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Find video protocols related to scientific articles indexed in Pubmed.
Strong type 1, but impaired type 2, immune responses contribute to Orientia tsutsugamushi-induced pathology in mice.
PLoS Negl Trop Dis
PUBLISHED: 09-01-2014
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Scrub typhus is a neglected, but important, tropical disease, which puts one-third of the world's population at risk. The disease is caused by Orientia tsutsugamushi, an obligately intracellular Gram-negative bacterium. Dysregulation in immune responses is known to contribute to disease pathogenesis; however, the nature and molecular basis of immune alterations are poorly defined. This study made use of a newly developed murine model of severe scrub typhus and focused on innate regulators and vascular growth factors in O. tsutsugamushi-infected liver, lungs and spleen. We found no activation or even reduction in base-line expression for multiple molecules (IL-7, IL-4, IL-13, GATA3, ROR-?t, and CXCL12) at 2, 6 and 10 days post-infection. This selective impairment in type 2-related immune responses correlated with a significant activation of the genes for IL-1?, IL-6, IL-10, TNF-?, IFN-?, as well as CXCR3- and CXCR1-related chemokines in inflamed tissues. The elevated angiopoietin (Ang)-2 expression and Ang-2/Ang-1 ratios suggested excessive inflammation and the loss of endothelial integrity. These alterations, together with extensive recruitment of myeloperoxidase (MPO)-expressing neutrophils and the influx of CD3+ T cells, contributed to acute tissue damage and animal death. This is the first report of selective alterations in a panel of immune regulators during early O. tsutsugamushi infection in intravenously inoculated C57BL/6 mice. Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation.
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Displacement back analysis for a high slope of the Dagangshan Hydroelectric Power Station based on BP neural network and particle swarm optimization.
ScientificWorldJournal
PUBLISHED: 07-20-2014
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The right bank high slope of the Dagangshan Hydroelectric Power Station is located in complicated geological conditions with deep fractures and unloading cracks. How to obtain the mechanical parameters and then evaluate the safety of the slope are the key problems. This paper presented a displacement back analysis for the slope using an artificial neural network model (ANN) and particle swarm optimization model (PSO). A numerical model was established to simulate the displacement increment results, acquiring training data for the artificial neural network model. The backpropagation ANN model was used to establish a mapping function between the mechanical parameters and the monitoring displacements. The PSO model was applied to initialize the weights and thresholds of the backpropagation (BP) network model and determine suitable values of the mechanical parameters. Then the elastic moduli of the rock masses were obtained according to the monitoring displacement data at different excavation stages, and the BP neural network model was proved to be valid by comparing the measured displacements, the displacements predicted by the BP neural network model, and the numerical simulation using the back-analyzed parameters. The proposed model is useful for rock mechanical parameters determination and instability investigation of rock slopes.
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An Ru(II)-Fe(III) bimetallic complex as a multifunctional device for detecting, signal amplifying, and degrading oxalate.
Analyst
PUBLISHED: 07-03-2014
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A tetranuclear bimetallic complex, [Ru(II)((t)Bubpy)(CN)4]2-[Fe(III)(H2O)3Cl]2·8H2O (1) has been synthesized and characterized. It was found to be a multifunctional device that can detect, signal amplify, and degrade an organic pollutant, oxalate. Results of the chemosensing studies of 1 toward common anions show that only oxalate selectively induces naked-eye colorimetric and luminometric responses with method detection limits down to 78.7 and 5.5 ppm, respectively from 1. Meanwhile, results of the photo-degradation studies of 1 toward oxalate show that the dissolved organic carbon content of oxalate decreased and reached complete mineralization into CO2 within 6 hours. Complex 1 was also found as the catalyst that amplified the detection signal toward oxalate. Through the photoassisted Fenton reaction by 1, methyl orange, an additional coloring agent, could be degraded so that the visual detection limit of 1 toward oxalate was magnified 50 times from 100 to 2 ppm. The detection, degradation, mineralization and signal amplification were found applicable in real water bodies such as river, pond and underground water with excellent recoveries and relative standard deviation.
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A hematogenously disseminated Orientia tsutsugamsushi-infected murine model of scrub typhus.
PLoS Negl Trop Dis
PUBLISHED: 07-01-2014
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Orientia tsutsugamushi, the etiologic agent of scrub typhus, is a mite-borne rickettsia transmitted by the parasitic larval stage of trombiculid mites. Approximately one-third of the world's population is at risk of infection with Orientia tsutsugamushi, emphasizing its importance in global health. In order to study scrub typhus, Orientia tsutsugamushi Karp strain has been used extensively in mouse studies with various inoculation strategies and little success in inducing disease progression similar to that of human scrub typhus. The objective of this project was to develop a disease model with pathology and target cells similar to those of severe human scrub typhus. This study reports an intravenous infection model of scrub typhus in C57BL/6 mice. This mouse strain was susceptible to intravenous challenge, and lethal infection occurred after intravenous inoculation of 1.25 × 10(6) focus (FFU) forming units. Signs of illness in lethally infected mice appeared on day 6 with death occurring ? 6 days later. Immunohistochemical staining for Orientia antigens demonstrated extensive endothelial infection, most notably in the lungs and brain. Histopathological analysis revealed cerebral perivascular, lymphohistiocytic infiltrates, focal hemorrhages, meningoencephalitis, and interstitial pneumonia. Disseminated infection of endothelial cells with Orientia in C57BL/6 mice resulted in pathology resembling that of human scrub typhus. The use of this model will allow detailed characterization of the mechanisms of immunity to and pathogenesis of O. tsutsugamushi infection.
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MicroRNA expression profile in myocardial bridging patients.
Scand. J. Clin. Lab. Invest.
PUBLISHED: 05-30-2014
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Abstract Background. Myocardial bridging (MB), a common benign coronary anomaly, may bring about some unwanted complications such as angina-like chest pain. The only way of MB detection is coronary arteriography or coronary computed tomographic angiography, which is costly and invasive. This study intended to profile a panel of circulating microRNAs (miRNAs) as potential biomarkers for the diagnosis of MB. Methods. Using TaqMan Low-Density Array followed by quantitative reverse transcriptase PCR (qRT-PCR) validation, we analyzed the expression of miRNAs in serum samples from 90 MB patients and 50 non-MB controls. Results. The Low-Density Array data showed that 196 miRNAs were differentially expressed in MB patient sera in comparison with controls. After qRT-PCR validation and receiver operating characteristic (ROC) analysis, a list of five miRNAs (miR-29b, miR-151-3p, miR-126, miR-503-3p and miR-645) showed the ability to distinguish MB patients from controls. The area under curve (AUC) values range from 0.722-0.938. Conclusions. We have demonstrated that this panel of five serum miRNAs is expected to become potential non-invasive biomarkers for detection of MB.
