Via Purinergic Receptor Pathways in Nasopharyngeal Carcinoma Cells.
J. Membr. Biol.
PUBLISHED: 04-29-2014
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Cisplatin-based concomitant chemoradiotherapy is considered as the standard treatment for locally advanced nasopharyngeal carcinoma patients. However, the curative efficacy of cisplatin-based chemotherapy is limited because of the occurrence of cisplatin resistance. Some researches indicate that activating the volume-sensitive Cl(-) channel might be a new strategy for the reduction of cisplatin resistance. However, little is known about the activation pathway of the Cl(-) channels activated by cisplatin. In this study, the cisplatin-activated chloride current was investigated using the whole cell patch-clamp technique in the poorly differentiated nasopharyngeal carcinoma cells (CNE-2Z cells), and the activation pathway of the current was also discussed. The results showed that extracellular application of cisplatin activated a Cl(-) current, showing the properties of significant outward rectification, intracellular ATP dependency, and a selectivity sequence of I(-) > Br(-) > Cl(-) > gluconate, and being inhibited by the Cl(-) channel inhibitors tamoxifen and extracellular ATP. These characteristics are similar to those of the volume-sensitive Cl(-) current in CNE-2Z cells, indicating that cisplatin induces the Cl(-) current by activating the volume-sensitive like chloride channel. The cisplatin-activated current was blocked by suramin (a wide-spectrum purinergic antagonist) and RB2 (a relatively selective P2Y antagonist). In addition, the current was depressed by extracellular application of apyrase. The apoptotic volume decrease induced by cisplatin was also attenuated by RB2. P2Y receptors were expressed in CNE-2Z cells. These results suggest that cisplatin can induce a Cl(-) current by activating volume-sensitive like Cl(-) channels through the P2Y purinoceptor pathway.
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The complex jujube genome provides insights into fruit tree biology.
Nat Commun
PUBLISHED: 03-21-2014
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The jujube (Ziziphus jujuba Mill.), a member of family Rhamnaceae, is a major dry fruit and a traditional herbal medicine for more than one billion people. Here we present a high-quality sequence for the complex jujube genome, the first genome sequence of Rhamnaceae, using an integrated strategy. The final assembly spans 437.65?Mb (98.6% of the estimated) with 321.45?Mb anchored to the 12 pseudo-chromosomes and contains 32,808 genes. The jujube genome has undergone frequent inter-chromosome fusions and segmental duplications, but no recent whole-genome duplication. Further analyses of the jujube-specific genes and transcriptome data from 15 tissues reveal the molecular mechanisms underlying some specific properties of the jujube. Its high vitamin C content can be attributed to a unique high level expression of genes involved in both biosynthesis and regeneration. Our study provides insights into jujube-specific biology and valuable genomic resources for the improvement of Rhamnaceae plants and other fruit trees.
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Prenylated coumarins: natural phosphodiesterase-4 inhibitors from Toddalia asiatica.
J. Nat. Prod.
PUBLISHED: 03-05-2014
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Bioassay-guided fractionation of the ethanolic extract of the roots of Toddalia asiatica led to the isolation of seven new prenylated coumarins (1-7) and 14 known analogues (8-21). The structures of 1-7 were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds 1-5, named toddalin A, 3?-O-demethyltoddalin A, and toddalins B-D, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds 1-21 and four modified analogues, 10a, 11a, 13a, and 17a, were screened by using tritium-labeled adenosine 3',5'-cyclic monophosphate ([3H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 3, 8, 10, 10a, 11, 11a, 12, 13, 17, and 21 exhibited inhibition with IC50 values less than 10 ?M. Toddacoumalone (8), the most active compound (IC50=0.14 ?M), was more active than the positive control, rolipram (IC50=0.59 ?M). In addition, the structure-activity relationship and possible inhibitory mechanism of the active compounds are also discussed.
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[Impact of continuous blood purification on T cell subsets in children with severe sepsis].
Zhongguo Dang Dai Er Ke Za Zhi
PUBLISHED: 02-27-2014
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To investigate the impact of continuous blood purification (CBP) on T-cell subsets and prognosis in children with severe sepsis.
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Natural phosphodiesterase-4 (PDE4) inhibitors from Crotalaria ferruginea.
Fitoterapia
PUBLISHED: 02-20-2014
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Bioassay-guided fractionation of the ethanol extract of the Chinese folk medicine Crotalaria ferruginea led to the isolation of a new isoflavonoid, 4'-hydroxy-2'-methylalpinum-isoflavone (1), and eight known analogs (2-9). Their structures were elucidated by spectroscopic analysis. Compounds 1, 2, 5, and 8 showed inhibitory activities against phosphodiesterase-4 (PDE4), a therapeutic target of asthma, with IC50 values ranging from 2.57 to 8.94 ?M. The possible action mechanism and the structure-activity relationship (SAR) of the active isoflavonoids were explored by using molecular docking and molecular dynamics (MD) simulation methods. Our study herein may explain the anti-inflammatory function of this plant in Chinese folk medicine.
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Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure.
Biochem. Pharmacol.
PUBLISHED: 02-12-2014
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Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC?? of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2? resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.
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Regulation of sheep ?-TTP by dietary vitamin E and preparation of monoclonal antibody for sheep ?-TTP.
Gene
PUBLISHED: 01-31-2014
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?-Tocopherol transfer protein (?-TTP) is a cytosolic protein that plays an important role in regulating concentrations of plasma ?-tocopherol (the most bio-active form of vitamin E). Despite the central roles that ?-TTP plays in maintaining vitamin E adequacy, we have only recently proved the existence of the ?-TTP gene in sheep and, for the first time, cloned its full-length cDNA. However, the study of sheep ?-TTP is still in its infancy. In the present study, thirty-five local male lambs of Tan sheep with similar initial body weight were randomly divided into five groups and fed with diets supplemented with 0 (control group), 20, 100, 200, 2000IU·sheep(-1)·d(-1) vitamin E for 120 days. At the end of the experiment, the plasma and liver vitamin E contents were analyzed first and then ?-TTP mRNA and protein expression levels were determined by quantitative real-time PCR (qRT-PCR) and Western-blot analysis, respectively. In addition, as no sheep ?-TTP antibody was available, a specific monoclonal antibody (McAb) against the ovine ?-TTP protein was prepared. The effect of vitamin E supplementation was confirmed by the significant changes in the concentrations of vitamin E in the plasma and liver. As shown by qRT-PCR and Western-blot analysis, dietary vitamin E does not affect sheep ?-TTP gene expression, except for high levels of vitamin E supplementation, which significantly increased expression at the protein level. Importantly, the specific sheep anti-?-TTP McAb we generated could provide optimal recognition in ELISA, Western-blot and immunohistochemistry assays, which will be a powerful tool in future studies of the biological functions of sheep ?-TTP.
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AG-690/11026014, a novel PARP-1 inhibitor, protects cardiomyocytes from AngII-induced hypertrophy.
Mol. Cell. Endocrinol.
