In this work the DBL3x domain of the erythrocyte membrane protein from Plasmodium Falciparum (PfEMP1), was revisited as a potential molecular target for the development of new drugs against malaria. This protein interacts with chondroitin sulfate A (CSA), a glycosaminoglycan present in the substance fundamental for connective tissues of vertebrates and is implicated in malaria complications in pregnant women. We performed molecular docking and molecular dynamic studies of DBL3x complexed with CSA and five analogues, where the sulfate group was replaced by phosphate, in order to evaluate if the better electrostatic interactions provided by phosphate groups could afford better binders capable of preventing the binding of CSA to DBL3x. Results suggest that all proposed compounds have high affinity towards DBL3x and could bind better to the DBL3x domain of PfEMP1 than CSA, qualifying as potential inhibitors of this protein and, therefore, new potential leads for the drug design against malaria.Communicated by Ramaswamy H. Sarma.
- MeSH
- antigeny protozoální chemie MeSH
- chondroitin sulfáty chemie metabolismus farmakologie MeSH
- erytrocyty metabolismus MeSH
- fosfáty MeSH
- glykosaminoglykany metabolismus MeSH
- lidé MeSH
- malárie * komplikace metabolismus MeSH
- membránové proteiny metabolismus MeSH
- parazitární komplikace těhotenství * metabolismus MeSH
- placenta metabolismus MeSH
- Plasmodium falciparum chemie MeSH
- protozoální proteiny chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- sírany metabolismus MeSH
- těhotenství MeSH
- tropická malárie * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.
- MeSH
- antitumorózní látky chemická syntéza chemie metabolismus farmakologie MeSH
- apoptóza účinky léků MeSH
- benzothiazoly chemická syntéza chemie metabolismus farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- estery kyseliny sírové metabolismus MeSH
- glykosaminoglykany metabolismus MeSH
- hydrofobní a hydrofilní interakce MeSH
- indoly chemická syntéza chemie metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- pyridinové sloučeniny chemická syntéza chemie metabolismus farmakologie MeSH
- racionální návrh léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
Conventional wisdom has it that proteins fold and assemble into definite structures, and that this defines their function. Glycosaminoglycans (GAGs) are different. In most cases the structures they form have a low degree of order, even when interacting with proteins. Here, we discuss how physical features common to all GAGs-hydrophilicity, charge, linearity and semi-flexibility-underpin the overall properties of GAG-rich matrices. By integrating soft matter physics concepts (e.g. polymer brushes and phase separation) with our molecular understanding of GAG-protein interactions, we can better comprehend how GAG-rich matrices assemble, what their properties are, and how they function. Taking perineuronal nets (PNNs)-a GAG-rich matrix enveloping neurons-as a relevant example, we propose that microphase separation determines the holey PNN anatomy that is pivotal to PNN functions.
- MeSH
- extracelulární matrix - proteiny metabolismus MeSH
- extracelulární matrix metabolismus MeSH
- glykosaminoglykany chemie metabolismus MeSH
- hydrofobní a hydrofilní interakce MeSH
- neurony metabolismus MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Kyselina hyaluronová je vysokomolekulární polysacharid extracelulární matrix účastnící se řady významných biologických účinků zahrnujících regulační, zánětlivé, imunosupresivní a antiproliferativní účinky. Je užitečný v řadě klinických aplikací a vhodným terapeutickým nástrojem. Přehledný článek shrnuje základní charakteristiky a možnosti klinického využití kyseliny hyaluronové.
Hyaluronic acid is a high molecular weight extracellular matrix polysaccharide involved in a variety of significant biological effects including regulatory, inflammatory, immunosuppressive and antiproliferative effects. It is useful in a number of clinical applications and is a suitable therapeutic tool. The article summarizes the basic characteristics and possibilities of clinical use of hyaluronic acid.