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Chemodosimetric analysis in food-safety monitoring: design, synthesis, and application of a bimetallic Re(I)-Pt(II) complex for detection of dimethyl sulfide in foods.
Analyst
PUBLISHED: 05-21-2014
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Detection of neutral biogenic sulfides plays a crucial role in food safety. A new heterobimetallic Re(I)-Pt(II) donor-acceptor complex--[Re(biq)(CO)3(CN)]-[Pt(DMSO)(Cl)2] (1, biq = 2,2'-biquinoline)--was synthesized and characterized. The X-ray crystallographic and photophysical data for 1 are reported in this study. Complex 1 indicated the luminescent chemodosimetric selectivity for dimethyl sulfide, which persisted even in the presence of a variety of interfering vapors, with a detection limit as low as 0.96 ppm. The binding constant (log?K) of 1 toward dimethyl sulfide was 3.63 ± 0.03. The analyte selectivity of the complexes was found to be dependent on the ligand coordinated to the Re(I) center. Real samples (beef, chicken, and pork) were monitored real-time for gaseous dimethyl sulfide. Complex 1 shows a linear spectrofluorimetric response with increasing storage time of the meats at 30 °C.
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Effects of individual and multiple fatty acids (palmitate, oleate and docosahaexenoic acid) on cell viability and lipid metabolism in LO2 human liver cells.
Mol Med Rep
PUBLISHED: 05-09-2014
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This study was designed to investigate the direct effects of fatty acids (FAs) on the cell viability and the expression levels of genes involved in lipid metabolism in LO2 human liver cells. Palmitate (PA), oleate (OA) and docosahaexenoic acid (DHA) were used to represent saturated, mono-unsaturated and polyunsaturated FAs, respectively. At concentrations of ?3.2 µg/ml, treatment with single FAs increased the viability of the LO2 cells. At FA concentrations of >3.2 µg/ml, cell viability following OA treatment was increased, but PA or DHA treatment at these concentrations reduced cell viability. Administration of mixtures of these FAs in three ratios (PA:OA:DHA = 1:2:1, 1:1:1 and 1:1:2, respectively) increased the cell viability compared with the control group. The intracellular triglyceride (TG) levels following all types of treatment were significantly increased and the accumulation of TGs was markedly increased with high doses of DHA. In addition, peroxisome proliferator-activated receptor-? was significantly upregulated in all groups, with the exception of the 1:1:1 group at 3.2 µg/ml and the 1:1:2 group at 12.8 µg/ml. The expression levels of sterol regulatory-element binding protein?1c, liver X receptor ? and apolipoprotein C?I were significantly reduced in all groups with the exception of the DHA?treated group and the 1:2:1 groups at 3.2 and 12.8 µg/ml. In conclusion, these results indicate that the type, concentration and mixture ratios of FAs are all important in determining the cell viability and lipid metabolism-related gene expression in LO2 hepatocytes.
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Effects of 5-hydroxymethyl furfural extracted from Rehmannia glutinosa Libosch on the expression of signaling molecules relevant to learning and memory among hippocampal neurons exposed to high concentration of corticosterone.
Chin J Integr Med
PUBLISHED: 03-02-2014
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To determine the effects of 5-hydroxymethyl furfural (5-HMF), an extract of Rehmannia glutinosa Libosch, on several down-regulated signaling molecules involved in learning and memory in hippocampal neurons.
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Graphene-cyclodextrin-cytochrome c layered assembly with improved electron transfer rate and high supramolecular recognition capability.
Mater Sci Eng C Mater Biol Appl
PUBLISHED: 03-01-2014
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This study aimed to develop a new graphene-based layered assembly, named graphene-cyclodextrin-cytochrome c with improved electron transfer rate. This assembly has combined high conductivity of graphene nanosheets (GNs), selectively binding properties and electronegativity of cyclodextrins (CDs), as well as electropositivity of cytochrome c (Cyt c). This assembly can also mimic the confined environments of the intermembrane space of mitochondria. A ?-cyclodextrin (?-CD) functionalized GN (GN-CD) assembly was initially prepared by a simple wet-chemical strategy, i.e., in situ thermal reduction of graphene oxide with hydrazine hydrate in the presence of ?-CD. Cyt c was then intercalated to the GN-CD assembly to form a layered self-assembled structure, GN-CD-Cyt c, through electrostatic interaction. Compared with GNs and GN-CD, GN-CD-Cyt c assembly displayed improved electron transfer rate and high supramolecular recognition capability toward six probe molecules.
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A three-year experiment confirms continuous immobilization of cadmium and lead in contaminated paddy field with biochar amendment.
J. Hazard. Mater.
PUBLISHED: 02-17-2014
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Heavy metal contamination in croplands has been a serious concern because of its high health risk through soil-food chain transfer. A field experiment was conducted in 2010-2012 in a contaminated rice paddy in southern China to determine if bioavailability of soil Cd and Pb could be reduced while grain yield was sustained over 3 years after a single soil amendment of wheat straw biochar. Contaminated biochar particles were separated from the biochar amended soil and microscopically analyzed to help determine where, and how, metals were immobilized with biochar. Biochar soil amendment (BSA) consistently and significantly increased soil pH, total organic carbon and decreased soil extractable Cd and Pb over the 3 year period. While rice plant tissues' Cd content was significantly reduced, depending on biochar application rate, reduction in plant Pb concentration was found only in root tissue. Analysis of the fresh and contaminated biochar particles indicated that Cd and Pb had probably been bonded with the mineral phases of Al, Fe and P on and around and inside the contaminated biochar particle. Immobilization of the Pb and Cd also occurred to cation exchange on the porous carbon structure.
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Oscillating high glucose enhances oxidative stress and apoptosis in human coronary artery endothelial cells.
J. Endocrinol. Invest.
PUBLISHED: 02-01-2014
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To investigate the toxic effect of oscillating high glucose (OHG) versus persistent high glucose (PHG) in inducing oxidative stress and cellular apoptosis in human coronary artery endothelial cells (HCAECs) in vitro.
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Complete next-to-leading-order study on the yield and polarization of ?(1S,2S,3S) at the Tevatron and LHC.
Phys. Rev. Lett.
PUBLISHED: 01-24-2014
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Based on the nonrelativistic QCD factorization scheme, we present the first complete next-to-leading-order study on the yield and polarization of ?(1S,2S,3S) hadroproduction. By using the color-octet long-distance matrix elements obtained from fits of the experimental measurements on ? yield and polarization at the Tevatron and LHC, our results can explain the measurements on the yield very well, and for the polarizations of ?(1S,2S,3S), they are in (good, good, bad) agreement with recent CMS measurement, but still have some distance from the CDF measurement.
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[Effect of bufalin combined gefitinib on lung cancer H1975 cells and its mechanisms research].