PUBLISHED: 01-28-2014
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Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, as a sensor of DNA damage, could convert nicotinamide adenine dinucleotide (NAD) into long poly(ADP-ribose) chains and regulate many cellular processes, including DNA repair, gene transcription, cell survival and chromatin remodeling. However, excessive activation of PARP-1 depletes its substrate NAD and leads to cell death. Mounting evidences have shown that PARP-1 overactivation plays a pivotal role in the pathogenesis of cardiac hypertrophy and heart failure. In present study, a novel PARP-1 inhibitor AG-690/11026014 (6014) was identified based on virtual screening and validated by bioassay. Our results further showed that 6014 prevented the cardiomyocytes from AngII-induced hypertrophy, accompanying attenuation of the mRNA and protein expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and reduce in the cell surface area. Additionally, 6014 reversed the depletion ofcellular NAD and SIRT6 deacetylase activity induced by AngII in cardiomyocytes. These observations suggest that anti-hypertrophic effect of 6014 might be partially attributed to the rescue of NAD depletion and subsequent restoring of SIRT6 activity by inhibition of PARP-1. Moreover, 6014 attenuated the generation of oxidative stress via suppression of NADPH oxidase 2 and 4, which might probably contribute to the inhibition of PARP-1.
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Dietary vitamin E affects ?-TTP mRNA levels in different tissues of the Tan sheep.
Gene
PUBLISHED: 01-21-2014
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The ?-tocopherol transfer protein (?-TTP) is a ~32kDa cytosolic protein that plays an important role in the efficient circulation of plasma ?-tocopherol in the body, a factor with great relevance in reproduction. The ?-TTP gene has been studied in a number of tissues; however, its expression and function in some ovine tissues remain unclear. A previous study from our laboratory has demonstrated ?-TTP expression in sheep liver. In the present study we determined whether ?-TTP is expressed in non-liver tissues and investigated the effects of dietary vitamin E on the ?-TTP mRNA levels. Thirty-five male Tan sheep with similar body weight were randomly allocated into five groups and supplemented 0, 20, 100, 200 and 2000IUsheep(-1)day(-1) vitamin E, for four months, respectively. At the end of the study, the animals were slaughtered and tissue samples from the heart, spleen, lung, kidney, longissimus dorsi muscle and gluteus muscle were immediately collected. We found that the ?-TTP gene is expressed in sheep tissues other than the liver. Moreover, dietary vitamin E levels had influenced the expression levels of ?-TTP gene in these tissues in a tissue-specific way. The technique of immunohistochemistry was used to detect ?-TTP in tissues of the heart, spleen, lung, and kidney and we found that ?-TTP was mainly located in the cytoplasm while no ?-TTP immunoreactivity was detected in the cytoplasm of longissimus dorsi and gluteus muscle samples. Importantly, our findings lay the foundation for additional experiments focusing on the absorption and metabolism of vitamin E in tissues other than the liver.
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miR-132 inhibits colorectal cancer invasion and metastasis via directly targeting ZEB2.
World J. Gastroenterol.
PUBLISHED: 01-13-2014
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To investigate the biological role and underlying mechanism of miR-132 in colorectal cancer (CRC) progression and invasion.
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Six new tetraprenylated alkaloids from the South China Sea gorgonian Echinogorgia pseudossapo.
Mar Drugs
PUBLISHED: 01-13-2014
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Six new tetraprenylated alkaloids, designated as malonganenones L-Q (1-6), were isolated from the gorgonian Echinogorgia pseudossapo, collected in Daya Bay of Guangdong Province, China. The structures of 1-6 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 1-6 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC?? values of 8.5 and 20.3 µM, respectively.
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Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer.
Oncol Lett
PUBLISHED: 01-08-2014
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Changes in the expression of the Notch1 intracellular domain (NICD) and p21 proteins have been shown to be closely associated with the development and progression of a number of cancers. The present study aimed to investigate the expression levels of the two proteins in gastric carcinoma and precancerous lesions, and to determine the clinical significance of this. A total of 109 gastric cancer, 57 precancerous gastric lesion, 50 chronic superficial gastritis and 17 normal gastric mucosa patients were recruited for immunohistochemical staining of NICD and p21 protein expression. The protein expression levels in the gastric cancer patient samples were associated with the clinicopathological and survival data. NICD protein levels were upregulated gradually from normal gastric mucosae through chronic superficial gastritis and precancerous gastric lesions to gastric cancer tissues (P<0.01), whereas p21 protein levels were downregulated accordingly (P<0.01). Increased NICD and a loss of p21 expression were closely associated with tumor dedifferentiation, depth of tumor invasion, lymph node metastasis, surface morphology and Lauren classification in gastric cancer. Thus, NICD expression was inversely associated with p21 expression. In addition, the overall survival rate was greater in NICD(-) and P21(+) patients than in NICD(+) and P21(-) patients, respectively (P<0.05). The COX regression multivariate analysis revealed that NICD(+), p21(-), depth of tumor invasion and lymph node metastasis were all independent prognostic factors for patients with gastric cancer. NICD and p21 proteins are differentially expressed in gastric cancer and the aberrant expression of these proteins is associated with an advanced tumor stage, tumor metastasis and overall patient survival. Future studies are required to further evaluate the two proteins as novel prognostic markers for patients with gastric cancer.
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Protonated primary amines induced thymine quintets studied by electrospray ionization mass spectrometry and density functional theory calculations.
J Mass Spectrom
PUBLISHED: 01-07-2014
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As the novel magic number clusters of nucleobases, the thymine quintets induced by ammonium ion (NH4(+)), and particularly by its derivatives such as protonated alkyl amines and protonated aryl amines, have been studied by electrospray ionization mass spectrometry (ESI-MS) and density functional theory (DFT) calculations. The DFT-optimized geometry of NH4(+) induced thymine quintet ([T5?+?NH4](+)) reveals some new features including three additional hydrogen bonds between NH4(+) and its surrounding thymine molecules when compared with that of the alkali metal ions induced thymine quintets. In addition, the fourth hydrogen atom of NH4(+) is sticking out the assembly, and, thus, it might be replaced by an organic group R to form the protonated primary amine induced thymine quintet ([T5?+?R?-?NH3](+)), a hypothesis that has been confirmed by both DFT calculations and ESI-MS experiments. Furthermore, the relative abilities of the different protonated primary amines for inducing the thymine quintets are investigated by ESI-MS competition experiments, and the results have shown a clear trend of stronger ability as the alkyl chain gets longer or as the aryl ring gets larger for the alkyl amines or the aryl amines. Two basic influence factors are consequently identified: one is the ability of the alkyl amine to accept proton, another is the ?-? stacking interaction between the aryl ring and the ?-surface of the thymine molecule(s), whose explanations are strongly supported by multiple types of thermochemical data, various control experiments and DFT calculations.
