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Find video protocols related to scientific articles indexed in Pubmed.
Flexible rectangular wave-breaking-free pulse generation in actively mode-locked ytterbium-doped fiber laser.
Opt Express
PUBLISHED: 11-18-2014
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We demonstrate nanosecond scale rectangular wave-breaking-free pulse generation in an actively mode locked Yb-doped fiber laser based on a combined action of active periodic cavity loss modulation and nonlinear polarization rotation effect. The pulse width of the laser can be controlled in the range of 890 ps to above 124 ns instantaneously by adjusting the electrical signal applied on the modulator. As high as 19.8 nJ wave-breaking-free pulse is achieved with maximum available pump power. The output pulse temporal dynamics exhibit various distinct characteristics under different modulation and polarization control. The laser presents unusually flexible tunabilities in pulse width, pulse energy and pulse shape.
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Salvia miltiorrhiza Injection on Pulmonary Heart Disease: A Systematic Review and Meta-Analysis.
Am. J. Chin. Med.
PUBLISHED: 11-15-2014
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Cor pulmonale (pulmonary heart disease) is a chronic progressive complicated disease for which treatment needs to be sustained all the time, creating a great financial burden on individuals and society. In order to improve the life quality of cor pulmonale patients and decrease the dosage and quantity of the routine treatment, in China, TCM is often administered to patients with cor pulmonale. The results of many clinical trials have indicated that Salvia miltiorrhiza and complex Salvia miltiorrhiza injection may be an alternative medicine for cor pulmonale. With the purpose to prove whether Salvia miltiorrhiza and complex Salvia miltiorrhiza benefit the cor pulmonale patients, respectively, we carried out a systematic review to evaluate the efficacy and safety of Salvia miltiorrhiza and complex Salvia miltiorrhiza injection in cor pulmonale patients. Overall, 2,715 patients were identified from 35 randomized controlled trials. The meta-analysis used I(2) test for heterogeneity and chose random or fixed model according to heterogeneity of included studies. Clinical outcomes were evaluated by total effectiveness rate, partial pressure of oxygen ( PaO 2) and carbon dioxide ( PaCO 2), hemorheology, mPAP and adverse effects. Compared with routine medicine treatment alone, routine medicine treatment plus Salvia miltiorrhiza or complex Salvia miltiorrhiza injection showed better outcomes: A significantly higher clinical effectiveness rate ratio (p < 0.001), increase in PaO 2 (p < 0.001) and decrease in PaCO 2 (p < 0.001), improvement in hemorheology (p < 0.001), and alleviation in mPAP (p < 0.05). There is no obvious adverse effect reported. In summary, there are some evidences suggesting that Salvia miltiorrhiza or complex Salvia miltiorrhiza injection are active in cor pulmonale, however, the results were limited by the methodological flaws of the included studies. Long-term and high quality clinical trials are needed to provide more conclusive evidence for the future use of Salvia miltiorrhiza injection.
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Chemical Bonding in a Linear Chromium Metal String Complex.
Inorg Chem
PUBLISHED: 11-11-2014
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A combined experimental and theoretical electron density study of the shortest trichromium metal wire, Cr3(dpa)4Cl2·(C2H5OC2H5)x(CH2Cl2)1-x (1, dpa = bis(2-pyridyl)amido), is reported. High resolution X-ray diffraction data has been collected both at 100 K using a conventional X-ray source (DS1) and at 15 K using a synchrotron X-ray source (DS2). The linear chromium string is terminated by Cl(-) ions at both ends, and each Cr atom is also coordinated by four N atoms from bridging dpa ligands. The two Cr-Cr bond distances are unequal at 100 K (with d(Cr1-Cr2) being 0.029 Å shorter than d(Cr2-Cr3)) but at 15 K they are almost equal (0.002 Å difference). Analysis of the slightly elongated thermal ellipsoids of the Cr2 atom suggests that it is not due to disorder, but the presence of a shallow potential energy surface. Laplacian maps clearly show local valence shell charge concentration (VSCC) in the electron density along the bisector of the equatorial Cr-N bonds. Integration over the atomic basins indicates that Cr2 has smaller atomic charge and volume than Cr1 and Cr3. The topological characterization of the Cr-Cr bonds indicates partly covalent characters with electron density at the bond critical point of ?0.3 e Å(-3) and negative total energy density. The delocalization index of Cr-Cr is 0.8 for Cr1-Cr2 and 0.08 for Cr1-Cr3. Second-order perturbation analysis shows high stabilization energy of the Cr-Cr bonds (E(2) ? 190 kcal mol(-1)). Delocalization indices and source function and natural bond orbital analyses are all indicative of localized Cr-Cr bonding interactions.
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Why a Lotus-like Superhydrophobic Surface Is Self-Cleaning? An Explanation from Surface Force Measurements and Analysis.
Langmuir
PUBLISHED: 11-04-2014
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The unique self-cleaning feature of the lotus-like superhydrophobic (SH) surface attracted worldwide interest in recent years. However, the mechanism of the self-cleaning phenomena remains unclear. Here, we attempt to provide a comprehensive understanding of why self-cleaning of the particles with a broad range of size can be realized on the lotus-like SH surfaces. After measurements and analysis of the force involved at the interface, we conclude that there are four main preconditions for self-cleaning: (1) contact angle (CA) > 90°, (2) low enough sliding angle, (3) low enough adhesion force, and (4) proper particle size. However, as far as the lotus-like SH surface and typical dust are concerned, all the preconditions will be satisfied automatically. We also observe that the particles with a broad range of size (from submicron level to the millimeter level) and density (virtually no limit) can be driven by a water droplet on the lotus-like SH surface. This interesting finding may be helpful for the design of novel engineering system at the micron-millimeter scale in the future.
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Facile Control of the Charge Density and Photocatalytic Activity of an Anionic Indium Porphyrin Framework via in Situ Metalation.
J. Am. Chem. Soc.
PUBLISHED: 10-28-2014
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An anionic indium porphyrin framework (UNLPF-10) consisting of rare Williams ?-tetrakaidecahedral cages was constructed using an octatopic ligand linked with 4-connected [In(COO)4](-) SBUs. Remarkably, the extent of indium metalation of porphyrin macrocycles in UNLPF-10 can be facilely tuned in situ depending on the M/L ratio during synthesis, resulting in a controllable framework charge density and photocatalytic activity toward the selective oxygenation of sulfides.
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Intermolecular interactions in solid-state metalloporphyrins and their impacts on crystal and molecular structures.
Inorg Chem
PUBLISHED: 10-23-2014
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A variable-temperature (VT) crystal structure study of [Fe(TPP)Cl] (TPP(2-) = meso-tetraphenylporphyrinate) and Hirshfeld surface analyses of its structures and previously reported structures of [M(TPP)(NO)] (M = Fe, Co) reveal that intermolecular interactions are a significant factor in structure disorder in the three metalloporphyrins and phase changes in the nitrosyl complexes. These interactions cause, for example, an 8-fold disorder in the crystal structures of [M(TPP)(NO)] at room temperature that obscures the M-NO binding. Hirshfeld analyses of the structure of [Co(TPP)(NO)] indicate that the phase change from I4/m to P1? leads to an increase in void-volume percentage, permitting additional structural compression through tilting of the phenyl rings to offset the close-packing interactions at the interlayer positions in the crystal structures with temperature decrease. X-ray and neutron structure studies of [Fe(TPP)Cl] at 293, 143, and 20 K reveal a tilting of the phenyl groups away from being perpendicular to the porphyrin ring as a result of intermolecular interactions. Structural similarities and differences among the three complexes are identified and described by Hirshfeld surface and void-volume calculations.