Zhongguo Zhong Xi Yi Jie He Za Zhi
PUBLISHED: 12-12-2013
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To observe the effect of bufalin combined Gefitinib on lung cancer H1975 cells, and to explore its potential mechanisms for anti-tumor.
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Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-11-2013
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Rickettsiae are responsible for some of the most devastating human infections. A high infectivity and severe illness after inhalation make some rickettsiae bioterrorism threats. We report that deletion of the exchange protein directly activated by cAMP (Epac) gene, Epac1, in mice protects them from an ordinarily lethal dose of rickettsiae. Inhibition of Epac1 suppresses bacterial adhesion and invasion. Most importantly, pharmacological inhibition of Epac1 in vivo using an Epac-specific small-molecule inhibitor, ESI-09, completely recapitulates the Epac1 knockout phenotype. ESI-09 treatment dramatically decreases the morbidity and mortality associated with fatal spotted fever rickettsiosis. Our results demonstrate that Epac1-mediated signaling represents a mechanism for host-pathogen interactions and that Epac1 is a potential target for the prevention and treatment of fatal rickettsioses.
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CETP gene polymorphisms and risk of coronary atherosclerosis in a Chinese population.
Lipids Health Dis
PUBLISHED: 10-24-2013
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Coronary atherosclerosis, the most common form of coronary artery disease (CAD), is characterized by accumulation of lipid in the walls of coronary arteries. Recent data from clinical trials have showed that high-density lipoprotein cholesterol (HDL-C) has causal role in the pathogenesis and development of coronary atherosclerosis. Cholesteryl ester transfer protein (CETP) is an important regulator of plasma HDL-C. Several genetic mutations in the CETP gene were found to be associated with HDL-C levels. The aim of the present study is to evaluate the association of HDL-C-related CETP polymorphisms and risk of coronary atherosclerosis.
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MicroRNA-34a Targets Bcl-2 and Sensitizes Human Hepatocellular Carcinoma Cells to Sorafenib Treatment.
Technol. Cancer Res. Treat.
PUBLISHED: 07-11-2013
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MiR-34a, a direct target of p53, has been shown to target several molecules associated with the cell cycle and cell survival pathways, and its dysregulation is implicated in cancer drug resistance or sensitivity in several human cancers. However, the correlation between miR-34a expression and chemoresistance has not been explored in HCC. In this study, we confirmed that miR-34a was significantly down-regulated in HCC tissues and HCC cell lines by qRT-PCR. HCC tissues with lower miR-34a expression displayed higher expression of Bcl-2 protein than those with high expression of miR-34a; therefore, an inverse correlation is evident between the miR-34a level and Bcl-2 expression. Moreover, patients with lower miR-34a expression had significantly poorer overall survival. Bioinformatics and luciferase reporter assays revealed that miR-34a binds the 3-UTR of the Bcl-2 mRNA and represses its translation. Western blotting analysis and qRT-PCR confirmed that Bcl-2 is inhibited by miR-34a overexpression. Functional analyses indicated that the restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression. This study is the first to demonstrate that miR-34a induces sensitivity to the anti-tumor effect of sorafenib in human HCC cells, suggesting a potential role of miR-34a in the treatment of HCC.
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Association of pericardial adipose tissue volume with presence and severity of coronary atherosclerosis.
Clin Invest Med
PUBLISHED: 06-05-2013
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This study was to investigate whether high pericardial adipose tissue (PAT) volume is related to the presence and severity of coronary artery disease (CAD).
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A hamster-derived West Nile virus isolate induces persistent renal infection in mice.
PLoS Negl Trop Dis
PUBLISHED: 06-01-2013
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West Nile virus (WNV) can persist long term in the brain and kidney tissues of humans, non-human primates, and hamsters. In this study, mice were infected with WNV strain H8912, previously cultured from the urine of a persistently infected hamster, to determine its pathogenesis in a murine host.
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[Insulin-like growth factor 1 induces bone mesenchymal stem cells differentiation into cardiomyocyte-like cells].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 05-29-2013
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To explore the ability and mechanism of insulin-like growth factor 1 (IGF-1) induced bone mesenchymal stem cells (BMSCs) differentiation into cardiomyocyte-like cells (CLCs).
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Compartmentalized, functional role of angiogenin during spotted fever group rickettsia-induced endothelial barrier dysfunction: evidence of possible mediation by host tRNA-derived small noncoding RNAs.
BMC Infect. Dis.
PUBLISHED: 04-26-2013
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Microvascular endothelial barrier dysfunction is the central enigma in spotted fever group (SFG) rickettsioses. Angiogenin (ANG) is one of the earliest identified angiogenic factors, of which some are relevant to the phosphorylation of VE-cadherins that serve as endothelial adherens proteins. Although exogenous ANG is known to translocate into the nucleus of growing endothelial cells (ECs) where it plays a functional role, nuclear ANG is not detected in quiescent ECs. Besides its nuclear role, ANG is thought to play a cytoplasmic role, owing to its RNase activity that cleaves tRNA to produce small RNAs. Recently, such tRNA-derived RNA fragments (tRFs) have been shown to be induced under stress conditions. All these observations raise an intriguing hypothesis about a novel cytoplasmic role of ANG, which is induced upon infection with Rickettsia and generates tRFs that may play roles in SFG rickettsioses.
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Characterization of Rift Valley fever virus MP-12 strain encoding NSs of Punta Toro virus or sandfly fever Sicilian virus.
PLoS Negl Trop Dis
PUBLISHED: 04-01-2013
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Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) is a mosquito-borne zoonotic pathogen which can cause hemorrhagic fever, neurological disorders or blindness in humans, and a high rate of abortion in ruminants. MP-12 strain, a live-attenuated candidate vaccine, is attenuated in the M- and L-segments, but the S-segment retains the virulent phenotype. MP-12 was manufactured as an Investigational New Drug vaccine by using MRC-5 cells and encodes a functional NSs gene, the major virulence factor of RVFV which 1) induces a shutoff of the host transcription, 2) inhibits interferon (IFN)-? promoter activation, and 3) promotes the degradation of dsRNA-dependent protein kinase (PKR). MP-12 lacks a marker for differentiation of infected from vaccinated animals (DIVA). Although MP-12 lacking NSs works for DIVA, it does not replicate efficiently in type-I IFN-competent MRC-5 cells, while the use of type-I IFN-incompetent cells may negatively affect its genetic stability. To generate modified MP-12 vaccine candidates encoding a DIVA marker, while still replicating efficiently in MRC-5 cells, we generated recombinant MP-12 encoding Punta Toro virus Adames strain NSs (rMP12-PTNSs) or Sandfly fever Sicilian virus NSs (rMP12-SFSNSs) in place of MP-12 NSs. We have demonstrated that those recombinant MP-12 viruses inhibit IFN-? mRNA synthesis, yet do not promote the degradation of PKR. The rMP12-PTNSs, but not rMP12-SFSNSs, replicated more efficiently than recombinant MP-12 lacking NSs in MRC-5 cells. Mice vaccinated with rMP12-PTNSs or rMP12-SFSNSs induced neutralizing antibodies at a level equivalent to those vaccinated with MP-12, and were efficiently protected from wild-type RVFV challenge. The rMP12-PTNSs and rMP12-SFSNSs did not induce antibodies cross-reactive to anti-RVFV NSs antibody and are therefore applicable to DIVA. Thus, rMP12-PTNSs is highly efficacious, replicates efficiently in MRC-5 cells, and encodes a DIVA marker, all of which are important for vaccine development for Rift Valley fever.
