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- ItemHigh glucose distinctively regulates Ca2+ influx in cytotoxic T lymphocytes upon target recognition and thapsigargin stimulation(Hoboken, NJ : Wiley, 2020) Zou, Huajiao; Yang, Wenjuan; Schwär, Gertrud; Zhao, Renping; Alansary, Dalia; Yin, Deling; Schwarz, Eva C.; Niemeyer, Barbara A.; Qu, BinIn CTLs: High glucose‐culture enhances thapsigargin‐induced SOCE but decreases target recognition‐induced Ca2+ influx. High glucose‐culture regulates expression of ORAIs and STIMs without affecting glucose uptake. More high glucose‐cultured CTLs are prone to necrosis after execution of killing.
- ItemSugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter(Dordrecht [u.a.] : Springer Science + Business Media B.V, 2019) Sztandera, Krzysztof; Działak, Paula; Marcinkowska, Monika; Stańczyk, Maciej; Gorzkiewicz, Michał; Janaszewska, Anna; Klajnert-Maculewicz, BarbaraPurpose: In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we set out to develop innovative, glucose-modified PAMAM dendrimer for the delivery of doxorubicin to breast cancer cells. Methods: PAMAM-dox-glc conjugate was synthesized and characterized by 1H NMR, FT-IR, size and zeta potential measurements. The drug release rate from conjugate was evaluated by dialysis under different pH conditions. The expression level of GLUT family receptors in cells cultured in full and glucose-deprived medium was evaluated by quantitative real-time RT-PCR and flow cytometry. The cytotoxicity of conjugate in presence or absence of GLUT1 inhibitors was determined by MTT assay. Results: We showed that PAMAM-dox-glc conjugate exhibits pH-dependent drug release and increased cytotoxic activity compared to free drug in cells cultured in medium without glucose. Further, we proved that these cells overexpress transporters of GLUT family. The toxic effect of conjugate was eliminated by the application of specific GLUT1 inhibitors. Conclusion: Our findings revealed that the glucose moiety plays a crucial role in the recognition of cells with high expression of GLUT receptors. By selectively blocking GLUT1 transporter we showed its importance for the cytotoxic activity of PAMAM-dox-glc conjugate. These results suggest that PAMAM-glucose formulations may constitute an efficient platform for the specific delivery of anticancer drugs to tumor cells overexpressing transporters of GLUT family. © 2019, The Author(s).
- ItemPreclinical Testing of New Hydrogel Materials for Cartilage Repair: Overcoming Fixation Issues in a Large Animal Model(New York, NY [u.a.] : Hindawi Publ. Corp., 2021) Lotz, Benedict; Bothe, Friederike; Deubel, Anne-Kathrin; Hesse, Eliane; Renz, Yvonne; Werner, Carsten; Schäfer, Simone; Böck, Thomas; Groll, Jürgen; von Rechenberg, Brigitte; Richter, Wiltrud; Hagmann, SebastienReinforced hydrogels represent a promising strategy for tissue engineering of articular cartilage. They can recreate mechanical and biological characteristics of native articular cartilage and promote cartilage regeneration in combination with mesenchymal stromal cells. One of the limitations of in vivo models for testing the outcome of tissue engineering approaches is implant fixation. The high mechanical stress within the knee joint, as well as the concave and convex cartilage surfaces, makes fixation of reinforced hydrogel challenging. Methods. Different fixation methods for full-thickness chondral defects in minipigs such as fibrin glue, BioGlue®, covering, and direct suturing of nonenforced and enforced constructs were compared. Because of insufficient fixation in chondral defects, superficial osteochondral defects in the femoral trochlea, as well as the femoral condyle, were examined using press-fit fixation. Two different hydrogels (starPEG and PAGE) were compared by 3D-micro-CT (μCT) analysis as well as histological analysis. Results. Our results showed fixation of below 50% for all methods in chondral defects. A superficial osteochondral defect of 1 mm depth was necessary for long-term fixation of a polycaprolactone (PCL)-reinforced hydrogel construct. Press-fit fixation seems to be adapted for a reliable fixation of 95% without confounding effects of glue or suture material. Despite the good integration of our constructs, especially in the starPEG group, visible bone lysis was detected in micro-CT analysis. There was no significant difference between the two hydrogels (starPEG and PAGE) and empty control defects regarding regeneration tissue and cell integration. However, in the starPEG group, more cell-containing hydrogel fragments were found within the defect area. Conclusion. Press-fit fixation in a superficial osteochondral defect in the medial trochlear groove of adult minipigs is a promising fixation method for reinforced hydrogels. To avoid bone lysis, future approaches should focus on multilayered constructs recreating the zonal cartilage as well as the calcified cartilage and the subchondral bone plate.