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Transcription factor Ets1 regulates expression of thioredoxin-interacting protein and inhibits insulin secretion in pancreatic ?-cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Long-term activation of extracellular-regulated kinase (ERK1/2) pathway has been shown to cause glucotoxicity and inhibit insulin gene expression in ?-cells. Transcription factor Ets1 is activated by ERK1/2-mediated phosphorylation at the Thr38 residue. We hypothesize that Ets1 plays an important role in mediating ERK1/2 induced glucotoxicity in ?-cells. We determined the role of Ets1 in Min6 cells and isolated mouse islets using overexpression and siRNA mediated knockdown of Ets1. The results show that Ets1 was localized in insulin-staining positive cells but not in glucagon-staining positive cells. Overexpression of Ets1 reduced glucose-stimulated insulin secretion in primary mouse islets. Overexpression of Ets1 in Min6 ?-cells and mouse islets increased expression of thioredoxin-interacting protein (TXNIP). Conversely, knockdown of Ets1 by siRNA reduced expression of TXNIP in Min6 cells. Ets1 was associated with the txnip promoter in min6 cells and transfection of 293 cells with Ets1 and p300 synergistically increased txnip promoter reporter activity. Moreover, overexpression of Ets1 inhibited Min6 cell proliferation. Our results suggest that Ets1, by promoting TXNIP expression, negatively regulates ?-cell function. Thus, over-activation of Ets1 may contribute to diet-induced ?-cell dysfunction.
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Pallidal index as biomarker of manganese brain accumulation and associated with manganese levels in blood: a meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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The current study was designed to evaluate the sensitivity, feasibility, and effectiveness of the pallidal index (PI) serving as a biomarker of brain manganese (Mn) accumulation, which would be used as an early diagnosis criteria for Mn neurotoxicity.
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Vulnerability of welders to manganese exposure - A neuroimaging study.
Neurotoxicology
PUBLISHED: 01-01-2014
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Increased manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn exposure occurs in different occupational settings, where the airborne Mn level and the size of respirable particulates may vary considerably. Recently the importance of the role of the cerebral cortex in Mn toxicity has been highlighted, especially in Mn-induced neuropsychological effects. In this study we used magnetic resonance imaging (MRI) to evaluate brain Mn accumulation using T1 signal intensity indices and to examine changes in brain iron content using T2* contrast, as well as magnetic resonance spectroscopy (MRS) to measure exposure-induced metabolite changes non-invasively in cortical and deep brain regions in Mn-exposed welders, Mn-exposed smelter workers and control factory workers with no measurable exposure to Mn. MRS data as well as T1 signal intensity indices and T2* values were acquired from the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. Smelters were exposed to higher air Mn levels and had a longer duration of exposure, which was reflected in higher Mn levels in erythrocytes and urine than in welders. Nonetheless, welders had more significant metabolic differences compared to controls than did the smelter workers, especially in the frontal cortex. T1 hyperintensities in the globus pallidus were observed in both Mn-exposed groups, but only welders showed significantly higher thalamic and hippocampal T1 hyperintensities, as well as significantly reduced T2* values in the frontal cortex. Our results indicate that (1) the cerebral cortex, in particular the frontal cortex, is clearly involved in Mn neurotoxic effects and (2) in spite of the lower air Mn levels and shorter duration of exposure, welders exhibit more extensive neuroimaging changes compared to controls than smelters, including measurable deposition of Mn in more brain areas. These results indicate that the type of exposure (particulate sizes, dust versus fume) and route of exposure play an important role in the extent of Mn-induced toxic effects on the brain.
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Construction and identification of the recombinant lentiviral expression vector targeting human Bax inhibitor-1 gene.
J BUON
PUBLISHED: 12-18-2013
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Purpose: The aim of this study was to construct a recombinant lentiviral expression vector targeting human BAX inhibitor- 1(BI-1) gene and observe its expression in NIH3T3 cells. Methods: Human BI-1 gene was amplified by polymerase chain reaction (PCR), and then cloned into the vector pLCMV- IG using DNA recombinant technique. After the inserted sequences in the recombinant plasmids were identified by PCR, and double digesting and DNA sequencing analysis, the recombinant lentivirus was packaged and administered into NIH3T3 cells. The BI-1 mRNA and protein expression were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Results: PCR double digesting analysis and DNA sequencing confirmed that the BI-1 DNA sequences were successfully inserted into the lentiviral vectors. After transfection with the recombinant lentivirus, BI-1 expression in NIH3T3 cells was significantly increased at both mRNA and protein levels. Conclusion: The lentiviral vector expressing BI-1 has been successfully constructed, which allowed for the subsequent analysis of the role of BI-1 in cell growth and transduction.
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Selaginpulvilins A-D, New Phosphodiesterase-4 Inhibitors with an Unprecedented Skeleton from Selaginella pulvinata.
Org. Lett.
PUBLISHED: 12-12-2013
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Selaginpulvilins A-D (1-4), four new phenols with an unprecedented 9,9-diphenyl-1-(phenylethynyl)-9H-fluorene skeleton, together with four known selaginellins (5-8) were isolated from Selaginella pulvinata. Their structures were elucidated by spectroscopic analysis and chemical correlation. The structure of 1 was confirmed by single-crystal X-ray diffraction. Compounds 1-8 exhibited remarkable inhibitory activities (IC50 values in the range of 0.11-5.13 ?M) against phosphodiesterase-4 (PDE4), a drug target for the treatment of asthma and chronic obstructive pulmonary disease.
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The Molecular Basis for the Selectivity of Tadalafil toward Phosphodiesterase 5 and 6: A Modeling Study.
J Chem Inf Model
PUBLISHED: 11-12-2013
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Great attention has been paid to the clinical significance of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil widely used for erectile dysfunction. However, sildenafil causes side effects on visual functions since it shows similar potencies to inhibit PDE5 and PDE6, whereas tadalafil gives a high selectivity of 1020-fold against PDE6. Till now, their molecular mechanisms of selectivity of PDE5 versus PDE6 have remained unknown in the absence of the crystal structure of PDE6. In order to elucidate its isoform-selective inhibitory mechanism, a 3D model of PDE6 was constructed by homology modeling, and its interaction patterns with tadalafil plus sildenafil were exploited by molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The present work reveals that tadalafil exhibits a less negative predicted binding free energy of -35.21 kcal/mol with PDE6 compared with the value of -41.12 kcal/mol for PDE5, which suggests that tadalafil prefers PDE5 rather than PDE6 and confers a high selectivity for PDE5 versus PDE6. The binding free energy results for tadalafil were consistent with external bioassay studies (IC50 = 5100 and 5 nM toward PDE6 and PDE5, respectively). Two important residues from the Q2 pockets (Val782 and Leu804 in PDE5 and their corresponding Val738 and Met760 in PDE6) were further identified to account for the high selectivity of tadalafil for PDE5 versus PDE6. These findings have shed light on the continuous puzzle of why sildenafil (IC50 = 74 and 6 nM toward PDE6 and PDE5, respectively) causes visual disorders because of its poor selectivity but tadalafil does not. In addition, the homology model of PDE6 can be used to design more potent and selective second-generation PDE5 inhibitors with less inhibitory potency against PDE6.
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Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimers Disease Based on the Fusion of Donepezil and Ebselen.