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Rift Valley fever virus MP-12 vaccine encoding Toscana virus NSs retains neuroinvasiveness in mice.
J. Gen. Virol.
PUBLISHED: 03-20-2013
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Rift Valley fever is a mosquito-borne zoonotic disease endemic to sub-Saharan Africa. Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) causes high rates of abortion and fetal malformation in pregnant ruminants, and haemorrhagic fever, neurological disorders or blindness in humans. The MP-12 strain is a highly efficacious and safe live-attenuated vaccine candidate for both humans and ruminants. However, MP-12 lacks a marker to differentiate infected from vaccinated animals. In this study, we originally aimed to characterize the efficacy of a recombinant RVFV MP-12 strain encoding Toscana virus (TOSV) NSs gene in place of MP-12 NSs (rMP12-TOSNSs). TOSV NSs promotes the degradation of dsRNA-dependent protein kinase (PKR) and inhibits interferon-? gene up-regulation without suppressing host general transcription. Unexpectedly, rMP12-TOSNSs increased death in vaccinated outbred mice and inbred BALB/c or C57BL/6 mice. Immunohistochemistry showed diffusely positive viral antigens in the thalamus, hypothalamus and brainstem, including the medulla. No viral antigens were detected in spleen or liver, which is similar to the antigen distribution of moribund mice infected with MP-12. These results suggest that rMP12-TOSNSs retains neuroinvasiveness in mice. Our findings demonstrate that rMP12-TOSNSs causes neuroinvasion without any hepatic disease and will be useful for studying the neuroinvasion mechanism of RVFV and TOSV.
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Novel Schiff-base-derived FabH inhibitors with dioxygenated rings as antibiotic agents.
ChemMedChem
PUBLISHED: 02-07-2013
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Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, ?-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad-spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine (10) showed the most potent antibacterial activity with a MIC value of 3.89-7.81 ?M(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 ?M. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.
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MyD88 controls human metapneumovirus-induced pulmonary immune responses and disease pathogenesis.
Virus Res.
PUBLISHED: 02-06-2013
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Human metapneumovirus (hMPV) is a common cause of lung and airway infections in infants and young children. Recently, we and others have shown that hMPV infection induces Toll-like receptor (TLR)-dependent cellular signaling. However, the contribution of TLR-mediated signaling in host defenses against pulmonary hMPV infection and associated disease pathogenesis has not been elucidated. In this study, mice deficient in MyD88, a common adaptor of TLRs, was used to investigate the contribution of TLRs to in vivo pulmonary response to hMPV infection. MyD88(-/-) mice have significantly reduced pulmonary inflammation and associated disease compared with wild-type (WT) C57BL/6 mice after intranasal infection with hMPV. hMPV-induced cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and isolated lung conventional dendritic cells (cDC) are also significantly impaired by MyD88 deletion. In addition, we found that MyD88 is required for the recruitment of DC, T cells, and other immune cells to the lungs, and for the functional regulation of DC and T cells in response to hMPV infection. Taken together, our data indicate that MyD88-mediated pathways are essential for the pulmonary immune and pathogenic responses to this viral pathogen.
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Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents.
Bioorg. Med. Chem.
PUBLISHED: 02-06-2013
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A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 ?M, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 ?M, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 ?g/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
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Bufalin Reverses HGF-Induced Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer Cells via Blockage of Met/PI3k/Akt Pathway and Induction of Apoptosis.
Evid Based Complement Alternat Med
PUBLISHED: 02-04-2013
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The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor- (EGFR-) activating mutation. However, the inevitable recurrence resulting from acquired resistance has limited the clinical improvement in therapy outcomes. Many studies demonstrate that hepatocyte growth factor- (HGF-) Met axis plays an important role in tumor progression and drug sensitivity. HGF may induce resistance to EGFR-TKIs in EGFR mutant lung cancer cells by Met/PI3K/Akt signaling. The purpose of this study was to determine whether bufalin, a major bioactive component of Venenum Bufonis, could reverse HGF-induced resistance to reversible and irreversible EGFR-TKIs in mutant lung cancer cells PC-9, HCC827, and H1975. Our studies showed that bufalin could reverse resistance to reversible and irreversible EGFR-TKIs induced by exogenous HGF in EGFR mutant lung cancer cells by inhibiting the Met/PI3K/Akt pathway and inducing death signaling. These results suggested that bufalin might have a potential to overcome HGF-induced resistance to molecular-targeted drugs for lung cancer.
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Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors.
PLoS ONE
PUBLISHED: 01-01-2013
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4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.
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IndelFR: a database of indels in protein structures and their flanking regions.
Nucleic Acids Res.
PUBLISHED: 11-29-2011
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Insertion/deletion (indel) is one of the most common methods of protein sequence variation. Recent studies showed that indels could affect their flanking regions and they are important for protein function and evolution. Here, we describe the Indel Flanking Region Database (IndelFR, http://indel.bioinfo.sdu.edu.cn), which provides sequence and structure information about indels and their flanking regions in known protein domains. The indels were obtained through the pairwise alignment of homologous structures in SCOP superfamilies. The IndelFR database contains 2,925,017 indels with flanking regions extracted from 373,402 structural alignment pairs of 12,573 non-redundant domains from 1053 superfamilies. IndelFR provides access to information about indels and their flanking regions, including amino acid sequences, lengths, locations, secondary structure constitutions, hydrophilicity/hydrophobicity, domain information, 3D structures and so on. IndelFR has already been used for molecular evolution studies and may help to promote future functional studies of indels and their flanking regions.
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V?4+ T cells regulate host immune response to West Nile virus infection.
FEMS Immunol. Med. Microbiol.