- MeSH
- antiflogistika nesteroidní terapeutické užití MeSH
- biologické markery chemie MeSH
- buňky pojivové tkáně chemie metabolismus MeSH
- diabetes mellitus 1. typu diagnóza MeSH
- extracelulární matrix fyziologie metabolismus účinky léků MeSH
- glykosaminoglykany analýza metabolismus terapeutické užití MeSH
- hodnocení léčiv * metody trendy MeSH
- imunosupresiva metabolismus terapeutické užití MeSH
- jaterní cirhóza diagnóza MeSH
- kyselina hyaluronová * analýza metabolismus terapeutické užití MeSH
- lidé MeSH
- nemoci kloubů farmakoterapie MeSH
- nosiče léků * chemie terapeutické užití MeSH
- sklivec anatomie a histologie chemie MeSH
- statistika jako téma MeSH
- synoviální tekutina chemie metabolismus účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Mucopolysaccharidosis type II (MPSII) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene (IDS, Xq28). MPSII is characterized by skeletal deformities, hearing loss, airway obstruction, hepatosplenomegaly, cardiac valvular disease, and progressive neurological impairment. At the cellular level, IDS deficiency leads to lysosomal storage of glycosaminoglycans (GAGs), dominated by accumulation of dermatan and heparan sulfates. Human induced pluripotent stem cells (iPSC) represent an alternative system that complements the available MPSII murine model. Herein we report on the reprogramming of peripheral white blood cells from male and female MPSII patients into iPSC using a non-integrating protocol based on the Sendai virus vector system. We differentiated the iPSC lines into IDS deficient and GAG accumulating β-Tubulin III+ neurons, GFAP+ astrocytes, and CNPase+ oligodendrocytes. The lysosomal system in these cells displayed structural abnormalities reminiscent of those previously found in patient tissues and murine IDS deficient neuronal stem cells. Furthermore, quantitative determination of GAGs revealed a moderate increase in GAG levels in IDS deficient neurons and glia. We also tested the effects of recombinant IDS and found that the exogenous enzyme was internalized from the culture media and partially decreased the intracellular GAG levels in iPSC-derived neural cells; however, it failed to completely prevent accumulation of GAGs. In summary, we demonstrate that this human iPSC based model expresses the cellular and biochemical features of MPSII, and thus represents a useful experimental tool for further pathogenesis studies as well as therapy development and testing.
- MeSH
- astrocyty enzymologie patologie MeSH
- buněčný rodokmen MeSH
- fenotyp MeSH
- glykosaminoglykany metabolismus MeSH
- iduronátsulfatasa genetika metabolismus MeSH
- indukované pluripotentní kmenové buňky enzymologie patologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- lyzozomy enzymologie patologie MeSH
- mukopolysacharidóza II enzymologie genetika patologie MeSH
- nervové kmenové buňky enzymologie patologie MeSH
- neurogeneze * MeSH
- neuroglie enzymologie patologie MeSH
- neurony enzymologie patologie MeSH
- oligodendroglie enzymologie patologie MeSH
- prekurzorové buňky oligodendrocytů enzymologie patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.
- MeSH
- antiflogistika farmakologie MeSH
- buněčná adheze účinky léků MeSH
- cékum mikrobiologie chirurgie MeSH
- chinazolinony farmakologie MeSH
- edém chemicky indukované metabolismus patologie prevence a kontrola MeSH
- glykosaminoglykany metabolismus MeSH
- infiltrace neutrofily účinky léků MeSH
- ligace MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- neutrofily účinky léků metabolismus mikrobiologie MeSH
- pankreatitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- peritonitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- punkce MeSH
- sepse metabolismus mikrobiologie patologie prevence a kontrola MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The glycosaminoglycan (GAG) molecules are a group of high molecular weight, negatively charged polysaccharides present abundantly in the mammalian organism. By their virtue of ion and water binding capacity, they may affect the redistribution of body fluids and ultimately the blood pressure. Data from the literature suggests that the mitogens Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C are able to regulate the amount and charge density of GAGs and their detachment from the cell surface. Based on these findings we investigated the relationship between the level of dietary sodium intake, the expression levels of VEGF-A and VEGF-C, and the amount of the skin GAGs hyaluronic acid and chondroitin sulfate in an in vivo rat model. Significant correlation between dietary sodium intake, skin sodium levels and GAG content was found. We confirmed the GAG synthesizing role of VEGF-C but failed to prove that GAGs are degraded by VEGF-A. No significant difference in blood pressure was registered between the different dietary groups. A quotient calculated form the ion and water content of the skin tissue samples suggests that - in contrast to previous findings - the osmotically inactive ions and bound water fractions are proportional.