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Photocrystallographic observation of halide-bridged intermediates in halogen photoeliminations.
J. Am. Chem. Soc.
PUBLISHED: 10-21-2014
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Polynuclear transition metal complexes, which frequently constitute the active sites of both biological and chemical catalysts, provide access to unique chemical transformations that are derived from metal-metal cooperation. Reductive elimination via ligand-bridged binuclear intermediates from bimetallic cores is one mechanism by which metals may cooperate during catalysis. We have established families of Rh2 complexes that participate in HX-splitting photocatalysis in which metal-metal cooperation is credited with the ability to achieve multielectron photochemical reactions in preference to single-electron transformations. Nanosecond-resolved transient absorption spectroscopy, steady-state photocrystallography, and computational modeling have allowed direct observation and characterization of Cl-bridged intermediates (intramolecular analogues of classical ligand-bridged intermediates in binuclear eliminations) in halogen elimination reactions. On the basis of these observations, a new class of Rh2 complexes, supported by CO ligands, has been prepared, allowing for the isolation and independent characterization of the proposed halide-bridged intermediates. Direct observation of halide-bridged structures establishes binuclear reductive elimination as a viable mechanism for photogenerating energetic bonds.
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Reduced tumorigenicity and drug resistance through the downregulation of octamer-binding protein 4 and Nanog transcriptional factor expression in human breast stem cells.
Mol Med Rep
PUBLISHED: 10-20-2014
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Breast cancer is the most common type of malignancy among females. Previous studies examining breast cancer tissue have demonstrated the presence of stem cells, and have detected octamer?binding protein 4 (Oct4) and Nanog transcription factor expression. In the present study, breast cancer stem cells (CSCs) were isolated and enriched from MDA?MB?231 breast cancer cell lines, and were defined as MDA?MB?231 stem cells using flow cytometry. The expression of Oct4 and Nanog in breast CSCs were detected by quantitative polymerase chain reaction and western blotting. RNA interference (RNAi) was used in order to downregulate the expression of Oct4 and Nanog. Drug resistance and tumor?initiating capability following in vivo injection of MDA?MB?231 stem cells trans-duced with negative RNAi, Oct4 RNAi and Nanog RNAi were compared with that of MDA?MB?231 stem cells without siRNA transfection as a control group. In addition the capability of MDA?MB?231 breast cancer cells to initiate tumor formation in mice was compared with that of MDA?MB?231 stem cells. A paclitaxel inhibition test was also conducted in order to detect resistance of MDA?MB?231 breast cancer stem cells to this treatment. The MDA?MB?231 stem cells were revealed to exhibit elevated percentages of the cluster of differentiation (CD)44+CD24?/low subset, high tumorigenicity and resistance to chemotherapy, all of which are characteristic stem cell properties. In addition, the MDA?MB?231 stem cells were more tumorigenic in vivo. Furthermore, the breast CSCs also expressed high levels of the Oct4 and Nanog transcription factors. Therefore, downregulation of Oct4 or Nanog expression may reduce chemotherapeutic drug resistance and tumorigenicity in breast CSCs. In conclusion, Oct4 and Nanog expression may be a key factor in the development of resistance to chemotherapy and tumor growth of breast CSCs. This finding indicates that Oct4 or Nanog?targeted therapy may be a promising means of overcoming resistance to chemotherapy and inhibiting tumor growth in breast cancer treatment.
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An elusive fulvene 1,7,11,24-C60(CF3)4 and its unusual reactivity.
Chem. Commun. (Camb.)
PUBLISHED: 10-15-2014
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The X-ray crystal structure of a trifluoromethylfullerene (TMF), 1,7,11,24-C60(CF3)4, is reported for the first time. This elusive intermediate, while highly air stable as a solid, exhibits highly regioselective reactivity towards molecular oxygen in polar solvents, and only when exposed to light.
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Electric Field Effect on Phospholipid Monolayers at an Aqueous-Organic Liquid-Liquid Interface.
J Phys Chem B
PUBLISHED: 10-08-2014
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The electric potential difference across cell membranes, known as the membrane potential, plays an important role in the activation of many biological processes. To investigate the effect of the membrane potential on the molecular ordering of lipids within a biomimetic membrane, a self-assembled monolayer of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) lipids at an electrified 1,2-dichloroethane/water interface is studied with X-ray reflectivity and interfacial tension. Measurements over a range of electric potential differences, -150 to +130 mV, that encompass the range of typical biomembrane potentials demonstrate a nearly constant and stable structure whose lipid interfacial density is comparable to that found in other biomimetic membrane systems. Measurements at higher positive potentials, up to 330 mV, illustrate a monotonic decrease in the lipid interfacial density and accompanying variations in the interfacial configuration of the lipid. Molecular dynamics simulations, designed to mimic the experimental conditions, show that the measured changes in lipid configuration are due primarily to the variation in area per lipid with increasing applied electric field. Rotation of the SOPC dipole moment by the torque from the applied electric field appears to be negligible, except at the highest measured potentials. The simulations confirm in atomistic detail the measured potential-dependent characteristics of SOPC monolayers. Our hybrid study sheds light on phospholipid monolayer stability under different membrane potentials, which is important for understanding membrane processes. This study also illustrates the use of X-ray surface scattering to probe the ordering of surfactant monolayers at an electrified aqueous-organic liquid-liquid interface.
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Expression of ABCB6 is related to resistance to 5-FU, SN-38 and vincristine.
Anticancer Res.
PUBLISHED: 09-10-2014
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A previously established arsenite-resistant cell line, KAS, is also resistant to a variety of anticancer drugs. In order to understand responsible molecules for the multidrug resistance phenotype of KAS cells, we examined the expressions of ATP-binding cassette (ABC) transporters and found that the ABCB6 and ABCC1/ multidrug resistance protein 1 (ABCC1/MRP1) were increased. ABCC1/MRP1 was not completely responsible for the drug resistance spectrum of KAS cells and several reports have suggested that ABCB6 is related to anticancer drug and metal resistance. We, therefore, established and examined ABCB6-expressing KB cells and ABCB6-knockdown KAS cells. ABCB6 expression enhanced resistance to 5-fluorouracil (5-FU), SN-38 and vincristine (Vcr) but not to arsenite. Conversely, down-regulation of ABCB6 in KAS cells increased the sensitivity of KAS cells to 5-FU, SN-38 and Vcr, but not to arsenite. Our findings suggest that ABCB6 is involved in 5-FU, SN-38 and Vcr resistance.
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miR-200c attenuates P-gp mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colorectal cancer.
Mol. Cancer Ther.
PUBLISHED: 09-09-2014
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MicroRNA-200c (miR-200c) recently emerged as an important regulator of tumorigenicity and cancer metastasis, however, its role in regulating multidrug resistance (MDR) remains unknown. In the current study, we found that the expression levels of miR-200c in recurred and metastatic colorectal cancers (CRC) were significantly lower, while the JNK2 expression was higher compared to primary tumors. We showed that in MDR CRC cells, miR-200c targeted the 3'UTR of JNK2 gene. Over-expression of miR-200c attenuated the levels of p-JNK, p-c-Jun, P-gp and MMP-2/-9, the downstream factors of JNK signaling pathway, resulting in increased sensitivity to chemotherapeutic drugs, which was accompanied by heightened apoptosis and decreased cell invasion and migration. Moreover, in an orthotopic MDR CRC mouse model, we demonstrated that over-expression of miR-200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from locally advanced CRC patients with routine post-surgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR-200c and JNK2, ABCB1, MMP-9 thus predicting patient therapeutic outcomes. In summary, we found that miR-200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR CRC cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ABCB1 signaling. Restoration of miR-200c expression in MDR CRC may serve as a promising therapeutic approach in MDR induced metastasis.