PUBLISHED: 11-15-2011
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The V?4(+) cells, a subpopulation of peripheral ?? T cells, are involved in West Nile virus (WNV) pathogenesis, but the underlying mechanism remains unclear. In this study, we found that WNV-infected V?4(+) cell-depleted mice had lower viremia and a reduced inflammatory response in the brain. The V?4(+) cells produced IL-17 during WNV infection, but blocking IL-17 signaling did not affect host susceptibility to WNV encephalitis. We also noted that there was an enhanced magnitude of protective splenic V?1(+) cell expansion in V?4(+) cell-depleted mice compared to that in controls during WNV infection. In addition, V?4(+) cells of WNV-infected mice had a higher potential for producing TGF-?. The ?? T cells of WNV-infected V?4(+) cell-depleted mice had a higher proliferation rate than those of WNV-infected controls upon ex vivo stimulation with anti-CD3, and this difference was diminished in the presence of TGF-? inhibitor. Finally, V?4(+) cells of infected mice contributed directly and indirectly to the higher level of IL-10, which is known to play a negative role in immunity against WNV infection. In summary, V?4(+) cells suppress V?1(+) cell expansion via TGF-? and increase IL-10 level during WNV infection, which together may lead to higher viremia and enhanced brain inflammation.
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Lipoprotein(a) complexes with beta2-glycoprotein I in patients with coronary artery disease.
J. Atheroscler. Thromb.
PUBLISHED: 11-07-2011
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To investigate the possible mechanisms and association of increased complexes of ?(2)-glycoprotein I with lipoprotein(a) [?(2)-GPI-Lp(a)] levels with the presence and extent of coronary artery disease (CAD).
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[Surgical strategy for ectopic kidneys: analysis of 35 cases].
Nan Fang Yi Ke Da Xue Xue Bao
PUBLISHED: 08-27-2011
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To explore the surgical strategy for ectopic kidney and evaluate the clinical outcomes.
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Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver.
Gastroenterology
PUBLISHED: 04-14-2011
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The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated antiviral signaling protein (MAVS) and block retinoic acid-inducible gene I-mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear.
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MicroRNA regulation constrains the organization of target genes on mammalian chromosomes.
FEBS Lett.
PUBLISHED: 01-25-2011
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The regulation of microRNAs (miRNAs) is a complicated process requiring a large number of molecular events to be coordinated in both space and time. It is not known whether this complicated regulation process constrains the organization of target genes on mammalian chromosomes. We performed a genome-wide analysis to provide a better picture of chromosomal organization of miRNA target genes. Our results showed clustering of the target genes (TGs) of miRNAs on mammalian chromosomes, and further revealed that the particular gene organization is constrained by miRNA regulation. The clustering pattern of TGs provides an insight into the complexity of miRNA regulation.
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[Overexpression of SERCA2a by gene transfer enhances myocardial systolic function in canines].
Sheng Li Xue Bao
PUBLISHED: 12-21-2010
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The present study is aimed to study the effect of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) gene transfer on the contractile function of isolated cardiomyocytes of canines. The cardiomyocytes were isolated with collagenases. The isolated cardiac cells were divided into untransfected group, empty vector group and SERCA2a-transfected group. Recombinant adenovirus vector carrying enhanced green fluorescent protein gene was used for SERCA2a gene delivery. The expression of SERCA2a protein in cardiomyocytes was determined by Western blot. Contractile function of cardiomyocytes was measured with motion edge-detection system of single cell at 48 h after transfection. The results showed, compared with untransfected group, SERCA2a protein level, percentage of peak contraction amplitude under normal condition, percentages of peak contraction amplitude under Ca(2+) or isoproterenol stimulation, time-to-peak contraction (TTP) and time-to-50% relaxation (R50) in SERCA2a-transfected group all increased significantly. While all the above indices in empty vector group did not show any differences with those in untransfected group. These results suggest that the overexpression of SERCA2a by gene transfer may enhance the contraction function of canine myocardial cells.
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Facile synthesis, stabilization, and anti-bacterial performance of discrete Ag nanoparticles using Medicago sativa seed exudates.
J Colloid Interface Sci
PUBLISHED: 08-17-2010
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The biogenic synthesis of metal nanomaterials offers an environmentally benign alternative to the traditional chemical synthesis routes. Colloidal silver (Ag) nanoparticles were synthesized by reacting aqueous AgNO(3) with Medicago sativa seed exudates under non-photomediated conditions. Upon contact, rapid reduction of Ag(+) ions was observed in <1 min with Ag nanoparticle formation reaching 90% completion in <50 min. Effect of Ag concentration, quantity of exudate and pH on the particle size and shape were investigated. At [Ag(+)]=0.01 M and 30°C, largely spherical nanoparticles with diameters in the range of 5-51 nm were generated, while flower-like particle clusters (mean size=104 nm) were observed on treatment at higher Ag concentrations. Pre-dilution of the exudate induced the formation of single-crystalline Ag nanoplates, forming hexagonal particles and nanotriangles with edge lengths of 86-108 nm, while pH adjustment to 11 resulted in monodisperse Ag nanoparticles with an average size of 12 nm. Repeated centrifugation and redispersion enhanced the percentage of nanoplates from 10% to 75% in solution. The kinetics of nanoparticle formation were monitored using ultraviolet-visible spectroscopy and the Ag products were characterized using transmission electron microscopy, selected-area electron diffraction, scanning electron microscopy, X-ray powder diffraction, and atomic force microscopy. X-ray photoelectron spectroscopy was used to investigate the elements and chemical environment in the top layers of the as-synthesized Ag nanoparticles, while the metabolites in the exudate were analyzed using gas chromatography-mass spectroscopy. To our knowledge, this is the first account of M. sativa seed exudate assisted synthesis and stabilization of biogenic Ag nanoparticles; the nanoplates are notably smaller and better faceted compared with those synthesized by vascular plant extracts previously reported. Stabilized films of exudate synthesized Ag nanoparticles were effective anti-bacterial agents.
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[Membrane testosterone receptors in cultured vascular smooth muscle cells].
Zhonghua Nan Ke Xue
PUBLISHED: 08-06-2010
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To determine the presence of membrane testosterone receptors in cultured vascular smooth muscle cells (VSMC), and investigate their relationship with classical intracellular androgen receptors (iAR).
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Cloning, expression, and genus-specificity analysis of 28-kDa OmpK from Vibrio alginolyticus.
J. Food Sci.
PUBLISHED: 06-16-2010
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Some Vibrio species are universal marine pathogens and Vibrio infections are often encountered due to consumption of raw or uncooked seafood. The outer membrane proteins, playing a key role in interaction between bacteria and hosts, are potential candidates for development of vaccine and markers of the genus Vibrio. In this study, the ompK (outer membrane protein K) genes of Vibrio alginolyticus, V. vulnificus, V. parahaemolyticus, V. fluvialis, and V. mimicu were cloned with 798 to 822 nucleotides encoding 266 to 274 amino acids. The ompK gene from V. alginolyticus was expressed in Escherichia coli using pET-22b expression vector. The recombinant fusion OmpK protein with 6xHis tag was purified with nickel chelate affinity chromatography. The polyclonal antibody (titer, 1:102400) against V. alginolyticus OmpK was developed in guinea pigs and it positively reacted with each of 5 Vibrio species but negative to other 18 Gram-negative bacterial strains. The result suggests that Vibrio OmpK protein could be a genus-specific antigen, which can be used for developing vaccines and rapid detection of multiple Vibrio species.