J. Med. Chem.
PUBLISHED: 11-12-2013
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A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimers disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 ?M for Electrophorus electricus acetylcholinesterase and 0.097 ?M for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 ?M), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (?0 = 123.5 ?M min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.
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Promoter hypermethylation of p14 (ARF) , RB, and INK4 gene family in hepatocellular carcinoma with hepatitis B virus infection.
Tumour Biol.
PUBLISHED: 10-03-2013
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Both hepatitis B virus (HBV) and gene methylation play important roles in hepatocarcinogenesis. However, their association between HBV infection and gene methylation is not fully understood. Cell cycle control involving RB1 gene-related cell inhibitors is one of the main regulatory pathways were reported to be altered in hepatocellular carcinoma (HCC). The purpose of this research is to assess the methylation status of p14 (ARF) and INK4 gene family (p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and p18 (INK4C) ) in HCC with HBV infection and HCC without it, and discuss possible role of HBV-induced hypermethylation in the mechanism of hepatocarcinogenesis. Methylation status of RB, p14 (ARF) , and INK4 gene family in 64 case of HCC with HBV infection and 24 cases without it were detected by methylation-specific polymerase chain reaction, and HBV-DNA of the plasma were detected by quantitative real-time polymerase chain reaction. p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB hypermethylation were observed in 30 (34.1 %), 50 (56.8 %), 62 (70.5 %), and 24(27.3 %) of 88 hepatocellular carcinomas, respectively. Methylation frequencies of them between HCC with HBV infection and HCC without it were 43.8 % versus 8.3 % (p14 (ARF) ), 68.9 % versus 25 % (p15 (INK4B) ), 90.6 % versus 16.7 % ( p16 (INK4A) ), and 28.1 % versus 25 % (RB), respectively. In HBV-associated HCC, the numbers of methylated genes were also more than HCC without virus infection, more than two methylated genes were seen in 48 of 64 (75 %) cases; more than three methylated genes were found in 32 of 64 (50 %); correspondently, no one case has more than two genes methylated. p18 (INK4C) methylation product was not found in cancerous or non-cancerous tissues of 88 HCC. HBV infection is associated with p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB gene methylation (P?=?0.048, 0.035, 0.02); HBV-DNA replication is associated with p14 (ARF) , p15 (INK4B) , p16 (INK4A) , and RB gene methylation (P?=?0.048, 0.035, 0.02); high rate of p14 (ARF) , p15 (INK4B) , and p16 (INK4A) in HCC with HBV infection suggests that HBV-induced hypermethylation may be one of the mechanisms of HBV involved in hepatocellular carcinogenesis.
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[Analysis of soil respiration and influence factors in wheat farmland under conservation tillage in southwest hilly region].
Huan Jing Ke Xue
PUBLISHED: 09-14-2013
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In order to investigate the effect of conservation tillage on soil respiration in dry cropping farmland in southwest purple hilly region, the LI6400-09 respiratory chamber was adopted in the experiment conducted in the experimental field in Southwest University in Beibei, Chongqing. The respiration and the hydrothermal and biotic factors of soil were measured and analyzed during the growth period of wheat in the triple intercropping system of wheat/maize/soybean. There were four treatments including T (traditional tillage), R (ridge tillage), TS (traditional tillage + straw mulching) and RS (ridge tillage + straw mulching), which were all in triplicates. The results indicated that the soil respiration rate changed in the range of 1.100-2.508 micromol x (m2 x s)(-1) during the reproductive growth stage of wheat. There were significant differences in soil respiration rate among different treatments, which could be ranked as RS > R > TS > T. The soil temperature in the 10cm layer was ranked as T > R > TS > RS. The relationship between soil respiration and soil temperature fitted well with an exponential function, in which the Q10 values were 1.25, 1.20, 1.31 and 1.26, respectively. The soil moisture in the 5cm layer was ranked as TS > RS > T > R. The best fitting model between soil moisture and soil respiration was a parabolic curve, indicating the presence of soil moisture with the strongest soil respiration. The response threshold of wheat to soil moisture was 14.80%-17.47% during the reproductive stage. The dominant groups of soil animals were Collembola and Acarina, which were correlated with soil respiration to some extent. The correlation was high in the treatments T and R, ranged from 0.669-0.921, whereas there was no remarkable correlation in the other treatments.
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Design of non-polarizing cut-off filters based on dielectric-metal-dielectric stacks.
Opt Express
PUBLISHED: 08-14-2013
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Cut-off filters are usually operating at oblique incidence and exhibit polarization dependence properties. We propose a simple approach to design cut-off filters with low linear polarization sensitivity (LPS) based on dielectric-metal-dielectric (DMD) stacks. The designing method is derived from the theory of optical film characteristic matrix. The admittance loci of the film are adjusted to achieve similar spectral properties of s- and p-polarized light at oblique incidence. Different film structures are designed non-polarizing at different angles of incidence with the method. The results show that the designing method is efficient for designing non-polarizing cut-off filters, which are widely used in non-polarizing optical system.
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[Effects of drought and re-watering on endogenous hormone contents of cotton roots and leaves under drip irrigation with mulch].
Ying Yong Sheng Tai Xue Bao
PUBLISHED: 08-01-2013
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Under the climatic and ecological conditions of Xingjiang, Northwest China, different degrees of drought stress were installed during the growth stages of cotton, and the drip irrigation with mulch was adopted, aimed to study the effects of drought stress and re-watering on the endogenous hormones (abscisic acid, ABA; and zeatins, ZRs) contents of cotton roots and leaves and the stomatal conductance (gs) of cotton leaves. With the increase of drought stress at different growth stages, the ABA contents of cotton roots and leaves increased, while the ZRs contents of cotton roots and leaves and the gsand photosynthetic rate (Pn) of cotton leaves decreased, with greater decrements in the treatment of soil moisture content being 40% -45% of field capacity at early flowering-full flowering stage. After re-watering, the ABA contents of cotton roots and leaves d:d not have a decrease with the improvement of soil moisture regime, while the ZRs contents of cotton roots recovered rapidly or exceeded the control after 1-3 days of re-watering. There was a positive correlation between the ZRs contents of cotton roots and the gs of cotton leaves. In the treatment of soil moisture content being 50% -55% of field capacity at full budding-early flowering stage, the ZRs contents and gs of cotton leaves recovered more quickly and with greater increments. It was suggested that the higher ZRs contents of cotton roots after re-watering could be the main cause for the higher stomatal conductance and photosynthetic rate of cotton leaves.
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Ghost cell differentiation and calcification in ameloblastic fibroma.
Chin J Dent Res
PUBLISHED: 07-24-2013
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Ghost cell differentiation within an ameloblastic fibroma is extremely rare. The ghost cells found in an ameloblastic fibroma in previously reported cases were all associated with a typical calcifying odontogenic cyst. Here, we report a case of an ameloblastic fibroma with focal ghost cells and calcifications in some neoplastic epithelial islands, but without other histologic manifestations consistent with a calcifying odontogenic cyst. The patient was a 13-year-old Chinese boy who presented with a bony-hard swelling in the posterior mandibular region over a 6-month period. Radiographs showed a well-defined multilocular radiolucency associated with an unerupted tooth. The lesion was mostly cystic-solid and comprised of odontogenic epithelial strands, islands and myxoid ectomesenchymal component microscopically. Small groups of ghost cells and calcification were noted in the epithelial islands.