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The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.
Oncotarget
PUBLISHED: 09-05-2014
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Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 ?M), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter.
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Tyrosine kinase inhibitors as reversal agents for ABC transporter mediated drug resistance.
Molecules
PUBLISHED: 09-04-2014
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Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases. These TKIs are remarkably effective in the treatment of various human cancers including head and neck, gastric, prostate and breast cancer and several types of leukemia. However, these TKIs are transported out of the cell by ATP-binding cassette (ABC) transporters, resulting in development of a characteristic drug resistance phenotype in cancer patients. Interestingly, some of these TKIs also inhibit the ABC transporter mediated multi drug resistance (MDR) thereby; enhancing the efficacy of conventional chemotherapeutic drugs. This review discusses the clinically relevant TKIs and their interaction with ABC drug transporters in modulating MDR.
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Annona squamosa Linn: cytotoxic activity found in leaf extract against human tumor cell lines.
Pak J Pharm Sci
PUBLISHED: 09-02-2014
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Cancer is a common cause of death in human populations. Surgery, chemotherapy and radiotherapy still remain the corner stone of treatment. However, herbal medicines are gaining popularity on account of their lesser harmful side effects on non-targeted human cells and biological environment. Annona squamosa Linn is a common delicious edible fruit and its leaf have been used for the treatment in various types of diseases. The objective of present study is to determine the anticancer potential of the organic and aqueous extracts of leaf of Annona squamosa L. MTT (3-(4, 5-dimethylthiazole-2yl)-2, 5-biphenyl tetrazolium bromide) assay against hepatocellular carcinoma cell line BEL-7404, lung cancer line H460, human epidermoid carcinoma cell line KB-3-1, prostatic cancer cell line DU145, breast carcinoma cell line MDA-MB-435, and colon cancer cell line HCT-116 Human primary embryonic kidney cell line HEK293 as control were used for the study. The crude extract (Zcd) and Ethyl acetate extract (ZE) were found significant anticancer activity only on human epidermoid carcinoma cell line KB-3-1 and colon cancer cell line HCT-116.
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Photoacoustic and ultrasound imaging using dual contrast perfluorocarbon nanodroplets triggered by laser pulses at 1064 nm.
Biomed Opt Express
PUBLISHED: 09-01-2014
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Recently, a dual photoacoustic and ultrasound contrast agent-named photoacoustic nanodroplet-has been introduced. Photoacoustic nanodroplets consist of a perfluorocarbon core, surfactant shell, and encapsulated photoabsorber. Upon pulsed laser irradiation the perfluorocarbon converts to gas, inducing a photoacoustic signal from vaporization and subsequent ultrasound contrast from the resulting gas microbubbles. In this work we synthesize nanodroplets which encapsulate gold nanorods with a peak absorption near 1064 nm. Such nanodroplets are optimal for extended photoacoustic imaging depth and contrast, safety and system cost. We characterized the nanodroplets for optical absorption, image contrast and vaporization threshold. We then imaged the particles in an ex vivo porcine tissue sample, reporting contrast enhancement in a biological environment. These 1064 nm triggerable photoacoustic nanodroplets are a robust biomedical tool to enhance image contrast at clinically relevant depths.
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Contemporary X-ray electron-density studies using synchrotron radiation.
IUCrJ
PUBLISHED: 09-01-2014
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Synchrotron radiation has many compelling advantages over conventional radiation sources in the measurement of accurate Bragg diffraction data. The variable photon energy and much higher flux may help to minimize critical systematic effects such as absorption, extinction and anomalous scattering. Based on a survey of selected published results from the last decade, the benefits of using synchrotron radiation in the determination of X-ray electron densities are discussed, and possible future directions of this field are examined.
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In vitro, in vivo and ex-vivo characterization of ibrutinib: A potent inhibitor of MRP1 efflux function.
Br. J. Pharmacol.
PUBLISHED: 08-28-2014
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Multidrug resistance protein 1 (MRP1, ABCC1) plays a critical role in the development of multidrug resistance (MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR.
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Size-Controlled Synthesis of Platinum-Copper Hierarchical Trigonal Bipyramid Nanoframes.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 08-20-2014
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Mastery over the structure of materials at nanoscale can effectively tailor and control their catalytic properties, enabling enhancement in both activity and durability. We report a size-controlled synthesis of novel Pt-Cu hierarchical trigonal bipyramid nanoframes (HTBNFs). The obtained nanocrystals looked like a trigonal bipyramid on the whole, composed of similar ordered frame structural units. By varying the amount of KI involved in the reaction, HTBNFs with variable sizes from 110 to 250 nm could be obtained. In addition, the structure of HTBNFs could be preserved only in a limited range of the Pt/Cu feeding ratio. Relative to the commercial Pt/C, these Pt-Cu HTBNFs with different Pt/Cu ratio exhibited enhanced electrocatalytic activity toward formic acid oxidation reaction as much as 5.5 times in specific activity and 2.1 times in mass activity. The excellent electrocatalytic activity and better durability are due to the unique structure of HTBNFs and probably synergetic effects between Pt and Cu.
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New localized/delocalized emitting state of Eu(2+) in orange-emitting hexagonal EuAl2O4.
Sci Rep
PUBLISHED: 08-12-2014
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Eu(2+)-activated phosphors are being widely used in illuminations and displays. Some of these phosphors feature an extremely broad and red-shifted Eu(2+) emission band; however, convincing explanation of this phenomenon is lacking. Here we report a new localized/delocalized emitting state of Eu(2+) ions in a new hexagonal EuAl2O4 phosphor whose Eu(2+) luminescence exhibits a very large bandwidth and an extremely large Stokes shift. At 77?K, two luminescent sites responsible for 550?nm and 645?nm broadband emissions are recognized, while at room temperature only the 645?nm emission band emits. The 645?nm emission exhibits a typical radiative lifetime of 1.27??s and an unusually large Stokes shift of 0.92?eV. We identify the 645?nm emission as originating from a new type of emitting state whose composition is predominantly that of localized 4f(6)5d character but which also contains a complementary component with delocalized conduction-band-like character. This investigation provides new insights into a unique type of Eu(2+) luminescence in solids whose emission exhibits both a very large bandwidth and an extremely large Stokes shift.
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Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance.
Cancers (Basel)
PUBLISHED: 07-31-2014
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The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.
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Oxygen transfer from an intramolecularly coordinated diaryltellurium oxide to acetonitrile. Formation and combined AIM and ELI-D analysis of a novel diaryltellurium acetimidate.
J. Am. Chem. Soc.
PUBLISHED: 07-25-2014
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The reaction of the intramolecularly coordinated diaryltellurium(IV) oxide (8-Me2NC10H6)2TeO with acetonitrile proceeds with oxygen transfer and gives rise to the formation of the novel zwitterionic diaryltelluronium(IV) acetimidate (8-Me2NC10H6)2TeNC(O)CH3 (1) in 57% yield. Hydrolysis of 1 with hydrochloric acid affords acetamide and the previously known diarylhydroxytelluronium(IV) chloride [(8-Me2NC10H6)2Te(OH)]Cl.