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Percutaneous coronary intervention results in acute increases in native and oxidized lipoprotein(a) in patients with acute coronary syndrome and stable coronary artery disease.
Clin. Biochem.
PUBLISHED: 05-11-2010
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To investigate possible changes of native and oxidized lipoprotein(a) [ox-Lp(a)] levels after percutaneous coronary intervention (PCI).
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From phenotype to gene: detecting disease-specific gene functional modules via a text-based human disease phenotype network construction.
FEBS Lett.
PUBLISHED: 05-05-2010
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Currently, some efforts have been devoted to the text analysis of disease phenotype data, and their results indicated that similar disease phenotypes arise from functionally related genes. These related genes work together, as a functional module, to perform a desired cellular function. We constructed a text-based human disease phenotype network and detected 82 disease-specific gene functional modules, each corresponding to a different phenotype cluster, by means of graph-based clustering and mapping from disease phenotype to gene. Since genes in such gene functional modules are functionally related and cause clinically similar diseases, they may share common genetic origin of their associated disease phenotypes. We believe the investigation may facilitate the ultimate understanding of the common pathophysiologic basis of associated diseases.
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Adenovirus-mediated overexpression of glutathione-s-transferase mitigates transplant arteriosclerosis in rabbit carotid allografts.
Transplantation
PUBLISHED: 02-24-2010
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Cardiac transplant arteriosclerosis or cardiac allograft vasculopathy remains the leading cause of graft failure and patient death in heart transplant recipients. Endothelial cell injury is crucial in the development of human atherosclerosis and may play a role in allograft vasculopathy. Glutathione-S-transferase (GST) is known to protect endothelial cells from damage by oxidants and toxins. However, the contribution of human GST A4-4 (hGSTA4-4) to vascular cell injury and consequent transplant arteriosclerosis is unknown.
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Establishment of HPLC-ESI-MS method for the determination of eplerenone in human plasma and its pharmacokinetics.
Yao Xue Xue Bao
PUBLISHED: 10-08-2009
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A sensitive high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) method was established for the determination of eplerenone (EP) in human plasma. The plasma samples of EP were extracted with ethyl acetate and separated by HPLC on a reversed phase C18 column with a mobile phase of 10 mmol x L(-1) ammonium acetate water solution-methanol (30 : 70, v/v). EP was determined with electrospray ionization-mass spectrometry (ESI-MS) in the selected ion monitoring (SIM) mode. The calibration curves were linear over the range of 2-4 000 ng x mL(-1) for EP. The lower limit of quantification was 2 ng x mL(-1). The method has been successfully applied in the pharmacokinetic study of the EP tablets. The main pharmacokinetic parameters of EP after oral administration of 25 mg, 50 mg, 100 mg were as follows, t1/2: (4.9 +/- 2.1), (4.7 +/- 1.5), (5.9 +/- 1.2) h; AUC(0-infinity): (4 402 +/- 1 735), (8 150 +/- 2 509), (13 783 +/- 4 102) microg x h x L(-1); and MRT: (6.2 +/- 2.1), (6.6 +/- 1.3), and (7.2 +/- 1.6) h. Parameters of EP after oral administration of multiple doses of 50 mg were as follows, t1/2: (6.1 +/- 1.7) h; AUC(ss): (10 071 +/- 4220) microg x h x L(-1); MRT: (8.1 +/- 2.3) h; and DF: (3.2 +/- 1.0).
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[Testosterone at physiological level inhibits PGF2alpha-induced increase in intracellular Ca2+ in cultured vascular smooth muscle cells].
Zhonghua Nan Ke Xue
PUBLISHED: 05-29-2009
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To explore the acute effects of testosterone at the physiological level on PGF2alpha-induced increase in intracellular Ca2+ in cultured vascular smooth muscle cells (VSMCs).
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Elevated concentrations of oxidized lipoprotein(a) are associated with the presence and severity of acute coronary syndromes.
Clin. Chim. Acta
PUBLISHED: 05-23-2009
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To investigate possible mechanisms and association of increased oxidized Lp(a) [ox-Lp(a)] levels with presence and extent of acute coronary syndromes (ACS).
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Determination of berberine and the study of fluorescence quenching mechanism between berberine and enzyme-catalyzed product.
Spectrochim Acta A Mol Biomol Spectrosc
PUBLISHED: 03-04-2009
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A new method for determining berberine has been established based on the principle of fluorescence quenching. The calibration curve was found to be linear between F(0)/F and the concentration of berberine with the range of 3.00-20.0 microg mL(-1). The detection limit was 0.51 microg mL(-1) and the relative standard derivative was 0.18%. Effects of pH, foreign ions and the optimization of variables on the determination of berberine have been examined. The mechanism of the fluorescence quenching has been discussed. The binding constant and the number of binding sites were 1.70x10(6) L mol(-1) and 1.14, respectively. The data, DeltaH = 42.71 kJ mol(-1), DeltaS = 264.3 J K(-1) mol(-1) and the mean value DeltaG = -39.65 kJ mol(-1) were estimated which showed that the reaction was spontaneous and endothermic. The main binding force was hydrophobic force because both DeltaH and DeltaS were positive.
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Next-to-leading-order QCD corrections to e+e- -->J/psi gg at the B factories.
Phys. Rev. Lett.
PUBLISHED: 01-04-2009
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We calculate the next-to-leading-order (NLO) QCD corrections to e;{+}e;{-}-->J/psi gg via color singlet J/psi(3S1) at the B factories. The result shows that the cross section is enhanced to 0.373 pb by a K factor (NLO/LO) of about 1.21. By considering its dependence on the charm quark mass and renormalization scale, the NLO cross section can range from 0.294 to 0.409 pb. Further including the psi;{} feed-down, sigma[e;{+}e;{-}-->J/psi X(non-cc[over ])] is enhanced by another factor of about 1.29 and reach 0.482 pb. In addition, the momentum distributions of J/psi production and polarization are presented. Recent measurements from Belle agree well with our prediction for the cross section and momentum distribution. It is expected that this process can serve as a very good channel to clarify the J/psi polarization puzzle by performing further experimental measurements.
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Reversible cardiogenic shock caused by atrioventricular junctional rhythm after percutaneous coronary intervention.