- MeSH
- glykosaminoglykany metabolismus MeSH
- krysa rodu rattus MeSH
- kůže účinky léků metabolismus MeSH
- náhodné rozdělení MeSH
- potkani Wistar MeSH
- sodík dietní aplikace a dávkování MeSH
- sodík fyziologie MeSH
- vaskulární endoteliální růstový faktor A biosyntéza MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400-1200IU) and calcium (1.0-1.5g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.
- MeSH
- aminokyseliny metabolismus MeSH
- analýza rozptylu MeSH
- fyziologická kalcifikace účinky léků MeSH
- glykosaminoglykany metabolismus MeSH
- kostní matrix účinky léků metabolismus MeSH
- lidé MeSH
- nanočástice chemie MeSH
- poréznost MeSH
- postmenopauzální osteoporóza farmakoterapie patofyziologie MeSH
- potravní doplňky * MeSH
- Ramanova spektroskopie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vápník farmakologie terapeutické užití MeSH
- vitamin D farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this study, fibrous scaffolds based on poly(γ-benzyl-l-glutamate) (PBLG) were investigated in terms of the chondrogenic differentiation potential of human tooth germ stem cells (HTGSCs). Through the solution-assisted bonding of the fibres, fully connected scaffolds with pore sizes in the range 20-400 µm were prepared. Biomimetic modification of the PBLG scaffolds was achieved by a two-step reaction procedure: first, aminolysis of the PBLG fibres' surface layers was performed, which resulted in an increase in the hydrophilicity of the fibrous scaffolds after the introduction of N5 -hydroxyethyl-l-glutamine units; and second, modification with the short peptide sequence azidopentanoyl-GGGRGDSGGGY-NH2 , using the 'click' reaction on the previously modified scaffold with 2-propynyl side-chains, was performed. Radio-assay of the 125 I-labelled peptide was used to evaluate the RGD density in the fibrous scaffolds (which varied in the range 10-3 -10 pm/cm2 ). All the PBLG scaffolds, especially with density 90 ± 20 fm/cm2 and 200 ± 100 fm/cm2 RGD, were found to be potentially suitable for growth and chondrogenic differentiation of HTGSCs. Copyright © 2015 John Wiley & Sons, Ltd.
- MeSH
- benzylové sloučeniny chemická syntéza chemie farmakologie MeSH
- chrupavka účinky léků fyziologie MeSH
- dítě MeSH
- glutamáty chemická syntéza chemie farmakologie MeSH
- glykosaminoglykany metabolismus MeSH
- kmenové buňky cytologie účinky léků MeSH
- kultivované buňky MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- mladiství MeSH
- peptidy farmakologie MeSH
- povrchové vlastnosti MeSH
- proliferace buněk účinky léků MeSH
- syntetická chemie okamžité shody MeSH
- tkáňové inženýrství metody MeSH
- tkáňové podpůrné struktury chemie MeSH
- viabilita buněk účinky léků MeSH
- zubní zárodek cytologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis.
- MeSH
- apolipoproteiny E genetika MeSH
- aterosklerotický plát genetika patologie terapie MeSH
- ateroskleróza genetika patologie terapie MeSH
- buněčná diferenciace genetika MeSH
- cévy cytologie MeSH
- chondrogeneze genetika MeSH
- cytokiny metabolismus MeSH
- glykosaminoglykany metabolismus MeSH
- interleukin-6 metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky * MeSH
- myši MeSH
- osteogeneze genetika MeSH
- vaskulární kalcifikace genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