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The structure and energetics of arsenic(III) oxide intercalated by ionic azides.
Dalton Trans
PUBLISHED: 07-15-2014
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Unprecedented intercalates of arsenic(iii) oxide with potassium azide and ammonium azide have been obtained and characterized by single crystal X-ray diffraction. The compounds are built of As2O3 sheets separated by charged layers of cations and azide anions perpendicular to the sheets. The intercalates are an interesting example of hybrid materials whose structure is governed by covalent bonds in two directions and ionic bond in the third one. The obtained compounds are the first examples of As2O3 intercalates containing linear pseudohalogen anions. Periodic DFT calculations of interlayer interaction energies were carried out with the B3LYP-D* functional. The layers are held together mainly by ionic bonds, although the computations indicate that interactions between cations and As2O3 sheets also play a significant role. A comparison of cation and anion interaction energies with neutral As2O3 sheets sheds light on the crystallisation process, indicating the templating effect of potassium and ammonium cations. It consist in the formation of sandwich complexes of cations with crown-ether-resembling As6O12 rings. Raman spectra of both compounds are recorded and computed ab initio and all vibrational bands are assigned.
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Novel hybrids of natural oridonin-bearing nitrogen mustards as potential anticancer drug candidates.
ACS Med Chem Lett
PUBLISHED: 07-10-2014
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A series of novel hybrids from natural product oridonin and nitrogen mustards were designed and synthesized to obtain more efficacious and less toxic antitumor agents. The antiproliferative evaluation showed that most conjugates were more potent than their parent compounds oridonin and clinically used nitrogen mustards against four human cancer cell lines (K562, MCF-7, Bel-7402, and MGC-803). Furthermore, the representative compounds 16a-c exhibited antiproliferative activities against the multidrug resistant cell lines (SW620/AD300 and NCI-H460/MX20). It was shown that the most effective compound 16b possesses a strong inhibitory activity with an IC50 value 21-fold lower than that of oridonin in MCF-7 cells and also exhibits selective cytotoxicity toward the cancer cells. Intriguingly, compound 16b has been demonstrated to significantly induce apoptosis and affect cell cycle progression in human hepatoma Bel-7402 cells.
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Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2.
Oncotarget
PUBLISHED: 07-02-2014
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ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
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Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2.
Oncotarget
PUBLISHED: 07-01-2014
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ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
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Transcriptome of the inflorescence meristems of the biofuel plant Jatropha curcas treated with cytokinin.
BMC Genomics
PUBLISHED: 06-21-2014
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Jatropha curcas, whose seed content is approximately 30-40% oil, is an ideal feedstock for producing biodiesel and bio-jet fuels. However, Jatropha plants have a low number of female flowers, which results in low seed yield that cannot meet the needs of the biofuel industry. Thus, increasing the number of female flowers is critical for the improvement of Jatropha seed yield. Our previous findings showed that cytokinin treatment can increase the flower number and female to male ratio and also induce bisexual flowers in Jatropha. The mechanisms underlying the influence of cytokinin on Jatropha flower development and sex determination, however, have not been clarified.
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Characterization of a Multicomponent Lithium Lithiate from a Combined X-Ray Diffraction, NMR Spectroscopy, and Computational Approach.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 06-17-2014
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An unusual lithium lithiate [Li(diglyme)2 ][(diglyme)Li2 (C4 H3 S)3 ], made up from three carbanions, two lithium cations, and a single donor base molecule in the anion and a single lithium cation, coordinated by two donor base molecules, is investigated in a combined study including X-ray diffraction, NMR spectroscopy and computational approaches in solution and the solid state. While the multicomponent lithiate is the only species present in the solid state, solution NMR spectroscopy and computational methods were employed to identify a second species in solution. The dimer [(diglyme)Li(C4 H3 S)]2 coexists with the lithiate in solution in a 1:1 ratio, the more the higher the polarity of the solvent is. Only the combination of this multitude of methods provides a firm picture of the whole.
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Cytokine detection by flow cytometry.
Methods Mol. Biol.
PUBLISHED: 06-09-2014
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Analysis of intracellular cytokines is extremely important in the clinical treatment of numerous diseases. Flow cytometry (FCM) is a highly effective technique that detects intracellular cytokines using specific fluorescence-labeled antibodies. The common steps of this assay include cell collection, fixation, permeabilization, blocking, intracellular staining and analysis by FCM. This technique also allows for analyzing the biological function of cytokines. In this chapter, we describe a modified method to detect the specific intracellular cytokine staining using FCM, with an emphasis on the effects of variables including samples, temperature, buffers, data acquisition, and analysis.
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Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells.
Mar Drugs
PUBLISHED: 05-29-2014
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ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1-12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure-activity relationship analysis inclusive of the natural products 1-12 and the synthetic analogues 13-19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.
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Thermally robust and porous noncovalent organic framework with high affinity for fluorocarbons and CFCs.
Nat Commun
PUBLISHED: 05-23-2014
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Metal-organic and covalent organic frameworks are porous materials characterized by outstanding thermal stability, high porosities and modular synthesis. Their repeating structures offer a great degree of control over pore sizes, dimensions and surface properties. Similarly precise engineering at the nanoscale is difficult to achieve with discrete molecules, since they rarely crystallize as porous structures. Here we report a small organic molecule that organizes into a noncovalent organic framework with large empty pores. This structure is held together by a combination of [N-H···N] hydrogen bonds between the terminal pyrazole rings and [?···?] stacking between the electron-rich pyrazoles and electron-poor tetrafluorobenzenes. Such a synergistic arrangement makes this structure stable to at least 250?°C and porous, with an accessible surface area of 1,159?m(2)?g(-1). Crystals of this framework adsorb hydrocarbons, CFCs and fluorocarbons-the latter two being ozone-depleting substances and potent greenhouse species-with weight capacities of up to 75%.
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CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function.
Biochem. Pharmacol.
PUBLISHED: 05-17-2014
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The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.
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In-vivo ultrasound and photoacoustic image- guided photothermal cancer therapy using silica-coated gold nanorods.
IEEE Trans Ultrason Ferroelectr Freq Control
PUBLISHED: 05-08-2014
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In nanoparticle-augmented photothermal therapy, evaluating the delivery and spatial distribution of nanoparticles, followed by remote temperature mapping and monitoring, is essential to ensure the optimal therapeutic outcome. The utility of ultrasound and photoacoustic imaging to assist photothermal therapy has been previously demonstrated. Here, using a mouse xenograft tumor model, it is demonstrated in vivo that ultrasound-guided photoacoustic imaging can be used to plan the treatment and to guide the therapy. To evaluate nanoparticle delivery and spatial distribution, three-dimensional ultrasound and spectroscopic photoacoustic imaging of a mouse with a tumor was performed before and after intravenous injection of silica-coated gold nanorods. After injection and sufficient circulation of nanoparticles, photothermal therapy was performed for 5 min using an 808-nm continuous-wave laser. During the photothermal therapy, photoacoustic images were acquired continuously and used to measure the temperature changes within tissue. A heterogeneous distribution of temperature, which was spatially correlated with the measured distribution of nanoparticles, indicated that peak temperatures of 53°C were achieved in the tumor. An Arrhenius thermal damage model determined that this thermal deposition would result in significant cell death. The results of this study suggest that ultrasound and photoacoustic imaging can effectively guide photothermal therapy to achieve the desired thermal treatment.
