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  • Cells, Cultured  (20)
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  • 1
    Language: English
    In: Toxicology Letters, 2011, Vol.206(1), pp.60-66
    Description: • We loaded the oxime HI 6 on human serum albumin nanoparticles. • We investigated the physico-chemical properties of the HI 6-loaded nanoparticles. • The transfer through an blood–brain barrier model was increased with HI 6-loaded nanoparticles. The standard treatment of intoxication with organophosphorus (OP) compounds includes the administration of oximes acting as acetylcholinesterase (AChE) reactivating antidotes. However, the blood–brain barrier (BBB) restricts the rapid transport of these drugs from the blood into the brain in therapeutically relevant concentrations. Since human serum albumin (HSA) nanoparticles enable the delivery of a variety of drugs across the BBB into the brain, HI 6 dimethanesulfonate and HI 6 dichloride monohydrate were bound to these nanoparticles in the present study. The resulting sorption isotherms showed a better fit to Freundlich's empirical adsorption isotherm than to Langmuir's adsorption isotherm. At the pH of 8.3 maximum drug binding capacities of 344.8 μg and 322.6 μg per mg of nanoparticles were calculated for HI 6 dimethanesulfonate and HI 6 dichloride monohydrate, respectively. These calculated values are higher than the adsorption capacity of 93.5 μg/mg for obidoxime onto HSA nanoparticles determined in a previous study. testing of the nanoparticulate oxime formulations in primary porcine brain capillary endothelial cells (pBCEC) demonstrated an up to two times higher reactivation of OP-inhibited AChE than the free oximes. These findings show that nanoparticles made of HSA may enable a sufficient antidote OP-poisoning therapy with HI 6 derivatives even within the central nervous system (CNS).
    Keywords: Nanoparticles ; Human Serum Albumin ; Hi 6 ; Adsorption Isotherm ; In Vitro Blood–Brain Barrier Model ; Drug Delivery ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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  • 2
    In: Anti-Cancer Drugs, 2015, Vol.26(7), pp.728-736
    Description: In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood–brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors.
    Keywords: Antineoplastic Agents, Alkylating -- Metabolism ; Blood-Brain Barrier -- Metabolism ; Busulfan -- Analogs & Derivatives ; Dacarbazine -- Analogs & Derivatives ; Endothelial Cells -- Metabolism;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 3
    Language: English
    In: Journal of Controlled Release, 2009, Vol.137(1), pp.78-86
    Description: The blood–brain barrier (BBB) represents a considerable obstacle to brain entry of the majority of drugs and thus severely restricts the therapy of many serious CNS diseases including brain tumours, brain HIV, Alzheimer and other neurodegenerative diseases. The use of nanoparticles coated with polysorbate 80 or with attached apolipoprotein E has enabled the delivery of drugs across the BBB. However, the mechanism of this enhanced transport is still not fully understood. In this present study, human serum albumin nanoparticles, with covalently bound apolipoprotein E (Apo E) as a targetor as well as without apolipoprotein E, were manufactured and injected intravenously into SV 129 mice. The animals were sacrificed after 15 and 30 min, and their brains were examined by transmission electron microscopy. Only the nanoparticles with covalently bound apolipoprotein E were detected in brain capillary endothelial cells and neurones, whereas no uptake into the brain was detectable with nanoparticles without apolipoprotein E. We have also demonstrated uptake of the albumin/ApoE nanoparticles into mouse endothelial (b.End3) cells in vitro and their intracellular localisation. These findings indicate that nanoparticles with covalently bound apolipoprotein E are taken up into the cerebral endothelium by an endocytic mechanism followed by transcytosis into brain parenchyma. Electron-microscopy of mouse brain tissue shows that nanoparticles with covalently bound apolipoprotein E are endocytosed after intravenous injection by brain endothelial cells and transported into the surrounding tissue by transcytosis.
