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  • 1
  • 2
    Keywords: CANCER ; IN-VITRO ; chemotherapy ; drug resistance ; MULTIDRUG-RESISTANCE ; LEUKEMIA-CELLS ; P-GLYCOPROTEIN ; MALARIA ; ANTIMALARIAL ARTESUNATE ; EXPRESSION PROFILES ; TUMOR-CELL LINES ; CASSETTE TRANSPORTER GENES ; INHIBITS ANGIOGENESIS ; DRUG-SENSITIVITY ; ENDOTHELIAL-GROWTH-FACTOR
    Abstract: Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer
    Type of Publication: Journal article published
    PubMed ID: 20629994
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  • 3
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    Drug Discovery Today 20 (2), 198-208 
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  • 4
    Keywords: ENVIRONMENT ; SPECTRA ; CELLS ; CELL ; Germany ; ALGORITHM ; IMAGES ; imaging ; VISUALIZATION ; VOLUME ; POPULATION ; GENE ; RNA ; SAMPLE ; SAMPLES ; EFFICIENCY ; MOLECULES ; RESOLUTION ; BIOLOGY ; MOLECULAR-BIOLOGY ; SEQUENCE ; MOLECULE ; ACID ; ELEMENT ; ELEMENTS ; EFFICIENT ; oligonucleotides ; SURVEILLANCE ; CELLULAR UPTAKE ; DELIVERY ; SMALL INTERFERING RNAS ; POPULATIONS ; DEGRADATION ; FLUORESCENCE ; CALIBRATION ; MOVEMENT ; molecular biology ; molecular ; RE ; INTERFERENCE ; RNA INTERFERENCE ; TRANSFECTION ; PH ; ENVIRONMENTS ; development ; methods ; RESONANCE ENERGY-TRANSFER ; technique ; LIPOSOMES ; SPECTRUM ; SMALL INTERFERING RNA ; EMISSION ; INTEGRITY ; STRAND
    Abstract: Techniques for investigation of exogenous small interfering RNA (siRNA) after penetration of the cell are of substantial interest to the development of efficient transfection methods as well as to potential medical formulations of siRNA. A FRET-based visualization method including the commonplace dye labels fluorescein and tetramethylrhodamin (TMR) on opposing strands of siRNA was found compatible with RNA interference (RNAi). Investigation of spectral properties of three labelled siRNAs with differential FRET efficiencies in the cuvette, including pH dependence and FRET efficiency in lipophilic environments, identified the ratio of red and green fluorescence (R/G-ratio) as a sensitive parameter, which reliably identifies samples containing 〉 90% un-degraded siRNA. Spectral imaging of siRNAs microinjected into cells showed emission spectra indistinguishable from those measured in the cuvette. These were used to establish a calibration curve for assessing the degradation state of siRNA in volume elements inside cells. An algorithm, applied to fluorescence images recorded in standard green and red fluorescence channels, produces R/G-ratio images of high spatial resolution, identifying volume elements in the cell with high populations of intact siRNA with high fidelity. To demonstrate the usefulness of this technique, the movement of intact siRNA molecules are observed after introduction into the cytosol by microinjection, standard transfection and lipofection with liposomes
    Type of Publication: Journal article published
    PubMed ID: 17890733
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  • 5
    Keywords: brain ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; CELL ; Germany ; MODEL ; MODELS ; VITRO ; SYSTEM ; SITE ; PROTEIN ; ACCUMULATION ; FAMILY ; SIMULATION ; BIOLOGY ; ACID ; TRANSPORT ; EPITHELIAL-CELLS ; organic anion transporters ; NETHERLANDS ; MOUSE MODEL ; specificity ; CHILDREN ; NATURAL-HISTORY ; EFFLUX ; endothelial cells ; TRANSPORTER ; SCIENCE ; blood-brain barrier ; BARRIER ; CAPILLARY ENDOTHELIAL-CELLS ; CELL BIOLOGY ; TRANSPORTERS ; Type ; ACIDEMIA ; COA DEHYDROGENASE-DEFICIENCY ; Dicarboxylic acids ; ENCEPHALOPATHIC CRISES ; Glutaric aciduria type I ; Methylmalonic aciduria ; Organic acid transporter ; Plexus choroideus
    Abstract: Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na+-dependent. ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na+-gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na+-dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specific efflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. (C) 2010 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20302929
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  • 6
    Keywords: RESOLUTION ; MEMBRANE ; MULTIDRUG TRANSPORTER ; LIMIT ; FLUORESCENT PROTEIN ; SIN vector ; OPTICAL RECONSTRUCTION MICROSCOPY ; ENDOTHELIAL-CELL LINE
    Abstract: P-glycoprotein (Pgp; also known as MDR1, ABCB1) is the most important and best studied efflux transporter at the blood-brain barrier (BBB); however, the organization of Pgp is unknown. The aim of this study was to employ the recently developed super-resolution fluorescence microscopy method spectral precision distance microscopy/spectral position determination microscopy (SPDM) to investigate the spatial distribution of Pgp in the luminal plasma membrane of brain capillary endothelial cells. Potential disturbing effects of cell membrane curvatures on the distribution analysis are addressed with computer simulations. Immortalized human cerebral microvascular endothelial cells (hCMEC/D3) served as a model of human BBB. hCMEC/D3 cells were transduced with a Pgp-green fluorescent protein (GFP) fusion protein incorporated in a lentivirus-derived vector. The expression and localization of the Pgp-GFP fusion protein was visualized by SPDM. The limited resolution of SPDM in the z-direction leads to a projection during the imaging process affecting the appeared spatial distribution of fluorescence molecules in the super-resolution images. Therefore, simulations of molecule distributions on differently curved cell membranes were performed and their projected spatial distribution was investigated. Function of the fusion protein was confirmed by FACS analysis after incubation of cells with the fluorescent probe eFluxx-ID Gold in absence and presence of verapamil. More than 112,000 single Pgp-GFP molecules (corresponding to approximately 5,600 Pgp-GFP molecules per cell) were detected by SPDM with an averaged spatial resolution of approximately 40 nm in hCMEC/D3 cells. We found that Pgp-GFP is distributed in clustered formations in hCMEC/D3 cells while the influence of present random cell membrane curvatures can be excluded based on the simulation results. Individual formations are distributed randomly over the cell membrane.