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Design and synthesis of human ABCB1 (P-glycoprotein) inhibitors by peptide coupling of diverse chemical scaffolds on carboxyl and amino termini of (S)-valine-derived thiazole amino acid.
J. Med. Chem.
PUBLISHED: 05-07-2014
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P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 ?M) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [(125)I]-iodoarylazidoprazosin with IC50 = 0.75 ?M and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 ?M). Compound 28 at 3 ?M reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.
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Poly(trifluoromethyl)azulenes: structures and acceptor properties.
Chem. Commun. (Camb.)
PUBLISHED: 05-02-2014
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Six new poly(trifluoromethyl)azulenes prepared in a single high-temperature reaction exhibit strong electron accepting properties in the gas phase and in solution and demonstrate the propensity to form regular ?-stacked columns in donor-acceptor crystals when mixed with pyrene as a donor.
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Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1.
Biochem. Pharmacol.
PUBLISHED: 05-01-2014
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Cancer cells often become resistant to chemotherapy through a phenomenon known as multidrug resistance (MDR). Several factors are responsible for the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP binding cassette (ABC) transporters. Some small molecule tyrosine kinase inhibitors (TKIs) were recently reported to modulate the activity of ABC transporters. Therefore, the purpose of this study was to determine if motesanib, a multikinase inhibitor, could reverse ABCB1-mediated MDR. The results showed that motesanib significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Motesanib significantly increased the accumulation of [(3)H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant change in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 3?M motesanib for 72h. Moreover, motesanib stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, the docking studies indicated favorable binding of motesanib within the transmembrane region of homology modeled human ABCB1. Here, we report for the first time, motesanib, at clinically achievable plasma concentrations, antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings may be useful for cancer combination therapy with TKIs in the clinic.
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Hepatitis B virus vaccination booster does not provide additional protection in adolescents: a cross-sectional school-based study.
BMC Public Health
PUBLISHED: 03-30-2014
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Current consensus does not support the use of a universal booster of hepatitis B virus (HBV) vaccine because there is an anamnestic response in almost all children 15 years after universal infant HBV vaccination. We aimed to provide a booster strategy among adolescents as a result of their changes in lifestyle and sexual activity.
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Acerinol, a cyclolanstane triterpenoid from Cimicifuga acerina, reverses ABCB1-mediated multidrug resistance in HepG2/ADM and MCF-7/ADR cells.
Eur. J. Pharmacol.
PUBLISHED: 03-27-2014
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Persistent cancer chemotherapy can lead to multidrug resistance which is one of the most common reasons for failure of chemotherapy. The ABCB1 transporter is a member of the ATP-binding cassette superfamily and it is frequently over-expressed in multidrug resistant cancer cells. Active ingredients derived from traditional Chinese medicinal herbs have been reported to reverse multidrug resistance mediated by ATP-binding cassette transporters. In this study, acerinol, isolated from Cimicifuga acerina, was tested for its potential to modulate the ABCB1 transporter. Our results demonstrated that acerinol could increase the chemosensitivity of ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to chemotherapeutic drugs, doxorubicin, vincristine and paclitaxel. Furthermore, it could also increase the retention of ABCB1 substrates doxorubicin and rhodamine 123 in HepG2/ADM and MCF-7/ADR cells. A mechanistic study showed that acerinol significantly stimulated the activity of ABCB1 ATPase without affecting the expression of ABCB1 on neither mRNA nor protein level. Acerinol was also found to reverse the resistance of MCF-7/ADR cells to vincristine, dependent partly on ABCB1. In addition, acerinol?s action was reversible, suggesting that acerinol may act as a competitive inhibitor of ABCB1 by competing with other drug substrates like doxorubicin. Indeed, docking analysis indicated that acerinol would most likely bind to the sites on ABCB1 that partly overlapped with that of verapamil. In conclusion, the present study is the first to show that acerinol from C. acerina significantly enhances the cytotoxicity of chemotherapeutic drugs by modulating the function of ABCB1. It is hopeful to develop acerinol as a new multidrug resistance reversal agent.
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AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.
Cancer Lett.
PUBLISHED: 03-26-2014
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AST1306, an inhibitor of EGFR and ErbB2, is currently in phase I of clinical trials. We evaluated the effect of AST306 on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters. We found that AST1306 significantly sensitized the ABC subfamily G member 2 (ABCG2)-overexpressing cells to ABCG2 substrate chemotherapeutics. AST1306 significantly increased intracellular accumulation of [(3)H]-mitoxantrone in ABCG2-overexpressing cells by blocking ABCG2 efflux function. Moreover, AST1306 stimulated the ATPase activity of ABCG2. Homology modeling predicted the binding conformation of AST1306 to be within the transmembrane region of ABCG2. In conclusion, AST1306 could notably reverse ABCG2-mediated MDR.
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Linsitinib (OSI-906) antagonizes ATP-binding cassette subfamily G member 2 and subfamily C member 10-mediated drug resistance.
Int. J. Biochem. Cell Biol.
PUBLISHED: 03-06-2014
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In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38 in ABCG2-overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10-overexpressing cells. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, linsitinib significantly increased the intracellular accumulation and decreased the efflux of [(3)H]-MX in ABCG2-overexpressing cells and [(3)H]-paclitaxel in ABCC10-overexpressing cells. However, linsitinib, at a concentration that reversed MDR, did not significantly alter the expression levels of either the ABCG2 or ABCC10 transporter proteins. Furthermore, linsitinib did not significantly alter the intracellular localization of ABCG2 or ABCC10. Moreover, linsitinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner. Overall, our study suggests that linsitinib attenuates ABCG2- and ABCC10-mediated MDR by directly inhibiting their function as opposed to altering ABCG2 or ABCC10 protein expression.
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[The clinical significance of preoperative enteral immune nutrition in patients with malignant gastrointestinal tumors].
Sichuan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 02-18-2014
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To study the impact of preoperative enteral immune nutrition on patients with malignant gastrointestinal tumors.
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Phase transition of [2,2]-paracyclophane--an end to an apparently endless story.
Chemistry
PUBLISHED: 02-17-2014
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In this contribution, the solid-state low-temperature phase structure of [2,2]-paracyclophane is unambiguously characterised by single-crystal X-ray analysis. Additionally, a heat capacity measurement was undertaken, which proves the existence of a ?-type phase transition at 45?K, a transition that is connected with the formation of a secondary Cp/T feature at 60?K. The low-temperature phase (<45?K) crystallises in the lower symmetry space group P4n2, whereas the high-temperature phase (>60?K) crystallises in space group P4(2)/mnm. This proves what has been postulated both by experimental and theoretical chemists but has repeatedly been dismissed as speculation many times.
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ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.
J. Cell. Biochem.
PUBLISHED: 02-12-2014
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ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0??M) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0??M) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2.
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Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo.
Biochem. Pharmacol.
PUBLISHED: 02-11-2014
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Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 ?M did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 ?M significantly enhanced the intracellular accumulation of [(3)H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 ?M significantly reduced the rate of [(3)H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [(3)H]-E?17?G in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15 mg/kg) with doxorubicin (1.8 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.
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Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.
Int. J. Oncol.