    Keywords: Apolipoprotein E ; Blood–Brain Barrier ; Brain Targeting ; Nanoparticles ; Transcytosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 4
    Language: English
    In: Nanomedicine: Nanotechnology, Biology, and Medicine, February 2015, Vol.11(2), pp.275-282
    Description: The cytokine secretion of primary cells of human macrophages during the interaction of TiO nanoparticles (with an average primary size of 100-120 nm) is investigated down to concentration levels suggested to be relevant for conditions. We find that high TiO concentrations induce the cytokines Interleukin IL-1β, IL-6, and IL-10 secretion, while at low concentrations only IL-6 secretion is observed. To obtain further evidence on conditions we investigated the development and structure of the protein corona of the nanoparticles. We demonstrated that the surface of TiO particles attract preferably secondary modified proteins which then induce cytokine secretion of macrophages. Our results indicate that concentration of corona covered TiO particles below 1 μg/ml induce IL-6 secretion which is reported to be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. This study investigates the effects of protein corona covered titanium dioxide nanoparticles on human macrophages, concluding that concentration of such particles below 1 μg/ml induces IL-6 secretion, which may be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. This finding has important implications on future applications of such nanoparticles. Macrophage interaction with protein corona covered TiO nanoparticles. The reaction of the immune cells to low concentration of TiO nanoparticles despite the intense use of this material is not well investigated. We have shown that the protein corona developed on the surface of this particle agglomerate secondary modified proteins. Using primary cells of macrophages, we demonstrated that this corona induced at low particle concentrations the secretion of interleukin-6 which mediates, among others, autoimmune diseases.
    Keywords: Titanium Dioxide ; Nanoparticles ; Human Macrophage ; Protein Corona ; Immunology ; Nanotoxicology ; Interleukin-6 ; Medicine
    ISSN: 1549-9634
    E-ISSN: 1549-9642
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  • 5
    Language: English
    In: PLOS ONE, 2013, Vol.8(10), pp.urn:issn:1932-6203
    Description: Transforming growth factor-beta 1 (TGF-[beta]1) stimulates a broad range of effects which are cell type dependent, and it has been suggested to induce cellular senescence. On the other hand, long-term culture of multipotent mesenchymal stromal cells (MSCs) has a major impact on their cellular physiology and therefore it is well conceivable that the molecular events triggered by TGF-[beta]1 differ considerably in cells of early and late passages. In this study, we analyzed the effect of TGF-[beta]1 on and during replicative senescence of MSCs. Stimulation with TGF-[beta]1 enhanced proliferation, induced a network like growth pattern and impaired adipogenic and osteogenic differentiation. TGF-[beta]1 did not induce premature senescence. However, due to increased proliferation rates the cells reached replicative senescence earlier than untreated controls. This was also evident, when we analyzed senescence-associated DNA-methylation changes. Gene expression profiles of MSCs differed considerably at relatively early (P 3 - 5) and later passages (P 10). Nonetheless, relative gene expression differences provoked by TGF-[beta]1 at individual time points or in a time course dependent manner (stimulation for 0, 1, 4 and 12 h) were very similar in MSCs of early and late passage. These results support the notion that TGF-[beta]1 has major impact on MSC function, but it does not induce senescence and has similar molecular effects during culture expansion.
    Keywords: Methylation -- Analysis ; Bone Morphogenetic Proteins -- Analysis ; Stem Cells -- Analysis ; Genes -- Analysis ; Transforming Growth Factors -- Analysis ; Gene Expression -- Analysis;
    ISSN: 1932-6203
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  • 6
    Language: English
    In: Biomaterials, August 2015, Vol.61, pp.316-326
    Description: Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ridge structures. Micro- and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 μm ridges increased adipogenic differentiation whereas 2 μm ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces – e.g. by multi beam laser interference in sub-micrometer scale – do not induce differentiation of MSCs , but support their directed differentiation.
    Keywords: Mesenchymal Stem Cells ; Microstructure ; Nanotopography ; Laser Ablation ; Gene Expression ; Osteogenesis ; Medicine ; Engineering
    ISSN: 0142-9612
    E-ISSN: 1878-5905
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  • 7
    Language: English
    In: Biomaterials, August 2014, Vol.35(24), pp.6351-6358
    Description: Matrix elasticity guides differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient – while the cells reside on the substrate – or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on tissue culture plastic (TCP) or on polydimethylsiloxane (PDMS) gels of different elasticity to compare impact on replicative senescence, differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively – but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate. Our results support the notion that matrix elasticity influences cellular behavior while the cells reside on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns.
