Dendritic polyglycerols (dPG), particularly dendritic polyglycerol sulfates (dPGS), have been intensively studied due to their intrinsic anti-inflammatory activity. As related to brain pathologies ...involving neuroinflammation, the current study examined if dPG and dPGS can (i) regulate neuroglial activation, and (ii) normalize the morphology and function of excitatory postsynaptic dendritic spines adversely affected by the neurotoxic 42 amino acid amyloid-β (Aβ
) peptide of Alzheimer disease (AD). The exact role of neuroglia, such as microglia and astrocytes, remains controversial especially their positive and negative impact on inflammatory processes in AD. To test dPGS effectiveness in AD models we used primary neuroglia and organotypic hippocampal slice cultures exposed to Aβ
peptide. Overall, our data indicate that dPGS is taken up by both microglia and astrocytes in a concentration- and time-dependent manner. The mechanism of action of dPGS involves binding to Aβ
, i.e., a direct interaction between dPGS and Aβ
species interfered with Aβ fibril formation and reduced the production of the neuroinflammagen lipocalin-2 (LCN2) mainly in astrocytes. Moreover, dPGS normalized the impairment of neuroglia and prevented the loss of dendritic spines at excitatory synapses in the hippocampus. In summary, dPGS has desirable therapeutic properties that may help reduce amyloid-induced neuroinflammation and neurotoxicity in AD.
The synthetic compound dendritic polyglycerol sulfate (dPGS) is a pleiotropic acting molecule but shows a high binding affinity to immunological active molecules as L‐/P‐selectin or complement ...proteins leading to well described anti‐inflammatory properties in various mouse models. In order to make a comprehensive evaluation of the direct effect on the innate immune system, macrophage polarization is analyzed in the presence of dPGS on a phenotypic but also metabolic level. dPGS administered macrophages show a significant increase of MCP1 production paralleled by a reduction of IL‐10 secretion. Metabolic analysis reveals that dPGS could potently enhance the glycolysis and mitochondrial respiration in M0 macrophages as well as decrease the mitochondrial respiration of M2 macrophages. In summary the data indicate that dPGS polarizes macrophages into a pro‐inflammatory phenotype in a metabolic pathway‐dependent manner.
The synthetic polymer dendritic polyglycerol sulfate (dPGS) has pleiotropic effects in biosystems. Here the effect of dPGS on bone marrow derived cells during macrophage differentiation is analyzed. dPGS does not alter the expression of macrophage cell surface markers, but changes their phenotype via metabolic switching to a pro‐inflammatory phenotype.
A thorough understanding of nanoparticle bio-distribution at the feto-maternal interface will be a prerequisite for their diagnostic or therapeutic application in women of childbearing age and for ...teratologic risk assessment. Therefore, the tissue interaction of biocompatible dendritic polyglycerol nanoparticles (dPG-NPs) with first- trimester human placental explants were analyzed and compared to less sophisticated trophoblast-cell based models. First-trimester human placental explants, BeWo cells and primary trophoblast cells from human term placenta were exposed to fluorescence labeled, ∼5 nm dPG-NPs, with differently charged surfaces, at concentrations of 1 µM and 10 nM, for 6 and 24 h. Accumulation of dPGs was visualized by fluorescence microscopy. To assess the impact of dPG-NP on trophoblast integrity and endocrine function, LDH, and hCG releases were measured. A dose- and charge-dependent accumulation of dPG-NPs was observed at the early placental barrier and in cell lines, with positive dPG-NP-surface causing deposits even in the mesenchymal core of the placental villi. No signs of plasma membrane damage could be detected. After 24 h we observed a significant reduction of hCG secretion in placental explants, without significant changes in trophoblast apoptosis, at low concentrations of charged dPG-NPs. In conclusion, dPG-NP's surface charge substantially influences their bio-distribution at the feto-maternal interface, with positive charge facilitating trans-trophoblast passage, and in contrast to more artificial models, the first-trimester placental explant culture model reveals potentially hazardous influences of charged dPG-NPs on early placental physiology.
A new class of fully synthetic shell cleavable multivalent polysulfates is prepared by introducing degradable linkers into a stable biocompatible dendritic polyglycerol scaffold and subsequent ...sulfation. The sulfated polymers show different degradation profiles, low anticoagulant and high anti‐inflammatory properties, are able to efficiently bind to L‐selectin and inhibit the complement activation at very low concentrations in vitro.
Targeting bone with anionic macromolecules is a potent approach for the development of novel diagnostics and therapeutics for bone related diseases. A highly efficient modular synthesis of dendritic ...polyglycerol (dPG) polyanion dye conjugates, namely, sulfates, sulfonates, carboxylates, phosphates, phosphonates, and bisphosphonates via click chemistry is presented. By investigating the microarchitecture of stained bone sections with confocal laser scanning microscopy, the bisphosphonate, phosphonate, and phosphate functionalized polymers are identified as strongly penetrating compounds, whereas sulfates, sulfonates, and carboxylates reveal a weaker binding to hydroxyapatite (HA) but a more pronounced affinity toward collagen. In a quantitative HA binding assay, the affinity of the dPG sulfonate, sulfate, and carboxylate toward collagen and the exceptional high HA affinity of the phosphorous containing polyelectrolytes are validated. This shows the potential of dendritic polyphosphates and phosphonates as alternatives to the commonly employed bisphosphonate modification. In cytotoxicity studies with murine fibroblasts, the conjugates have no significant effect on the cell viability at 10‐5m. All polyanions are taken up into the cells within 24 h. The presented synthetic approach allows versatile extensions for preparing conjugates for selective bone imaging applications, tissue engineering, and drug delivery.
Fully synthetic, multivalent polyanion dye conjugates are applied for selective bone targeting. The in vitro binding affinity toward hydroxyapatite and collagen is strongly dependent on the anionic moiety. Polyglycerol‐based polyelectrolytes are shown to be potent candidates for selective, bone‐targeted imaging applications, tissue engineering, or drug delivery.
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Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Objectives/Hypothesis
The aim of this study was to evaluate the effects of olfactory training (OT) on olfactory function in patients with persistent postinfectious olfactory dysfunction (PIOD).
Study ...Design
Randomized, single‐blind, controlled, multicenter crossover study.
Methods
Twelve tertiary university medical centers participated. Investigations were performed at three visits (baseline, after 18 weeks, and after 36 weeks), including only subjects with PIOD of <24‐months duration. At each visit, participants received detailed assessment of olfactory function. Seventy subjects trained with high concentrations of four odors for 18 weeks; the other half (n = 74) trained with low concentrations of odors. For the following 18 weeks this regimen was switched.
Results
After 18 weeks, olfactory function improved in the high‐training group in 18 of 70 participants (26%), whereas only 11/74 improved in the low‐training group (15%). In subjects with a duration of olfactory dysfunction of <12 months, olfactory function improved in 15/24 participants (63%) of the high‐training group and in 6/31 participants (19%) of the low‐training group (P = .03).
Conclusions
OT improves PIOD, and the use of odors at higher concentrations is beneficial to improvement. OT is a safe procedure and appears to be particularly useful in patients who start OT within 12 months after the onset of the disorder. OT is the first successful therapy regime in patients with PIOD.
Level of Evidence
1b. Laryngoscope, 124:826–831, 2014
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