PUBLISHED: 02-06-2014
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In this in vitro study, we determined whether masitinib could reverse multidrug resistance (MDR) in cells overexpressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter. Masitinib (1.25 and 2.5 µM) significantly decreases the resistance to mitoxantrone (MX), SN38 and doxorubicin in HEK293 and H460 cells overexpressing the ABCG2 transporter. In addition, masitinib (2.5 µM) significantly increased the intracellular accumulation of [(3)H]-MX, a substrate for ABCG2, by inhibiting the function of ABCG2 and significantly decreased the efflux of [(3)H]-MX. However, masitinib (2.5 µM) did not significantly alter the expression of the ABCG2 protein. In addition, a docking model suggested that masitinib binds within the transmembrane region of a homology-modeled human ABCG2 transporter. Overall, our in vitro findings suggest that masitinib reverses MDR to various anti-neoplastic drugs in HEK293 and H460 cells overexpressing ABCG2 by inhibiting their transport activity as opposed to altering their levels of expression.
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Direct X-ray observation of trapped CO? in a predesigned porphyrinic metal-organic framework.
Chemistry
PUBLISHED: 02-01-2014
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Metal-organic frameworks (MOFs) are emerging microporous materials that are promising for capture and sequestration of CO2 due to their tailorable binding properties. However, it remains a grand challenge to pre-design a MOF with a precise, multivalent binding environment at the molecular level to enhance CO2 capture. Here, we report the design, synthesis, and direct X-ray crystallographic observation of a porphyrinic MOF, UNLPF-2, that contains CO2-specific single molecular traps. Assembled from an octatopic porphyrin ligand with [Co2(COO)4] paddlewheel clusters, UNLPF-2 provides an appropriate distance between the coordinatively unsaturated metal centers, which serve as the ideal binding sites for in situ generated CO2. The coordination of Co(II) in the porphyrin macrocycle is crucial and responsible for the formation of the required topology to trap CO2. By repeatedly releasing and recapturing CO2, UNLPL-2 also exhibits recyclability.
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Ponatinib enhances anticancer drug sensitivity in MRP7-overexpressing cells.
Oncol. Rep.
PUBLISHED: 01-28-2014
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The presence of acquired multidrug resistance (MDR) is one of the primary impediments to the success of chemotherapy. MDR is often a result of overexpression of ATP-binding cassette (ABC) transporters, which are involved in the extrusion of therapeutic drugs. Recently, it was shown that several ABC transporters could be modulated by specific tyrosine-kinase inhibitors (TKIs). Ponatinib, a multi-targeted TKI, inhibits the activity of BCR-ABL with very high potency and broad specificity, including the T315I mutation which confers resistance to other TKIs. It was reported that ponatinib was capable of reversing breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated MDR. In the present study, we report for the first time that ponatinib also potentiates the cytotoxicity of widely used therapeutic substrates of MRP7, such as paclitaxel, docetaxel, vincristine and vinblastine. Ponatinib significantly enhances the accumulation of [3H]-paclitaxel in cells expressing MRP7. Furthermore, accumulation of [3H]-paclitaxel was achieved by inhibition of MRP7-mediated transport. Ponatinb limited drug export via MRP7 by multiple mechanisms. In addition to inhibition of pump function, ponatinib also downregulated MRP7 protein expression in a time- and concentration-dependent manner. Thus, ponatinib may represent a potential reversal agent for the treatment of MDR and may be useful for combination therapy in MDR cancer patients in clinical practice.
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A novel manganese-doped large polyoxotitanate nanocluster.
Dalton Trans
PUBLISHED: 01-25-2014
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A large manganese-doped polyoxotitanate nanocluster Ti28MnO38(OEt)40H2, has been synthesized solvothermally. Its structure is arranged around the four-coordinate Mn(2+) dopant atom in a Keggin-type structure. A significant reduction of the band gap relative to that of undoped polyoxotitanate clusters is observed.
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WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.
Cancer Sci.
PUBLISHED: 01-23-2014
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ATP-binding cassette (ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 ?M). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.
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Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.
Mol. Cancer Ther.
PUBLISHED: 01-15-2014
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Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 ?mol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10.
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Host perturbation in a ?-hydroquinone clathrate studied by combined X-ray/neutron charge-density analysis: implications for molecular inclusion in supramolecular entities.
Chemistry
PUBLISHED: 01-12-2014
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X-ray/neutron (X/N) diffraction data measured at very low temperature (15?K) in conjunction with ab initio theoretical calculations were used to model the crystal charge density (CD) of the host-guest complex of hydroquinone (HQ) and acetonitrile. Due to pseudosymmetry, information about the ordering of the acetonitrile molecules within the HQ cavities is present only in almost extinct, very weak diffraction data, which cannot be measured with sufficient accuracy even by using the brightest X-ray and neutron sources available, and the CD model of the guest molecule was ultimately based on theoretical calculations. On the other hand, the CD of the HQ host structure is well determined by the experimental data. The neutron diffraction data provide hydrogen anisotropic thermal parameters and positions, which are important to obtain a reliable CD for this light-atom-only crystal. Atomic displacement parameters obtained independently from the X-ray and neutron diffraction data show excellent agreement with a |?U| value of 0.00058?Å(2) indicating outstanding data quality. The CD and especially the derived electrostatic properties clearly reveal increased polarization of the HQ molecules in the host-guest complex compared with the HQ molecules in the empty HQ apohost crystal structure. It was found that the origin of the increased polarization is inclusion of the acetonitrile molecule, whereas the change in geometry of the HQ host structure following inclusion of the guest has very little effect on the electrostatic potential. The fact that guest inclusion has a profound effect on the electrostatic potential suggests that nonpolarizable force fields may be unsuitable for molecular dynamics simulations of host-guest interaction (e.g., in protein-drug complexes), at least for polar molecules.
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Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
Cell Res.
PUBLISHED: 01-10-2014
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The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
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Crystal engineering of an nbo topology metal-organic framework for chemical fixation of CO2 under ambient conditions.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 01-05-2014
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Crystal engineering of the nbo metal-organic framework (MOF) platform MOF-505 with a custom-designed azamacrocycle ligand (1,4,7,10-tetrazazcyclododecane-N,N',N'',N'''-tetra-p-methylbenzoic acid) leads to a high density of well-oriented Lewis active sites within the cuboctahedral cage in MMCF-2, [Cu2(Cu-tactmb)(H2O)3(NO3)2]. This MOF demonstrates high catalytic activity for the chemical fixation of CO2 into cyclic carbonates at room temperature under 1?atm pressure.
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An Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio Predicts Favorable Response and Prognosis in Locally Advanced Breast Cancer following Neoadjuvant Chemotherapy.
PLoS ONE
PUBLISHED: 01-01-2014
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Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer.
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Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP).
Future Oncol
PUBLISHED: 12-03-2013
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 Aim: This study aimed to investigate the mechanism of reversal of multidrug resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors. Materials & methods: ABCB1- and ABCG2-overexpressing cell lines were treated with respective substrate antineoplastic agents in the presence or absence of tivozanib. Results: The results indicate that tivozanib can significantly reverse ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux assays showed that tivozanib increased the intracellular accumulation of substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2. Conclusion: We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters.
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Antineoplastic activity of Holoptelea integrifolia (Roxb.) Planch bark extracts (in vitro).