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Discovery of Bufadienolides as a Novel Class of ClC-3 Chloride Channel Activators with Antitumor Activities.
J. Med. Chem.
PUBLISHED: 07-10-2013
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ClC-3 chloride (Cl(-)) channel has been shown to be involved in cell proliferation, cell cycle, and cell migration processes. Herein, we found that a series of bufadienolides isolated from toad venom were a novel class of ClC-3 Cl(-) channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15?-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl(-) channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl(-) channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl(-) channel blockers [tamoxifen and 5-nitro-2-(3-phenylpropylamino)benzoic acid, NPPB] or ClC-3 small interfereing RNA. In summary, we discovered that activation of the ClC-3 Cl(-) channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides.
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Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimers disease.
J. Med. Chem.
PUBLISHED: 07-08-2013
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A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimers disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced ?-amyloid (A?) aggregation and Cu(II)-induced A?1-42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 ?M and 10d, IC50 = 6.51 ?M for self-induced A? aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured A? fibrils generated by self- and Cu(II)-induced A? aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD.
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[Effects of water and nitrogen management modes on the leaf photosynthetic characters and yield formation of cotton with under-mulch drip irrigation].
Ying Yong Sheng Tai Xue Bao
PUBLISHED: 05-28-2013
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Taking different genotype cotton varieties as test materials, a soil column culture experiment was conducted to study the effects of water and nitrogen management modes on the photosynthetic characters and yield formation of cotton with under-mulch drip irrigation in Xinjiang, Northwest China. Under the management mode W4N2, i.e., pre-sowing irrigation + limited drip irrigation before full-flowering + abundant drip irrigation after full-flowering in combining with basal 20% N + topdressing 80% N, the chlorophyll content, net photosynthetic rate (Pn), stomatal conductance (gs) , actual photochemical efficiency of photosystem II (Psi PSII), and photochemical quenching coefficient (qp) at full-flowering stage all decreased significantly, the non-photochemical quenching (NPQ) increased, and the aboveground dry matter accumulation was inhibited, as compared with those under common drip irrigation. From full-flowering stage to boll-opening stage, the chlorophyll content, gs, Pn, Psi PSII, and qp increased with increasing water and nitrogen supply, and the aboveground dry matter accumulation was enhanced by compensation, which benefited the translocation and distribution of photosynthates to seed cotton. Under the fertilization mode of basal 20% N + topdressing 80% N, the seed cotton yield of Xinluzaol3 was the highest in treatment pre-sowing irrigation + common drip irrigation (W3), but that of Xinluzao43 was the highest in treatment pre-sowing irrigation + limited drip irrigation before full-flowering + abundant drip irrigation after full-flowering (W4). It was concluded that under the condition of pre-sowing irrigation, to appropriately decrease the water and nitrogen supply before full-flowering stage and increase the water and nitrogen supply at middle and late growth stages could extend the active photosynthesis duration and promote the photosynthates allocation to reproductive organ, which would fully exploit the yield-increasing potential of cotton with under-mulch drip irrigation.
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ZD1839 and cisplatin alone or in combination for treatment of a nasopharyngeal carcinoma cell line and Xenografts.
Asian Pac. J. Cancer Prev.
PUBLISHED: 05-18-2013
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This study evaluated the effects of ZD1839, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, on nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Influence of ZD1839 alone or combined with cisplatin on the NPC cell line CNE2 was detected by MTT assay with flow cytometry assessment of cell cycle distribution and apoptosis rates. Nude mice NPC xenografts were also used to evaluate the effects of ZD1839 alone or combined with cisplatin. The Students t test evaluated statistical significance. ZD1839 alone or combined with cisplatin inhibited CNE2 cell line proliferation. ZD1839 induced CNE2 cell cycle arrest in the G1 phase, and higher concentrations induced apoptosis. Xenograft tumors were significantly smaller when treated with 200 mg/kg ZD1839, cisplatin, or cisplatin combined with 100 mg/kg ZD1839 than untreated controls. ZD1839 (200 mg/kg) alone showed good tumor inhibition effects, reduction of tumor weights, and smaller tumor volume without loss of body weight. ZD1839 (200 mg/kg) might provide a good and effective therapeutic reagent for NPC.
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The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.
Biochim. Biophys. Acta
PUBLISHED: 05-10-2013
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The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2,3,5,5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0?M, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (?RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.
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Biophysical analysis of the putative acetyltransferase SACOL2570 from methicillin-resistant Staphylococcus aureus.
J. Struct. Funct. Genomics
PUBLISHED: 04-12-2013
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Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of a myriad of insidious and intractable infections in humans, especially in patients with compromised immune systems and children. Here, we report the apo- and CoA-bound crystal structures of a member of the galactoside acetyltransferase superfamily from methicillin-resistant S. aureus SACOL2570 which was recently shown to be down regulated in S. aureus grown in the presence of fusidic acid, an antibiotic used to treat MRSA infections. SACOL2570 forms a homotrimer in solution, as confirmed by small-angle X-ray scattering and dynamic light scattering. The protein subunit consists of an N-terminal alpha-helical domain connected to a C-terminal L?H domain. CoA binds in the active site formed by the residues from adjacent L?H domains. After determination of CoA-bound structure, molecular dynamics simulations were performed to model the binding of AcCoA. Binding of both AcCoA and CoA to SACOL2570 was verified by isothermal titration calorimetry. SACOL2570 most likely acts as an acetyltransferase, using AcCoA as an acetyl group donor and an as-yet-undetermined chemical moiety as an acceptor. SACOL2570 was recently used as a scaffold for mutations that lead the generation of cage-like assemblies, and has the potential to be used for the generation of more complex nanostructures.
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Effect of bulking agents on maturity and gaseous emissions during kitchen waste composting.
Chemosphere
PUBLISHED: 03-29-2013
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This study investigated the effect of bulking agents on the maturity and gaseous emissions of composting kitchen waste. Three different bulking agents (cornstalks, sawdust, and spent mushroom substrate) were used to compost kitchen waste under aerobic conditions in 60-L reactors for a 28-d period. A control treatment was also studied using kitchen waste without a bulking agent. During the experiment, maturity indexes such as temperature, pH value, C/N ratio, and germination index were determined, and continuous measurements of leachate and gaseous emissions (CH?, N?O, and NH?) were taken. The results showed that all of the composts with bulking agents reached the required maturity standard, and the addition of spent mushroom substrate gave the highest maturity (C/N ratio decreased from 23 to 16 and germination index increased from 53% to 111%). The bulking agents also reduced leachate production and CH? and N?O emissions, but had little impact on NH3 emissions. Composting with sawdust as a bulking agent was found to emit less total greenhouse gas (33 kg CO?-eqt(-1) dry matter) than the other treatments.