J Geriatr Cardiol
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An 82-year-old female patient undergoing cardiogenic shock caused by atrioventricular junctional rhythm immediately after percutaneous coronary intervention (PCI) is described. Pharmacotherapy was invalid, and subsequent application of atrial pacing reversed the cardiogenic shock. PCI-related injury of sinuatrial nodal artery leading to acute atrial contractility loss, accompanied by atrioventricular junctional arrhythmia, was diagnosed. We recommend that preoperative risk evaluation be required for multi-risk patients. Likewise, emergent measures should to be established in advance. This case reminds us that atrial pacing can be an optimal management technique once cardiogenic shock has occurred.
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Synthesis, biological evaluation and molecular modeling of dihydro-pyrazolyl-thiazolinone derivatives as potential COX-2 inhibitors.
Bioorg. Med. Chem.
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A series of dihydro-pyrazolyl-thiazolinone derivatives (5a-5t) have been synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 2-(3-(3,4-dimethylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (5a) displayed the most potent COX-2 inhibitory activity with IC(50) of 0.5?M, but weak to COX-1. Docking simulation was performed to position compound 5a into the COX-2 active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity and low toxicity would be a potential and selective anti-cyclooxygenase-2 agent.
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Several important in vitro improvements in the amplification, differentiation and tracing of fetal liver stem/progenitor cells.
PLoS ONE
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We previously isolated fetal liver stem/progenitor cells (FLSPCs), but there is an urgent need to properly amplify FLSPCs, effectively induce FLSPCs differentiation, and steadily trace FLSPCs for in vivo therapeutic investigation.
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Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis.
J. Immunol.
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Although CD4(+) Th17 cells are enriched in normal intestines, their role in regulation of the host response to microbiota, and whether and how they contribute to intestinal homeostasis, is still largely unknown. It is also unclear whether Th17 cells regulate intestinal IgA production, which is also abundant in the intestinal lumen and has a crucial role as the first defense line in host response to microbiota. In this study, we found that intestinal polymeric Ig receptor (pIgR) and IgA production was impaired in T cell-deficient TCR-?x?(-/-) mice. Repletion of TCR-?x?(-/-) mice with Th17 cells from CBir1 flagellin TCR transgenic mice, which are specific for a commensal Ag, increased intestinal pIgR and IgA. The levels of intestinal pIgR and IgA in B6.IL-17R (IL-17R(-/-)) mice were lower than wild type mice. Treatment of colonic epithelial HT-29 cells with IL-17 increased pIgR expression. IL-17R(-/-) mice demonstrated systemic antimicroflora Ab response. Consistently, administering dextran sulfate sodium (DSS) to C57BL/6 mice after treatment with IL-17-neutralizing Ab resulted in more severe intestinal inflammation compared with control Ab. Administering DSS to IL-17R(-/-) mice resulted in increased weight loss and more severe intestinal inflammation compared with wild type mice, indicating a protective role of Th17 cells in intestinal inflammation. Individual mice with lower levels of pIgR and intestinal-secreted IgA correlated with increased weight loss at the end of DSS administration. Collectively, our data reveal that microbiota-specific Th17 cells contribute to intestinal homeostasis by regulating intestinal pIgR expression and IgA secretion.
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Characterization of the direct physical interaction of nc886, a cellular non-coding RNA, and PKR.
FEBS Lett.
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We have recently shown that nc886 (pre-miR-886 or vtRNA2-1) is not a genuine microRNA precursor nor a vault RNA, but a novel type of non-coding RNA that represses PKR, a double-stranded RNA (dsRNA) dependent kinase. Here we have characterized their direct physical association. PKRs two RNA binding domains form a specific and stable complex with nc886s central portion, without any preference to its 5-end structure. By binding to PKR with a comparable affinity, nc886 competes with dsRNA and attenuates PKR activation by dsRNA. Our data suggest that nc886 sets a threshold for PKR activation so that it occurs only during genuine viral infection but not by a minute level of fortuitous cellular dsRNA.
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Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors.
Bioorg. Med. Chem.
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A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 ?M for MCF-7 and IC(50) = 0.45 ?M for WM266.5, IC(50) = 0.22 ?M for BRAF(V600E), 3m: IC(50) = 0.97 ?M for MCF-7 and IC(50) = 0.72 ?M for WM266.5, IC(50) = 0.46 ?M for BRAF(V600E), which were comparable with the positive control Erlotinib.
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[Impact of anti-OX-LDL antibodies on CD36 mRNA expression in monocytes].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
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To investigate the impact of antibodies to oxidized low-density lipoprotein (OX-LDL) on CD36 mRNA expression in monocytes and explore the mechanism underlying the impact on the formation of foam cells.
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[Effects of exogenous gamma-aminobutyric acid on polyamine metabolism of melon seedlings under hypoxia stress].
Ying Yong Sheng Tai Xue Bao
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Taking melon cultivar Xiyu No. 1 as test material, a hydroponic experiment was conducted to investigate the effects of exogenous gamma-aminobutyric acid (GABA) on the seedlings polyamine metabolism under hypoxia stress. Compared with the control in normoxic treatment, the seedlings under hypoxia stress had significantly higher glutamic acid decarboxylase (GAD) activity and GABA content, and their polyamine synthesis enzymes activities all enhanced significantly, which led to a marked increase of polyamines contents. Meanwhile, the seedlings leaf- and root diamine oxidase (DAO) and polyamine oxidase (PAO) activities also had a significant increase. The increment of root arginine decarboxylase (ADC) activity was higher, which induced a higher content of free putrescine (Put) in roots, while the increment of leaf ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activities were higher, inducing a higher content of free spermidine (Spd) in leaves. The PBs-extractable DAO and PAO activies in roots were significantly lower than those in leaves, but the cell wall-bound PAO activity was in adverse. Under hypoxia stress, the addition of exogenous GABA increased the leaf- and root GABA and glutamic acid contents and decreased the GAD activity significantly. The increase of arginine, ornithine, and methionine contents promoted the activities of polyamines synthesis enzymes, which led to the significant increase of polyamines contents and the significant decrease of DAO and PAO activities.
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Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors.
Bioorg. Med. Chem. Lett.
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It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.
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Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents.
Bioorg. Med. Chem.
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In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25?M to 7.60 ?M against the T cells, and the IC(50) of positive control (csa) is 2.12 ?M. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 ?M and 4.75 ?M for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3K?/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3K? binding site in order to indicate the potential target.
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Discovery and modification of sulfur-containing heterocyclic pyrazoline derivatives as potential novel class of ?-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.
Bioorg. Med. Chem. Lett.
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A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis (MIC values: 1.56-3.13 ?g/mL), being comparable with the positive control, while D6 performed the best in the thiazolidinone series (MIC values: 3.13-6.25 ?g/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.6 and 8.4 ?M, respectively, comparable with the positive control DDCP (IC(50)=2.8 ?M). Docking simulation was performed to position compound C14 and D6 into the E. coli FabH structure active site to determine the probable binding model. The structurally modification of previous compounds and the attempt in innovative target have brought a positive progress.