    Type of Publication: Journal article published
    PubMed ID: 22984556
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  81. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20100512-20100516; Wiesbaden; DOC10hnod222 /20100422/
    Publication Date: 2010-04-23
    Keywords: ddc: 610
    Type: conferenceObject
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  • 8
    Keywords: brain ; CELLS ; ENDOTHELIAL-CELLS ; IN-VITRO ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; INHIBITION ; VITRO ; ACCUMULATION ; ASSAY ; leukemia ; FRUIT ; CYTOTOXICITY ; EFFLUX ; CHEMISTRY ; RE ; monitoring ; endothelial cells ; P-GLYCOPROTEIN ; interaction ; cell proliferation ; FRUITS ; pharmacology ; CAPILLARIES ; ENDOTHELIAL-CELL ; BLOOD-BRAIN-BARRIER ; brain capillary endothelial cell ; CEM LEUKEMIA-CELLS ; FLUORESCENT ; MULTIDRUG ; NOV
    Abstract: Four anti mycobacterial geranylated furocoumarins, from the fruits of Tetradium daniellii (Rutaceae), were tested in a bioassay using CCRF-CEM leukemia cells and their P-glycoprotein (p-gp) over-expressing subline CEM/ADR5000, to asses their cytotoxicity and effects on cellular efflux pumps. All showed considerable cell proliferation inhibition with IC50 values ranging from 1.72 to 11.02 mu M against CCRF-CEM and 2.09 to 13.56 mu M against CEM/ADR5000, respectively. An assay monitoring the p-gp-dependent accumulation of a calcein fluorescent dye in porcine brain capillary endothelial cells was used to study interactions of the test substances with this efflux pump. Here, they all were shown to be only weak to moderate modulators of p-gp
    Type of Publication: Journal article published
    PubMed ID: 17992628
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 6; DOC21 /20100422/
    Publication Date: 2010-04-23
    Description: Einleitung: Die Traditionelle Chinesische Medizin fundiert auf einer ca. 5000 Jahre alten Erfahrung mit medizinischen Heilpflanzen. Unter diesen findet Artemisinin, die Grundsubstanz aus der Artemisia annua L., nicht nur Anwendung in der Malaria Behandlung, sondern auch in der Krebsbehandlung. Aus diesem Grund haben wir eine Reihe von Artemisinin-Derivaten (Artesunate) auf ihre anti-tumoröse Wirkung geprüft und deren Aktivität mit denen von etablierten Zytostatika als Kontrollen verglichen. Material und Methoden: Artesunate (ART) wurde von Saokim Ltd (Hanoi, Vietnam) und 24 Artesunate-Derivate von ElSohly (NCI, USA) zur Verfügung gestellt. Cisplatin, 5-fluorouracil (5-FU), Carboplatin und Docetaxel wurden von der Klinikapotheke der Universitätsklinik Heidelberg ausgehändigt. Als Test-Modell benutzten wir die etablierte Plattenepithel-Carcinom-Zelllinie eines Kopf-Hals-Tumors (Mundboden-Ca, T2N0M0), UMSCC1. Die Aktivität der Zytotoxizität dieser Verbindungen wurde mit dem XTT-Test (Roche) getestet.Ergebnisse: Artesunate zeigte eine IC50 von 25 µM, exemplarisch zeigten ART-Derivat 72-4 IC50=19,8 µM und ART-Derivat 9-1 IC50=17,9 µM. Docetaxel IC50=0.015 M. Hingegen, wurden keine zytotoxischen Effekte mit den Chemotherapeutika 5-FU, Carboplatin und Cisplatin in den Konzentrationen 10-5-10-9,5 M beobachtet. Schlussfolgerung: Die Toxizität nimmt mit den Artesunate-Derivaten im Vergleich zu den klinisch angewendeten Chemotherapeutika gegenüber der UMSCC1 Tumorzellen zu. Artesunate und seine Derivate haben somit ein höheres zyotoxisches Potential als 5-Fu, Carboplatin und Cisplatin. Weiterführende Analysen sind derzeit in Arbeit, um die verantwortlichen Molekularbiologischen Mechanismen für die zytotoxische Wirkung der Verbindungen aufzuklären.
    Keywords: ddc: 610
    Type: article
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  • 10
    ISSN: 1573-904X
    Keywords: cyclosporins ; liposomal membranes ; lipid dose ; rat ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. Methods. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Results. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. Conclusions. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.
    Type of Medium: Electronic Resource
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