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Identification of novel phosphodiesterase-4D inhibitors prescreened by molecular dynamics-augmented modeling and validated by bioassay.
J Chem Inf Model
PUBLISHED: 03-29-2013
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Phosphodiesterase-4D (PDE4D) has been proved to be a potential therapeutic target against strokes. In the present study, a procedure of integrating pharmacophore, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and finally validation with bioassay was developed and described to search for novel PDE4D inhibitors from the SPECS database. Among the 29 compounds selected by our MD-augmented strategy, 15 hits were found with IC50 between 1.9 and 50 ?M (a hit rate of 52%) and 6 potent hits showed IC50 less than 10 ?M, which suggested that MD simulations can explore the intermolecular interactions of PDE4D-inhibitor complexes more precisely and thus significantly enhanced the hit rate of this screening. The effective and efficient integrated procedures described in this study could be readily applied to screening studies toward other drug targets.
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[Changes in T cell subsets in children with sepsis, and their clinical significance].
Zhongguo Dang Dai Er Ke Za Zhi
PUBLISHED: 03-19-2013
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To observe changes in T cell subsets in children with sepsis and their prognosis, and to investigate the clinical significance of these changes in the occurrence and development of sepsis.
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The ClC-3 chloride channel associated with microtubules is a target of paclitaxel in its induced-apoptosis.
Sci Rep
PUBLISHED: 03-08-2013
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Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl(-) channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with ?-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation.
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Quantification of serum HBXAP DNA in lung cancer patients by quantitative fluorescent polymerase chain reaction.
Mol. Biol. Rep.
PUBLISHED: 03-02-2013
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Hepatitis B virus x associated protein (HBXAP), as a subunit of chromatin remodeling and spacing factor, plays a critical role in cancer development through gene amplification. In this study, we aimed to quantify the levels of serum HBXAP DNA, to analyze and compare its diagnostic value with existing clinical parameters in lung cancer, and to potentially provide a novel tumor marker for lung cancer. Serum HBXAP DNA from 65 lung cancer patients and 20 healthy controls was quantified using real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) analysis. The data were analyzed by statistical software SPSS 13.0. We found that serum HBXAP DNA levels in lung cancer patients were higher compared to healthy controls (u = 219.0, p = 0.001) and were closely associated with TNM stage and lymph node metastasis (p = 0.015 and p = 0.016, respectively). However, serum HBXAP DNA levels were not associated with patient age, gender, smoking status, histological type, or tumor size (p > 0.05). We identified a sensitivity of 61.9 % and a specificity of 93.7 % for the ability of HBXAP DNA levels to detect lung cancer at a cutoff value of 1,557.6 copies/?l. The sensitivity for existing lung-tumor markers, such as squamous cell carcinoma antigen, cytokeratin fragment 21-1, and neuron specific enolase, was increased from 35.7 %, 53.5 %, and 56.0 % to 75.0 %, 86.0 %, and 80.0 %, respectively, by inclusion of serum HBXAP DNA. Taken together, quantification of serum HBXAP DNA by FQ-PCR could potentially serve as a novel complementary tool for the clinical screening and detection of lung cancer.
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Involvement of volume-activated chloride channels in H2O 2 preconditioning against oxidant-induced injury through modulating cell volume regulation mechanisms and membrane permeability in PC12 Cells.
Mol. Neurobiol.
PUBLISHED: 02-26-2013
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The functions of chloride channels in preconditioning-induced cell protection remain unclear. In this report, we show that the volume-activated chloride channels play a key role in hydrogen peroxide (H2O2) preconditioning-induced cell protection in pheochromocytoma PC12 cells. The preconditioning with 100 ?M H2O2 for 90 min protected the cells from injury induced by long period exposure to 300 ?M H2O2. The protective effect was attenuated by pretreatment with the chloride channel blockers, 5-nitro-2-3-phenylpropylamino benzoic acid (NPPB) and tamoxifen. H2O2 preconditioning directly activated a chloride current, which was moderately outward-rectified and sensitive to the chloride channel blockers and hypertonicity-induced cell shrinkage. H2O2 preconditioning functionally up-regulated the activities of volume-activated chloride channels and enhanced the regulatory volume decrease when exposure to extracellular hypotonic challenges. In addition, acute application of H2O2 showed distinctive actions on cell volume and membrane permeability in H2O2 preconditioned cells. In H2O2 preconditioned cells, acute application of 300 ?M H2O2 first promptly induced a decrease of cell volume and enhancement of cell membrane permeability, and then, cell volume was maintained at a relatively stable level and the facilitation of membrane permeability was reduced. Conversely, in control cells, 300 ?M H2O2 induced a slow but persistent apoptotic volume decrease (AVD) and facilitation of membrane permeability. H2O2 preconditioning also significantly up-regulated the expression of ClC-3 protein, the molecular candidate of the volume-activated chloride channel. These results suggest that H2O2 preconditioning can enhance the expression and functional activities of volume-activated chloride channels, thereby modulate cell volume and cell membrane permeability, which may contribute to neuroprotection against oxidant-induced injury.
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Direct analysis of samples under ambient condition by high-voltage-assisted laser desorption ionization mass spectrometry in both positive and negative ion mode.
Rapid Commun. Mass Spectrom.
PUBLISHED: 02-16-2013
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With the rapid development of ambient mass spectrometry, the hybrid laser-based ambient ionization methods which can generate multiply charged ions of large biomolecules and also characterize small molecules with good signal-to-noise in both positive and negative ion modes are of particular interest.
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Laser desorption dual spray post-ionization mass spectrometry for direct analysis of samples via two informative channels.
J Mass Spectrom
PUBLISHED: 02-05-2013
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A laser desorption dual spray post-ionization mass spectrometry method is described, and its usefulness is demonstrated with the examples of selective detection of food components, manipulation of protein charge state distribution and investigation on the formation of magic number clusters. The method is carried out by adopting two spray emitters for post-ionization of analytes desorbed by a pulsed infrared laser. Various components in a complex sample or distinct behavior of an analyte in two different spray reagents can be rapidly probed by the method quasi-simultaneously, highlighting the potential applications of this method for protein characterization, reaction study and food analysis.
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3D-QSAR studies of azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives as anti-AChE and anti-AD agents by the CoMFA method.
J. Mol. Graph. Model.
PUBLISHED: 02-04-2013
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In the present study, a series of novel azaoxoisoaporphine derivatives were reported and their inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and A? aggregation were evaluated. The new compounds remained high inhibitory potency on A? aggregation, with inhibitory activity from 29.42% to 89.63% at a concentration of 10?M, but had no action on AChE or BuChE, which was very different from our previously reported oxoaporphine and oxoisoaporphine derivatives. By 3D-QSAR studies, we constructed a reliable CoMFA model (q(2)=0.856 and r(2)=0.986) based on the inhibitory activities toward AChE and discovered key information on structure and anti-AChE activities among the azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives. The model was further confirmed by the test-set validation (q(2)=0.873, r(2)=0.937, and slope k=0.902) and Y-randomization examination. The statistically significant and physically meaningful 3D-QSAR/CoMFA model provided better insight into understanding the inhibitory behaviors of those chemicals, which may provide useful information for the rational molecular design of azaoxoisoaporphine derivatives anti-AChE and anti-AD agents.
