9 research outputs found

    D<sub>3</sub> blocks RHOA and ARF6 activation in destabilized endothelial cells.

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    <p>Endothelial cells were exposed to 10 ╬╝M D<sub>3</sub> or 7-DHC in combination with 2ng/mL TNF-╬▒ or IL-1╬▓. Lysates were analyzed for RHOA-GTP and ARF6-GTP levels using appropriate precipitation assays. All graphs depict mean ┬▒ SEM. * denotes P<0.05, ** denotes P<0.01, and *** denotes P<0.001.</p

    Vitamin D sterol activity.

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    <p>Graphical models of the different vitamin D3 sterols, their metabolism, and a summary of their normal circulating levels, the minimum active dose for stabilizing the endothelium and doses in which the sterols have been reported to interact with vitamin D receptor [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref029" target="_blank">29</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref051" target="_blank">51</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140370#pone.0140370.ref052" target="_blank">52</a>]. *Normal circulating levels vary upon many conditions including diet and UV exposure.</p

    D<sub>3</sub> stabilizes endothelial cells through a non-genomic mechanism.

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    <p><b>(A)</b> Endothelial cells were exposed to D<sub>3</sub> or its metabolites for 24 hours and lysates were probed for VDR transcription targets FOX01 and CYP24. Endothelial cells were exposed to D<sub>3</sub> or its metabolites in the presence of inhibitors of transcription (actinomycin D) and translation (cycloheximide) <b>(B, C)</b> and were assessed for transendothelial resistance or VDR target gene expression. All graphs depict mean ┬▒ SEM. * denotes P<0.05, and **** denotes P<0.0001. ### denotes P<0.001, and #### denotes P<0.0001 versus the respective control.</p

    D<sub>3</sub> abrogates inflammatory leak in culture and <i>ex</i> vivo.

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    <p>Monolayers of HMVEC were stimulated with D<sub>3</sub> (10 ╬╝M), 7-DHC(10 ╬╝M), or 0.5% DMSO (vehicle control) in the presence of inflammatory cytokines: IL-1╬▓ (10 ng/mL), TNF-╬▒ (2 ng/mL), and LPS (100 ng/mL) in an (<b>A-C</b>) ECIS or (<b>D</b>) transwell leak assay. (<b>E</b>) VEGF-induced leak of a fluorescent reporter in arterioles isolated from wild-type mice fed either standard chow or a D<sub>3</sub>-enhanced chow. All panels depict mean ┬▒ SEM. * denotes P<0.05, ** denotes P<0.01, and **** denotes P<0.0001.</p

    Vitamin D stabilizes the endothelium.

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    <p>Dose/time resistance (endothelial stability) surfaces generated with ECIS are shown from 100 pM to 10 ╬╝M and from zero to 21 hours for: (<b>A</b>) D<sub>3</sub>; (<b>F</b>) 25(OH)D<sub>3</sub>; (<b>K</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>. Detailed time-responses are shown at 1 nM and 10 ╬╝M respectively for: (<b>B</b> and <b>C)</b> D<sub>3</sub>; (<b>G</b> and <b>H</b>) 25(OH)D<sub>3</sub>; and (<b>L</b> and <b>M</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>. Detailed dose-response are shown at 4 hours and 12 hours respectively for (<b>D</b> and <b>E)</b> D<sub>3</sub>, (<b>I</b> and <b>J</b>) 25(OH)D<sub>3</sub>, and (<b>N</b> and <b>O</b>) 1,25(OH)<sub>2</sub>D<sub>3</sub>.</p

    Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

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    Poly┬ş(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, <i>in vitro</i> assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood

    Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

    No full text
    Poly┬ş(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, <i>in vitro</i> assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood
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