Pak J Pharm Sci
PUBLISHED: 11-06-2013
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Cancer remains the major public health concern with a number of cancer patients relying on chemotherapy as a treatment option. Although, advances in biomedical research have led to increased anticancer agents in recent years, the treatment is not always effective due to resistance, toxicity or other factors. Phytochemicals and their active components isolated from plants have provided diversified effective drugs many of them are currently used against cancer and other diseases. Holoptelea integrifolia (Roxb) Planch (Ulmaceae) is a widely distributed plant in many parts of the world, also grown in gardens of Pakistan. It is an ornamental plant with certain medicinal characteristics due to many valuable and active phyto constituents in various parts of the plant. We looked at in vitro antineoplastic effects of four different extracts, in butanol (BMBU), hexane (BMHx), ethyl acetate (BMET) and chloroform (BMCHF), from bark of Holoptelea integrifolia on small cell lung cancer, breast, prostate, coloretal and hepatocellular cancer cell lines. Plant extracts BMHx and BMET showed significant cytotoxic effects on breast and prostate cancer cells. These preliminary studies are encouraging to proceed further this research in future, regarding the isolation of active phytoconstituents in these extracts as well as its mechanism in chemoprevention and combination anticancer therapy.
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Role of the Metal in the Bonding and Properties of Bimetallic Complexes Involving Manganese, Iron, and Cobalt.
J. Am. Chem. Soc.
PUBLISHED: 11-06-2013
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A multidentate ligand platform is introduced that enables the isolation of both homo- and heterobimetallic complexes of divalent first-row transition metal ions such as Mn(II), Fe(II), and Co(II). By means of a two-step metalation strategy, five bimetallic coordination complexes were synthesized with the general formula M1M2Cl(py3tren), where py3tren is the triply deprotonated form of N,N,N-tris(2-(2-pyridylamino)ethyl)amine. The metal-metal pairings include dicobalt (1), cobalt-iron (2), cobalt-manganese (3), diiron (4), and iron-manganese (5). The bimetallic complexes have been investigated by X-ray diffraction and X-ray anomalous scattering studies, cyclic voltammetry, magnetometry, Mössbauer spectroscopy, UV-vis-NIR spectroscopy, NMR spectroscopy, combustion analyses, inductively coupled plasma optical emission spectrometry, and ab initio quantum chemical methods. Only the diiron chloride complex in this series contains a metal-metal single bond (2.29 Å). The others show weak metal-metal interactions (2.49 to 2.53 Å). The diiron complex is also distinct with a septet ground state, while the other bimetallic species have much lower spin states from S = 0 to S = 1. We propose that the diiron system has delocalized metal-metal bonding electrons, which seems to correlate with a short metal-metal bond and a higher spin state. Multiconfigurational wave function calculations revealed that, indeed, the metal-metal bonding orbitals in the diiron complex are much more delocalized than those of the dicobalt analogue.
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A structural study of a three-membered linear metal chain compound at elevated pressure.
Dalton Trans
PUBLISHED: 11-05-2013
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Single crystal X-ray diffraction studies of the symmetrical molecular wire compound Co3(dpa)4Cl2·(dcm) have been performed up to a pressure of 3.6 GPa using both synchrotron and conventional sources. It is found that the terminal Co-Cl bond distance initially increases by 0.013(4) Å at 0.32 GPa after which it continuously decreases. Extensive theoretical calculations show that population of a thermally excited state containing increased Co-Cl anti-bonding character is a possibility at 0.32 GPa. The relative occupancy of the disordered dcm solvent molecule changes significantly with pressure and this is explained by the analysis of void spaces and Hirshfeld surfaces at different pressures. At 3.2 GPa, fingerprint plots derived from Hirshfeld surfaces indicate that neighbouring metal chain compounds approach each other such that short HH interactions appear.
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Development and optimization of near-IR contrast agents for immune cell tracking.
Biomed Opt Express
PUBLISHED: 11-01-2013
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Gold nanorods (NRs) are attractive for in vivo imaging due to their high optical cross-sections and tunable absorbance. However, the feasibility of using NRs for cell tracking has not been fully explored. Here, we synthesized dye doped silica-coated NRs as multimodal contrast agents for imaging of macrophages - immune cells which play an important role in cancer and cardiovascular diseases. We showed the importance of silica coating in imaging of NR-labeled cells. Photoacoustic (PA) imaging of NRs labeled macrophages showed high sensitivity. Therefore, these results provide foundation for applications of silica-coated NRs and PA imaging in tracking of immune cells.
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Silica-coated gold nanoplates as stable photoacoustic contrast agents for sentinel lymph node imaging.
Nanotechnology
PUBLISHED: 10-11-2013
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A biopsy of the first lymph node to which a tumor drains-the sentinel lymph node (SLN)-is commonly performed to identify micrometastases. Image guidance of the SLN biopsy procedure has the potential to improve its accuracy and decrease its morbidity. We have developed a new stable contrast agent for photoacoustic image-guided SLN biopsy: silica-coated gold nanoplates (Si-AuNPs). The Si-AuNPs exhibit high photothermal stability when exposed to pulsed and continuous wave laser irradiation. This makes them well suited for in vivo photoacoustic imaging. Furthermore, Si-AuNPs are shown to have low cytotoxicity. We tested the Si-AuNPs for SLN mapping in a mouse model where they exhibited a strong, sustained photoacoustic signal. Real-time ultrasound and photoacoustic imaging revealed that the Si-AuNPs quickly drain to the SLN, gradually spreading throughout a large portion of the node.
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Recent advances regarding the role of ABC subfamily C member 10 (ABCC10) in the efflux of antitumor drugs.
Chin J Cancer
PUBLISHED: 10-09-2013
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ABCC10, also known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily. ABCC10 mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs. The ABCC10 transporter is a 170-kDa protein that is localized on the basolateral cell membrane. ABCC10 is a broad-specificity transporter of xenobiotics, including antitumor drugs, such as taxanes, epothilone B, vinca alkaloids, and cytarabine, as well as modulators of the estrogen pathway, such as tamoxifen. In recent years, ABCC10 inhibitors, including cepharanthine, lapatinib, erlotinib, nilotinib, imatinib, sildenafil, and vardenafil, have been reported to overcome ABCC10-mediated MDR. This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy, particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.
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[Diagnostic investigation of the detection of granulocyte-macrophage colony stimulating factor antibody in serum for pulmonary alveolar proteinosis].
Zhonghua Jie He He Hu Xi Za Zhi
PUBLISHED: 09-20-2013
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To evaluate the diagnostic value of granulocyte-macrophage colony stimulating factor (GM-CSF) antibody in serum for pulmonary alveolar proteinosis (PAP).
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?-elemene, a compound derived from Rhizoma zedoariae, reverses multidrug resistance mediated by the ABCB1 transporter.
Oncol. Rep.