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Clinical significance of serum transforming growth factor-?1 in lung cancer.
Cancer Epidemiol
PUBLISHED: 01-17-2013
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Transforming growth factor-?1 (TGF-?1) plays a critical role in human cancer development. Present study aimed to explore the clinical significance of serum TGF-?1 levels in patients with lung cancer and analyze the relationship between TGF-?1 and existing tumor markers for lung cancer.
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miR-125b regulates side population in breast cancer and confers a chemoresistant phenotype.
J. Cell. Biochem.
PUBLISHED: 01-09-2013
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Resistance to chemotherapy is a major obstacle for the effective treatment of breast cancer and is partially due to the presence of drug resistant stem cell-like side population (SP). Previous studies have shown elevated miR-125b is associated with chemoresistance and metastasis; however, the relationship between miR-125b and SP cells remains unknown. In this study, we isolated and characterized SP cells in a panel of breast cancer cell lines and primary cancer cells from breast cancer patients. SP cells showed cancer stem cells (CSCs) properties, including self-renewal, resistance to chemotherapy and high expression of stem cell markers. The percentage of SP cells was higher in chemotherapy resistant patients compared to that in chemotherapy responsive patients (5.8 ± 2.4% in non-responsive patients vs. 1.2 ± 0.5% in responsive patients, P = 0.012). Importantly, SP cells had higher level of miR-125b than NSP cells and the elevated miR-125b expression in chemoresistant cancer cells were due to high percentage of SP cells. Overexpression of miR-125b correlated with an increase in tumor SP and CSC property, whereas knockdown of miR-125b correlated with decreased incidence of SP. In addition, miR-125b overexpression in breast cancer cells induced epithelial-mesenchymal transition (EMT)-like cellular marker alteration, suggesting a potential mechanism of miR-125b in the regulation of cancer stem-like SP cells. Taken together, these results suggest an important role for miR-125b in breast cancer chemoresistance by maintaining cancer stem-like SP fraction, and raise the possibility that miR-125b may be a significant prognostic response marker for cancer therapy.
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PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review.
PLoS ONE
PUBLISHED: 01-01-2013
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The keratocystic odontogenic tumor (KCOT) is a locally aggressive cystic jaw lesion that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). PTCH1, the gene responsible for NBCCS, may play an important role in sporadic KCOTs. In this study, we analyzed and compared the distribution pattern of PTCH1 mutations in patients with sporadic and NBCCS-associated KCOTs.
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Angiotensin II facilitates fibrogenic effect of TGF-?1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II.
PLoS ONE
PUBLISHED: 01-01-2013
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Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isnt fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-?1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-?1 inhibitory pseudo-receptor-BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-?1 and LPS on collagen 1? production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-?1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-?1 were used. We also found that only LPS and TGF-?1 werent enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-?1. Angiotensin II, LPS and TGF-?1 act synergistically during hepatic fibrogenesis, showing crosstalks between angiotensin II-AT1, LPS-TLR4 and TGF-?1-BAMBI signal pathways in rat HSCs.
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[Quantitative spectrum analysis of characteristic gases of spontaneous combustion coal].
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 11-22-2011
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Aimed at the characteristics of spontaneous combustion gas such as a variety of gases, lou limit of detection, and critical requirement of safety, Fourier transform infrared (FTIR) spectral analysis is presented to analyze characteristic gases of spontaneous combustion In this paper, analysis method is introduced at first by combing characteristics of absorption spectra of analyte and analysis requirement. Parameter setting method, sample preparation, feature variable abstract and analysis model building are taken into consideration. The methods of sample preparation, feature abstraction and analysis model are introduced in detail. And then, eleven kinds of gases were tested with Tensor 27 spectrometer. CH4, C2H6, C3H8, iC4H10, nC4H10, C2 H4, C3 H6, C3 H2, SF6, CO and CO2 were included. The optical path length was 10 cm while the spectra resolution was set as 1 cm(-1). The testing results show that the detection limit of all analytes is less than 2 x 10(-6). All the detection limits fit the measurement requirement of spontaneous combustion gas, which means that FTIR may be an ideal instrument and the analysis method used in this paper is competent for spontaneous combustion gas measurement on line.
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Molecular cloning and characterization of the sheep ?-TTP gene and its expression in response to different vitamin E status.
Gene
PUBLISHED: 10-21-2011
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The ?-tocopherol transfer protein (?-TTP) is a ~32 kDa protein that exhibits a marked ligand specificity and selectively recognizes of ?-tocopherol, which is the most active form of vitamin E. The ?-TTP gene has been cloned and its physiological functions have been studied in numbers of species, however, the understanding of sheep ?-TTP is still in his infancy. In this study, the full-length cDNA of sheep ?-TTP gene was cloned from sheep liver by using of rapid amplification of complementary DNA ends (RACE). As a result, the sheep ?-TTP gene was 1098 bp in nucleotide which contained 23 bp 5-untranslated region (UTR), 226 bp 3-UTR and 849 bp open reading frame (ORF) that encoded a basic protein of 282 amino acids. Further bioinformatic analysis indicated that the sheep ?-TTP gene had a high homologous of both nucleotide and amino acid sequences compared with that of other species and had a Sec14p-like lipid-binding domain which called the CRAL-TRIO domain. Moreover, the expression of sheep ?-TTP mRNA and protein in response to different vitamin E supplemented levels were observed according to quantitative real-time PCR (qRT-PCR) and Western blotting analysis. The results showed that dietary vitamin E levels did not affect ?-TTP mRNA expression significantly while the low vitamin E supplemented level groups of sheep had significantly higher ?-TTP protein compared to high-vitamin E groups.
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[Design of high performance DSP-based gradient calculation module for MRI].
Zhongguo Yi Liao Qi Xie Za Zhi
PUBLISHED: 09-30-2011
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A gradient calculation module based on high performance DSP was designed to meet the needs of digital MRI spectrometer. According to the requirements of users, this apparatus can achieve rotation transformation, pre-emphasis, shimming and other gradient calculation functions in a single chip of DSP. It then outputs gradient waveform data of channel X, Y, Z and shimming data of channel B0. Experiments show that the design has good versatility and can satisfy the functional, speed and accuracy requirements of MRI gradient calculation. It provides a practical gradient calculation solution for the development of digital spectrometer.
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Stanozolol regulates proliferation of growth plate chondrocytes via activation of ERalpha in GnRHa-treated adolescent rats.