- ItemDisturbing-free determination of yeast concentration in DI water and in glucose using impedance biochips(Basel : MDPI AG, 2020) Kiani, M.; Du, N.; Vogel, M.; Raff, J.; Hübner, U.; Skorupa, I.; Bürger, D.; Schulz, S.E.; Schmidt, O.G.; Blaschke, D.; Schmidt, H.Deionized water and glucose without yeast and with yeast (Saccharomyces cerevisiae) of optical density OD600 that ranges from 4 to 16 has been put in the ring electrode region of six different types of impedance biochips and impedance has been measured in dependence on the added volume (20, 21, 22, 23, 24, 25 µL). The measured impedance of two out of the six types of biochips is strongly sensitive to the addition of both liquid without yeast and liquid with yeast and modelled impedance reveals a linear relationship between the impedance model parameters and yeast concentration. The presented biochips allow for continuous impedance measurements without interrupting the cultivation of the yeast. A multiparameter fit of the impedance model parameters allows for determining the concentration of yeast (cy) in the range from cy = 3.3 × 107 to cy = 17 × 107 cells/mL. This work shows that independent on the liquid, i.e., DI water or glucose, the impedance model parameters of the two most sensitive types of biochips with liquid without yeast and with liquid with yeast are clearly distinguishable for the two most sensitive types of biochips.
- ItemIntestinal flow rates, absorption of felodipine from the small intestine and attributes of chyme collected at midgut from Labradors(Tübingen : Universitätsbibliothek Tübingen, 2023) Diebold, Steffen M.The objectives of the present study were (1) to investigate gastrointestinal hydrodynamics of Labradors as a model for human midgut (2) to examine various attributes of intestinal fluids in vivo and (3) to study the influence of hydrodynamics on the dissolution and absorption of a poorly soluble drug from various suspensions. Gastrointestinal flow rates were determined volumetrically using an aspiration method. Isotonic saline and 20 % glucose solutions were used to alter gastrointestinal hydrodynamics. Felodipine, a BCS class II substance, was suspended in these fluids. Osmolality, pH, bile acid concentration and drug solubility in various chyme samples were determined. Blood plasma levels of felodipine were recorded while gastrointestinal dissolution was ongoing. Fluid recovery at midgut fistula was significantly higher (>100 %) for glucose 20 % than for isotonic saline solutions (70 %). After administration of 200 ml glucose 20 % the (overall) grand median of differential gastrointestinal flow rates (DFR) was 8.3 ml/min.. Individual spike flow ranged from 20 up to 60 ml/min. Corresponding flow rates after administration of 200 ml isotonic saline were 35.0 ml/min. for the grand median including individual spike flows beyond 100 ml/min.. Within and between-dog variability in flow rate data was similar. In general, glucose solutions released more evenly. Following oral administration of glucose solution 20 % osmolality of intestinal fluids decreased within 40 min. from about 1000 mOsm. towards more physiological values of about 350 mOsm.. Saturation solubility of felodipine (Cs) in jejunal chyme after administration of either solution (saline or glucose) was determined to be about 10 (µg/ml) on average (median), exposing high variability with time! The intestinal solubility varied greatly within the course of an experiment. However, a strong correlation was observed between the aspirated fluid volume and the dissolved amount of felodipine confirming the well known relationship of Noyes, Whitney, Nernst and Brunner in-vivo. Grand median of pH in jejunal chyme of labradors was determined to be 6.68. Median values range from 4.38-7.62. The pharmacokinetic data showed a slight trend to differences based on particle size and on fluid administered.