416 research outputs found
Прогностическая роль уровня цитокинов амниотической жидкости плода и крови матери в вероятности развития гестационной гипертензии
Pregnancy induced hypertension, which includes both gestational hypertension (GH) and preeclampsia, is the most common medical disorder and remains one of the major causes of maternal and fetal death. The pathogenesis of GH is still unknown, yet immunologic and inflammatory causes may play an important role in the pathophysiology of this disease. The purpose of this study is to investigate the midtrimester IL-6, IL-8, IL-10, IL-12, TNF-α, SDF-1a and VEGF in the amniotic fluid (AF) and maternal blood regarding the above as being predictive for the gestational hypertension outcome. In the group of 128 pregnant women over 35 years old the six ones have developed GH. Our study results demonstrate that GH is associated with a strong
increase of IL-6, IL-12 in maternal blood and a significant decrease of serum IL-10. Although AF level of both IL-6 and IL-10 has been significantly lower in GH subjects. In conclusion this study shows the relationship between the midtrimester IL-6, IL-12 and IL-10 concentrations in AF and maternal serum and GH outcome.Артериальная гипертензия при беременности, включающая в себя гестационную гипертензию и преэклампсию, является наиболее частым из осложнений беременности и остаётся одной из основных причин материнской смертности и гибели плода. Патогенез гестационной гипертензии до сих пор полностью не изучен, однако иммунологические и воспалительные факторы могут играть важную роль в патофизиологии этого заболевания. Целью данного исследования является изучение в период второго триместра беременности соотношения концентраций IL-6, IL-8, IL-10, IL-12, TNF-α, SDF-1a и VEGF в амниотической жидкости плода и материнской сыворотке крови и их связь с последующим
развитием гестационной гипертензии. В группе из 128 беременных в возрасте старше 35 лет, в шести случаях выявлено развитие гестационной гипертензии. Полученные результаты определили, что наличие гестационной гипертензии связано с существенным увеличением концентрации сывороточного IL-6 и IL-12 и одновременным снижением IL-10 в крови матери, при том, что в амниотической жидкости выявлено существенное снижение как IL-10, так и IL-6. В заключении данное исследование доказывает связь между уровнями IL-6, IL-10 и IL-12 в амниотической жидкости плода и крови матери, выявленными во втором триместре беременности, и последующим развитием гестационной гипертензии
Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis
Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in
local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the
development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN)
induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation,
proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the
transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq
approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary
human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand.
Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene
Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of
immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators,
negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly
downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is
altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature
dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the
suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different
mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome
sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated
with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed
iDCs
A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity
The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50 % wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive “T11” mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials
IgG and fibrinogen driven nanoparticle aggregation
A thorough understanding of how proteins induce nanoparticle (NP) aggregation is crucial when designing in vitro and in vivo assays and interpreting experimental results. This knowledge is also crucial when developing nano-applications and formulation for drug delivery systems. In this study, we found that extraction of immunoglobulin G (IgG) from cow serum results in lower polystyrene NPs aggregation. Moreover, addition of isolated IgG or fibrinogen to fetal cow serum enhanced this aggregation, thus demonstrating that these factors are major drivers of NP aggregation in serum. Counter-intuitively, NP aggregation was inversely dependent on protein concentration; i.e., low protein concentrations induced large aggregates, whereas high protein concentrations induced small aggregates. Protein-induced NP aggregation and aggregate size were monitored by absorbance at 400 nm and dynamic light scattering, respectively. Here, we propose a mechanism behind the protein concentration dependent aggregation; this mechanism involves the effects of multiple protein interactions on the NP surface, surface area limitations, aggregation kinetics, and the influence of other serum proteins.We thank Professor Sara Linse for scientific discussions and advice and Professor Patrik Brundin for enabling access to the light microscope. The project received financial support from Nanometer structure consortium at Lund University (nmC@LU), Lars Hierta Foundation, and the research school FLAK of Lund University
Identifying New Therapeutic Targets via Modulation of Protein Corona Formation by Engineered Nanoparticles
We introduce a promising methodology to identify new therapeutic targets in cancer. Proteins bind to nanoparticles to form a protein corona. We modulate this corona by using surface-engineered nanoparticles, and identify protein composition to provide insight into disease development.Using a family of structurally homologous nanoparticles we have investigated the changes in the protein corona around surface-functionalized gold nanoparticles (AuNPs) from normal and malignant ovarian cell lysates. Proteomics analysis using mass spectrometry identified hepatoma-derived growth factor (HDGF) that is found exclusively on positively charged AuNPs ((+)AuNPs) after incubation with the lysates. We confirmed expression of HDGF in various ovarian cancer cells and validated binding selectivity to (+)AuNPs by Western blot analysis. Silencing of HDGF by siRNA resulted s inhibition in proliferation of ovarian cancer cells.We investigated the modulation of protein corona around surface-functionalized gold nanoparticles as a promising approach to identify new therapeutic targets. The potential of our method for identifying therapeutic targets was demonstrated through silencing of HDGF by siRNA, which inhibited proliferation of ovarian cancer cells. This integrated proteomics, bioinformatics, and nanotechnology strategy demonstrates that protein corona identification can be used to discover novel therapeutic targets in cancer
In situ measurement of bovine serum albumin interaction with gold nanospheres
Here we present in situ observations of adsorption of bovine serum albumin (BSA) on citratestabilized
gold nanospheres. We implemented scattering correlation spectroscopy as a tool to
quantify changes in the nanoparticle Brownian motion resulting from BSA adsorption onto the
nanoparticle surface. Protein binding was observed as an increase in the nanoparticle
hydrodynamic radius. Our results indicate the formation of a protein monolayer at similar albumin
concentrations as those found in human blood. Additionally, by monitoring the frequency and
intensity of individual scattering events caused by single gold nanoparticles passing the
observation volume, we found that BSA did not induce colloidal aggregation, a relevant result
from the toxicological viewpoint. Moreover, to elucidate the thermodynamics of the gold
nanoparticle-BSA association, we measured an adsorption isotherm which was best described by
an anti-cooperative binding model. The number of binding sites based on this model was
consistent with a BSA monolayer in its native state. In contrast, experiments using poly-ethylene
glycol capped gold nanoparticles revealed no evidence for adsorption of BSA
Shear-Thinning Nanocomposite Hydrogels for the Treatment of Hemorrhage
Internal hemorrhaging is a leading cause of death after traumatic injury on the battlefield. Although several surgical approaches such as the use of fibrin glue and tissue adhesive have been commercialized to achieve hemostasis, these approaches are difficult to employ on the battlefield and cannot be used for incompressible wounds. Here, we present shear-thinning nanocomposite hydrogels composed of synthetic silicate nanoplatelets and gelatin as injectable hemostatic agents. These materials are demonstrated to decrease in vitro blood clotting times by 77%, and to form stable clot-gel systems. In vivo tests indicated that the nanocomposites are biocompatible and capable of promoting hemostasis in an otherwise lethal liver laceration. The combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency conditions.United States. Army Research Office (Contract W911NF-13-D-0001)National Institutes of Health (U.S.) (Interdepartmental Biotechnology Training Program NIH/NIGMS 5T32GM008334
Recommendations for Nanomedicine Human Subjects Research Oversight: An Evolutionary Approach for an Emerging Field
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96363/1/j.1748-720X.2012.00703.x.pd
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