    Keywords: Mesenchymal Stem Cells ; Elasticity ; Long-Term Culture ; Platelet Lysate ; DNA-Methylation ; Epigenetic ; Medicine ; Engineering
    ISSN: 0142-9612
    E-ISSN: 1878-5905
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e65324
    Description: Induced pluripotent stem cells (iPSCs) are usually clonally derived. The selection of fully reprogrammed cells generally involves picking of individual colonies with morphology similar to embryonic stem cells (ESCs). Given that fully reprogrammed cells are highly proliferative and escape from cellular senescence, it is conceivable that they outgrow non-pluripotent and partially reprogrammed cells during culture expansion without the need of clonal selection. In this study, we have reprogrammed human dermal fibroblasts (HDFs) with episomal plasmid vectors. Colony frequency was higher and size was larger when using murine embryonic fibroblasts (MEFs) as stromal support instead of HDFs or human mesenchymal stromal cells (MSCs). We have then compared iPSCs which were either clonally derived by manual selection of a single colony, or derived from bulk-cultures of all initial colonies. After few passages their morphology, expression of pluripotency markers, and gene expression profiles did not reveal any significant differences. Furthermore, clonally-derived and bulk-cultured iPSCs revealed similar in vitro differentiation potential towards the three germ layers. Therefore, manual selection of individual colonies does not appear to be necessary for the generation of iPSCs - this is of relevance for standardization and automation of cell culture procedures.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Nucleic Acids Research, 2016, Vol. 44(22), pp.10631-10643
    Description: There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively. Modification of HOTAIR expression evoked only very moderate effects on gene expression, particularly of polycomb group target genes. Furthermore, overexpression and knockdown of HOTAIR resulted in DNAm changes at HOTAIR binding sites. Five potential triple helix forming domains were predicted within the HOTAIR sequence based on reverse Hoogsteen hydrogen bonds. Notably, the predicted triple helix target sites for these HOTAIR domains were also enriched in differentially expressed genes and close to DNAm changes upon modulation of HOTAIR . Electrophoretic mobility shift assays provided further evidence that HOTAIR domains form RNA–DNA–DNA triplexes with predicted target sites. Our results demonstrate that HOTAIR impacts on differentiation of MSCs and that it is associated with senescence-associated DNAm. Targeting of epigenetic modifiers to relevant loci in the genome may involve triple helix formation with HOTAIR .
    Keywords: Gene Regulation, Chromatin And Epigenetics;
    ISSN: 0305-1048
    E-ISSN: 1362-4962
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  • 10
    Language: English
    In: Cytotherapy, April 2012, Vol.14(4), pp.401-411
    Description: Mesenchymal stromal cells (MSC) are heterogeneous and only a subset possesses multipotent differentiation potential. It has been proven that long-term culture has functional implications for MSC. However, little is known how the composition of subpopulation changes during culture expansion. We addressed the heterogeneity of MSC using limiting-dilution assays at subsequent passages. In addition, we used a cellular automaton model to simulate population dynamics under the assumption of mixed numbers of remaining cell divisions until replicative senescence. The composition of cells with adipogenic or osteogenic differentiation potential during expansion was also determined at subsequent passages. Not every cell was capable of colony formation upon passaging. Notably, the number of fibroblastoid colony-forming units (CFU-f) decreased continuously, with a rapid decay within early passages. Therefore the CFU-f frequency might be used as an indicator of the population doublings remaining before entering the senescent state. Predictions of the cellular automaton model suited the experimental data best if most cells were already close to their replicative limit by the time of culture initiation. Analysis of differentiated clones revealed that subsets with very high levels of adipogenic or osteogenic differentiation capacity were only observed at early passages. These data support the notion of heterogeneity in MSC, and also with regard to replicative senescence. The composition of subpopulations changes during culture expansion and clonogenic subsets, especially those with the highest differentiation capacity, decrease already at early passages.
    Keywords: Cellular Aging ; Cellular Automaton ; Colony-Forming Units ; Computational Model ; Limiting Dilution ; Long-Term Culture ; Mesenchymal Stromal Cells ; Senescence ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1465-3249
    E-ISSN: 1477-2566
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