PUBLISHED: 09-17-2013
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In the present in vitro study, we examined the effect of the compound ?-elemene on the response of KB-C2 cells overexpressing the ABCB1 transporter to specific antineoplastic compounds. The MTT assay was used to determine the effects of ?-elemene in combination with other anticancer drugs on ABCB1-overexpressing cancer cell lines. Furthermore, we used [3H]-paclitaxel accumulation, efflux assay, immunofluorescence experiments, western blot assays and docking analysis to ascertain the mechanism of action of ?-elemene. The incubation of KB-C2 cells overexpressing ABCB1 transporter with ?-elemene (100 µM) significantly augmented the antineoplastic efficacy of colchicine, vinblastine and paclitaxel when compared to KB-C2 cells incubated with these drugs alone. In HEK293 cells overexpressing the ABCB1 transporter, ?-elemene significantly increased the cytotoxicity of paclitaxel. In addition, 100 µM of ?-elemene significantly increased the accumulation of [3H]-paclitaxel and this was due to a decrease in [3H]-paclitaxel efflux when compared to controls. The incubation of KB-C2 cells with ?-elemene (100 µM) for 72 h did not significantly alter the expression of ABCB1 protein levels. Immunofluorescence experiments indicated that ?-elemene did not significantly alter the subcellular localization of the ABCB1 transporter. Docking analysis indicated that ?-elemene binds to the drug-binding site of ABCB1 transporter. Finally, ?-elemene at 100 µM partially (~50%) increased the sensitivity of the BCRP-overexpressing cell line, NCI-H460/MX20, to mitoxantrone, but ?-elemene did not significantly alter the resistance of MRP1-transfected HEK293/MRP1 cells to vincristine. Overall, our in vitro findings indicated that ?-elemene potentiates the cytotoxic effects of various antineoplastic drugs in cell lines overexpressing the ABCB1 transporter and that this is due to the inhibition of the efflux component of the ABCB1 transporter.
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Synthesis of open-shell, bimetallic Mn/Fe trinuclear clusters.
J. Am. Chem. Soc.
PUBLISHED: 09-11-2013
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Concomitant deprotonation and metalation of hexadentate ligand platform (tbs)LH6 ((tbs)LH6 = 1,3,5-C6H9(NHC6H4-o-NHSiMe2(t)Bu)3) with divalent transition metal starting materials Fe2(Mes)4 (Mes = mesityl) or Mn3(Mes)6 in the presence of tetrahydrofuran (THF) resulted in isolation of homotrinuclear complexes ((tbs)L)Fe3(THF) and ((tbs)L)Mn3(THF), respectively. In the absence of coordinating solvent (THF), the deprotonation and metalation exclusively afforded dinuclear complexes of the type ((tbs)LH2)M2 (M = Fe or Mn). The resulting dinuclear species were utilized as synthons to prepare bimetallic trinuclear clusters. Treatment of ((tbs)LH2)Fe2 complex with divalent Mn source (Mn2(N(SiMe3)2)4) afforded the bimetallic complex ((tbs)L)Fe2Mn(THF), which established the ability of hexamine ligand (tbs)LH6 to support mixed metal clusters. The substitutional homogeneity of ((tbs)L)Fe2Mn(THF) was determined by (1)H NMR, (57)Fe Mössbauer, and X-ray fluorescence. Anomalous scattering measurements were critical for the unambiguous assignment of the trinuclear core composition. Heating a solution of ((tbs)LH2)Mn2 with a stoichiometric amount of Fe2(Mes)4 (0.5 mol equiv) affords a mixture of both ((tbs)L)Mn2Fe(THF) and ((tbs)L)Fe2Mn(THF) as a result of the thermodynamic preference for heavier metal substitution within the hexa-anilido ligand framework. These results demonstrate for the first time the assembly of mixed metal cluster synthesis in an unbiased ligand platform.
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Mixed-valent dicobalt and iron-cobalt complexes with high-spin configurations and short metal-metal bonds.
Inorg Chem
PUBLISHED: 07-31-2013
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Cobalt-cobalt and iron-cobalt bonds are investigated in coordination complexes with formally mixed-valent [M2](3+) cores. The trigonal dicobalt tris(diphenylformamidinate) compound, Co2(DPhF)3, which was previously reported by Cotton, Murillo, and co-workers (Inorg. Chim. Acta 1996, 249, 9), is shown to have an energetically isolated, high-spin sextet ground-state by magnetic susceptibility and electron paramagnetic resonance (EPR) spectroscopy. A new tris(amidinato)amine ligand platform is introduced. By tethering three amidinate donors to an apical amine, this platform offers two distinct metal-binding sites. Using the phenyl-substituted variant (abbreviated as L(Ph)), the isolation of a dicobalt homobimetallic and an iron-cobalt heterobimetallic are demonstrated. The new [Co2](3+) and [FeCo](3+) cores have high-spin sextet and septet ground states, respectively. Their solid-state structures reveal short metal-metal bond distances of 2.29 Å for Co-Co and 2.18 Å for Fe-Co; the latter is the shortest distance for an iron-cobalt bond to date. To assign the positions of iron and cobalt atoms as well as to determine if Fe/Co mixing is occurring, X-ray anomalous scattering experiments were performed, spanning the Fe and Co absorption energies. These studies show only a minor amount of metal-site mixing in this complex, and that FeCoL(Ph) is more precisely described as (Fe0.94(1)Co0.06(1))(Co0.95(1)Fe0.05(1))L(Ph). The iron-cobalt heterobimetallic has been further characterized by Mössbauer spectroscopy. Its isomer shift of 0.65 mm/s and quadrupole splitting of 0.64 mm/s are comparable to the related diiron complex, Fe2(DPhF)3. On the basis of spectroscopic data and theoretical calculations, it is proposed that the formal [M2](3+) cores are fully delocalized.
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New phenstatin-fatty acid conjugates: synthesis and evaluation.
Bioorg. Med. Chem. Lett.
PUBLISHED: 05-15-2013
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New phenstatin-fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7 and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar level paralleling an increase in un-saturation in the fatty acid component.
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Triterpenoids as reversal agents for anticancer drug resistance treatment.
Drug Discov. Today
PUBLISHED: 05-11-2013
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Overexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR), which is one of the major obstacles in the treatment of cancer patients. None of the strategies to overcome MDR has been successfully applied in the clinic until now. Plenty of evidence shows that some triterpenoids function as reversal agents of MDR for anticancer drug resistance treatment. Here, we review the latest findings of reversing cancer MDR with triterpenoids. Findings are summarized showing that triterpenoids are MDR modulators and potential chemosensitizers. Finally, we contemplate future prospects of modulating MDR in the clinic.
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Modulation of photoacoustic signal generation from metallic surfaces.
J Biomed Opt
PUBLISHED: 05-09-2013
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The ability to image metallic implants is important for medical applications ranging from diagnosis to therapy. Photoacoustic (PA) imaging has been recently pursued as a means to localize metallic implants in soft tissue. The work presented herein investigates different mechanisms to modulate the PA signal generated by macroscopic metallic surfaces. Wires of five different metals are tested to simulate medical implants/tools, while surface roughness is altered or physical vapor deposition (PVD) coatings are added to change the wires overall optical absorption. PA imaging data of the wires are acquired at 970 nm. Results indicate that PA signal generation predominately occurs in a wires metallic surface and not its aqueous surroundings. PA signal generation is similar for all metals tested, while addition of PVD coatings offers significant modulations (i.e., 4-dB enhancement and 26-dB reduction achieved) in PA signal generation. Results also suggest that PA signal increases with increasing surface roughness. Different coating and roughness schemes are then successfully utilized to generate spatial PA signal patterns. This work demonstrates the potential of surface modifications to enhance or reduce PA signal generation to permit improved PA imaging of implants/tools (i.e., providing location/orientation information) or to allow PA imaging of surrounding tissue.
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Assembly and stepwise oxidation of interpenetrated coordination cages based on phenothiazine.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 03-26-2013
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A breath of fresh air is sufficient for the eightfold S-monooxygenation of an interpenetrated double cage based on eight phenothiazine ligands and four square-planar-coordinated Pd(II) cations. Besides these two cages, which were both characterized by X-ray crystallography, an eightfold S-dioxygenated double-cage was obtained under harsher oxidation conditions.
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