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Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE-cadherins: evidence from atomic force microscopy and biochemical studies.
PLoS Negl Trop Dis
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The most prominent pathophysiological effect of spotted fever group (SFG) rickettsial infection of microvascular endothelial cells (ECs) is an enhanced vascular permeability, promoting vasogenic cerebral edema and non-cardiogenic pulmonary edema, which are responsible for most of the morbidity and mortality in severe cases. To date, the cellular and molecular mechanisms by which SFG Rickettsia increase EC permeability are largely unknown. In the present study we used atomic force microscopy (AFM) to study the interactive forces between vascular endothelial (VE)-cadherin and human cerebral microvascular EC infected with R. montanensis, which is genetically similar to R. rickettsii and R. conorii, and displays a similar ability to invade cells, but is non-pathogenic and can be experimentally manipulated under Biosafety Level 2 (BSL2) conditions. We found that infected ECs show a significant decrease in VE-cadherin-EC interactions. In addition, we applied immunofluorescent staining, immunoprecipitation phosphorylation assay, and an in vitro endothelial permeability assay to study the biochemical mechanisms that may participate in the enhanced vascular permeability as an underlying pathologic alteration of SFG rickettsial infection. A major finding is that infection of R. montanensis significantly activated tyrosine phosphorylation of VE-cadherin beginning at 48 hr and reaching a peak at 72 hr p.i. In vitro permeability assay showed an enhanced microvascular permeability at 72 hr p.i. On the other hand, AFM experiments showed a dramatic reduction in VE-cadherin-EC interactive forces at 48 hr p.i. We conclude that upon infection by SFG rickettsiae, phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions, and may lead to endothelial paracellular barrier dysfunction causing microvascular hyperpermeability. These new approaches should prove useful in characterizing the antigenically related SFG rickettsiae R. conorii and R. rickettsii in a BSL3 environment. Future studies may lead to the development of new therapeutic strategies to inhibit the VE-cadherin-associated microvascular hyperpermeability in SFG rickettsioses.
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Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors.
Bioorg. Med. Chem.
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Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli ?-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 ?g/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 ?g/mL were most potent inhibitors of Escherichia coli FabH.
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Synthesis, biological evaluation and molecular docking studies of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives as inhibitors of HDAC activity.
Bioorg. Med. Chem.
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In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 ?M for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.
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Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors.
Bioorg. Med. Chem.
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A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 ?M, GI(50)=0.89 ?M) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.
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The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of Rift Valley fever virus MP-12 vaccine.
J. Virol.
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Rift Valley fever virus (RVFV), belonging to the genus Phlebovirus, family Bunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-?) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-? nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans.
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Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents.
Bioorg. Med. Chem. Lett.
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A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines with IC(50) values of 0.39±0.06?M and 0.46±0.04 ?M, respectively, which were comparable to the positive control. Compound 10e also exhibited significant Aurora-A kinase inhibitory activity (IC(50)=0.16±0.03 ?M). Docking simulation was performed to position compound 10e into the active site of Aurora-A kinase, in order to get the probable binding model for further study. The results of Western-blot assay demonstrated that compound 10e possessed good Aurora-A kinase inhibitory activity against HCT116. Based on the preliminary results, it is deduced that compound 10e with potent Aurora-A kinase inhibitory activity may be a potential anticancer agent.
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Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives.
Bioorg. Med. Chem.
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In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC(50) values of 140 ± 10 nM and 10 ± 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC(50)=20 ± 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model.
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Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents.
Bioorg. Med. Chem.
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A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 ?M for PI3K?). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3K? structure active site to determine the probable binding model.
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Synthesis, biological evaluation, and molecular docking studies of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives as novel antitubulin agents.
Bioorg. Med. Chem.
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A series of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives (1h-20h) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 2h showed the most potent activity in vitro, which inhibited the growth of MCF-7, Hep-G2 and A549 cell lines with IC(50) values of 0.70 ± 0.05, 0.68 ± 0.02 and 0.86 ± 0.05 ?M, respectively. Compound 2h also exhibited significant tubulin polymerization inhibitory activity (IC(50)=3.06 ± 0.05 ?M). The result of flow cytometry (FCM) demonstrated that compound 2h induced cell apoptosis. Docking simulation was performed to insert compound 2h into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 2h with potent inhibitory activity in tumor growth may be a potential anticancer agent.
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Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents.
Bioorg. Med. Chem.
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A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 ?g/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 ?g/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.
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Synthesis, biological evaluation, and molecular docking studies of 1,3,4-thiadiazol-2-amide derivatives as novel anticancer agents.
Bioorg. Med. Chem.
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A series of 1,3,4-thiadiazol-2-amide derivatives (5a-5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC(50) values of 0.45 and 0.31 ?M, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC(50)=5.32 ?M). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent.
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Systemic treatment with CpG-B after sublethal rickettsial infection induces mouse death through indoleamine 2,3-dioxygenase (IDO).
PLoS ONE
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Due to its strong immune stimulatory effects through TLR9, CpG-containing oligodeoxynucleotides (CpG ODN) have been tested in multiple clinical trials as vaccine adjuvant for infectious diseases and cancer. However, immune suppression induced by systemic administration of CpGs has been reported recently. In this study, we evaluated the impact of CpGs in an acute rickettsiosis model. We found that systemic treatment with type B CpG (CpG-B), but not type A CpG (CpG-A), at 2 days after sublethal R. australis infection induced mouse death. Although wild-type (WT) B6 and IDO(-/-) mice showed similar survival rates with three different doses of R. australis infection, treatment with CpG-B after sublethal infection consistently induced higher mortality with greater tissue bacterial loads in WT but not IDO(-/-) mice. Also, CpG-B treatment promoted the development of higher serum concentrations of proinflammatory cytokines/chemokines through IDO. Furthermore, while T cell-mediated immune responses enhanced by CpG-B were independent of IDO, treatment with CpG-B promoted T cell activation, PD-1 expression and cell apoptosis partially through IDO. A depletion study using anti-mPDCA-1 mAb indicated that plasmacytoid dendritic cells (pDC) were not required for CpG-B-induced death of R. australis-infected mice. Additionally, the results in iNOS(-/-) mice suggested that nitric oxide (NO) was partially involved in CpG-B-induced death of R. australis-infected mice. Surprisingly, pre-treatment with CpG-B before administration of a lethal dose of R. australis provided effective immunity in WT, IDO(-/-) and iNOS(-/-) mice. Taken together, our study provides evidence that CpGs exert complex immunological effects by both IDO-dependent and -independent mechanisms, and that systemic treatment with CpGs before or after infection has a significant and distinct impact on disease outcomes.
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