J. Pediatr. Endocrinol. Metab.
PUBLISHED: 08-10-2011
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Improving the final adult height is one of the most important aims for treatment of central precocious puberty. Stanozolol (ST) is a synthetic derivative of androgen. In this study, we investigated the effects and the mechanisms of ST on the proliferation of growth plate chondrocytes isolated from adolescent rats treated with gonadotropin-releasing hormone analogue (GnRHa). Treatment with ST resulted in time- and concentration-dependent effects on proliferation as determined by MTT and proliferating cell nuclear antigen (PCNA) assays. Western blotting showed that ST increased the phosphorylation level of the estrogen receptor alpha (ERalpha), but not the androgen receptor (AR). Pharmacological inhibition of ERalpha and mitogen-activated protein kinase (MAPK) attenuated the effects of ST on the proliferation of growth plate chondrocytes. A molecular dynamics simulation showed hydrophobic interactions between ST and ERalpha. These results suggested that ERalpha, but not AR, partially mediates the ST-driven proliferation of growth plate chondrocytes, and that multiple pathways may be involved in the mechanism of action of ST.
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Impact of planarity of unfused aromatic molecules on G-quadruplex binding: learning from isaindigotone derivatives.
Org. Biomol. Chem.
PUBLISHED: 08-02-2011
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G-quadruplex structures are a new class of attractive targets for DNA-interactive anticancer agents. The primary building block of this structure is the G-quartet, which is composed of four coplanar guanines and serves as the major binding site for small molecules. NMR studies and molecular dynamics simulations have suggested that the planarity of G-quartet surface has been highly dynamic in solution. To better investigate how the planarity of unfused aromatic ligand impacts on its quadruplex binding properties, a variety of planarity controllable isaindigotone derivatives were designed and synthesized. The interaction of G-quadruplex DNA with these designed ligands was systematically explored using a series of biophysical studies. The FRET-melting, SPR, and CD spectroscopy results showed that reducing the planarity of their unfused aromatic core resulted in their decreased binding affinity and stabilization ability for G-quadruplex. NMR studies also suggested that these compounds could stack on the G-quartet surface. Such results are in parallel with subsequent molecular modeling studies. A detailed binding energy analysis indicated that van der Waals energy (?E(vdw)) and entropy (T?S) are responsible for their decreased quadruplex binding and stabilization effect. All these results provided insight information about how quadruplex recognition could be controlled by adjusting the planarity of ligands, which shed light on further development of unfused aromatic molecules as optimal G-quadruplex binding ligands.
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[Effect of sodium para-aminosalicylic on concentrations of amino acid neurotransmitters in basal ganglia of manganese-exposed rats].
Zhonghua Yu Fang Yi Xue Za Zhi
PUBLISHED: 07-16-2011
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To probe the effect of sodium para-aminosalicylate (PAS-Na) on concentration of amino acid neurotransmitters including glutamate (Glu), glutamine (Gln), glycine (Gly) and gamma-aminobutyric acid (GABA) in basal ganglia of subacute manganese (Mn)-exposed rats.
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Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population.
DNA Cell Biol.
PUBLISHED: 06-11-2011
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Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR]?= 0.51, 95% confidence interval [CI]: 0.31-0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53-0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma.
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A new protocol for predicting novel GSK-3? ATP competitive inhibitors.
J Chem Inf Model
PUBLISHED: 06-09-2011
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Glycogen synthase kinase 3? (GSK-3?) is a potential therapeutic target for cancer, type-2 diabetes, and Alzheimers disease. This paper proposes a new lead identification protocol that predicts new GSK-3? ATP competitive inhibitors with topologically diverse scaffolds. First, three-dimensional quantitative structure-activity relationship (3D QSAR) models were built and validated. These models are based upon known GSK-3? inhibitors, benzofuran-3-yl-(indol-3-yl) maleimides, by means of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Second, 28?826 maleimide derivatives were selected from the PubChem database. After filtration via Lipinskis rules, 10?429 maleimide derivatives were left. Third, the FlexX-dock program was employed to virtually screen the 10?429 compounds against GSK-3?. This resulted in 617 virtual hits. Fourth, the 3D QSAR models predicted that from the 617 virtual hits, 93 compounds would have GSK-3? inhibition values of less than 15 nM. Finally, from the 93 predicted active hits, 23 compounds were confirmed as GSK-3? inhibitors from literatures; their GSK-3? inhibition ranged from 1.3 to 480 nM. Therefore, the hits rate of our virtual screening protocol is greater than 25%. The protocol combines ligand- and structure-based approaches and therefore validates both approaches and is capable of identifying new hits with topologically diverse scaffolds.
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Thymine quintets and their higher order assemblies studied by electrospray ionization mass spectrometry and theoretical calculation.
J Mass Spectrom
PUBLISHED: 06-02-2011
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We previously reported that thymine molecules can specifically form a pentameric magic number cluster named as thymine quintet in the presence of K(+) , Rb(+) and Cs(+) . Actually, thymine decamer and doubly charged thymine 15-mer metaclusters can be observed along with thymine quintet in the ESI mass spectra of thymine with the addition of K(+) , Rb(+) and Cs(+) . The product ion spectra of these metaclusters, especially the 15-mer with hetero central ions, indicate that they are higher order assemblies of thymine quintets. The collision-induced dissociation experiments show that the gas-phase stabilities of these metaclusters depend on the size of the central ions, following the order Cs(+) > Rb(+) > K(+) , while K(+) leads to the highest dissociation energy of a thymine quintet. The optimized structures of thymine quintet and decamer were provided by density functional theory calculations, which showed that thymine quintet is bowl-shaped and its tilting angle increases with the size of the central ion. Furthermore, the chirality of thymine quintet was defined for the first time and the resulting different diastereoisomers of thymine decamers were also revealed by the calculation study. Copyright © 2011 John Wiley & Sons, Ltd.
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[Effects of low level manganese exposure on the serum neuroendocrine hormones in the welders].
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi
PUBLISHED: 05-31-2011
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To study the effects of low level manganese (Mn) exposure on the serum neuroendocrine hormones levels of the welders.
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One-pot synthesis of sustained-released doxorubicin silica nanoparticles for aptamer targeted delivery to tumor cells.
Nanoscale
PUBLISHED: 05-27-2011
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Site-specific delivery of drugs can significantly reduce drug toxicity and increase the therapeutic effect. Here, we report a one-pot synthesis of doxorubicin-doped silica nanoparticles (Dox/SiNPs) by using sodium fluoride (NaF) catalyzed hydrolysis of tetraethyl orthosilicate in a water-in-oil microemulsion. Through further surface chemical modification, carboxyl-terminated Dox/SiNPs (COOH-Dox/SiNPs) exhibiting high drug entrapment efficiency, strong fluorescence and long sustained release are obtained. Cell toxicity tests demonstrate that the COOH-Dox/SiNPs kill tumor cells effectively, while pure COOH-SiNPs are nontoxic. An aptamer is further conjugated to the nanoparticles for delivering loaded Dox to target cells. It is demonstrated that Dox/SiNPs modified with the aptamer sgc8c (sgc8c-Dox/SiNPs) could deliver loaded doxorubicin to CCRF-CEM cells with high specificity and excellent efficiency. Furthermore, ex vivo imaging studies show that the COOH-Dox/SiNPs are able to accumulate highly in the tumor areas, thanks to the enhanced permeability and retention (EPR) effects. Our data suggest that the sgc8c-Dox/SiNPs may be a useful new tumor therapy system.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.