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At least 739 records · Page 41Linked to original sources
PubMed2005

Increased lysosomal uptake of methotrexate-polyglutamates in two methotrexate-resistant cell lines with distinct mechanisms of resistance.

Methotrexate (MTX) resistance in mitoxantrone-selected MCF7/MX cells and in MTX-selected CEM/MTX cells is associated with reduced drug accumulation, albeit caused by different mechanisms. In addition, in both resistant cell lines the proportion of active long-chain MTX-polyglutamate (MTX-PG) metabolites is reduced relative to that in the respective parental cell line. Previous studies by others have implied that increased lysosomal uptake could affect the rate of MTX-PG hydrolysis, and hence the length distribution of the polyglutamate chains. However, in the two cell line pairs studied, the number of lysosomes per cell was not different between the corresponding parental and resistant cells. Instead, we observed a two- to three-fold increased facilitative uptake of MTX-Glu4 by the lysosomes from these two independently derived MTX-resistant cell lines, compared to uptake by lysosomes from their corresponding parental cells. Enhanced lysosomal uptake of MTX-Glu4 was reflected in an increased maximal uptake velocity, without a change in the apparent substrate affinity. In addition, the rate of MTX efflux from lysosomes from CEM/MTX cells was two-fold faster than from lysosomes from CEM cells. Consistent with this observation, the relative amount of short-chain MTX-Glu(1+2) species, as a fraction of the total amount of all MTX-Glu(1-4) species combined, was only half as large in lysosomes from CEM/MTX cells as in lysosomes from CEM cells. Together, these results suggest the possibility that increased lysosomal uptake, and hence enhanced sequestration of MTX-PGs in resistant cells, contributes to the development of high-level MTX resistance by decreasing the cytosolic levels of MTX-PGs.

Biological Transport↗
PubMed2005

Biodegradable cationic PEG-PEI-PBLG hyperbranched block copolymer: synthesis and micelle characterization.

A novel amphiphilic biodegradable cationic hyperbranched poly(ethylene glycol)-polyethylenimine-poly(gamma-benzyl L-glutamate) (PEG-PEI-PBLG) block copolymer was successfully synthesized by ring-opening polymerization (ROP) of N-carboxyanhydride of gamma-benzyl-L-glutamate (BLG-NCA) with PEG-PEI as a macroinitiator. PEG-PEI was firstly prepared by coupling of PEG and PEI using hexamethylene diisocyanate (HMDI). The structural properties of PEG-PEI-PBLG copolymers were confirmed by 1H NMR and GPC. The copolymers were found to be self-assembled in water with critical micelle concentration (CMC) in the range of 0.00368-0.0125 g/l and high hydrophobic micelle core. The micelle size and CMC obviously depended on the hydrophobic block content in the copolymer and the ionic state of the PEI block. The CMC decreased with the increase in the PBLG block content. The decrease of micelle size and the increase of CMC simultaneously occurred with the protonated degree of PEI block by addition of HCl solution. ESEM and Gel retardation assay showed that the cationic micelles had ability to encapsulate plasmid DNA. The copolymer has potential medical applications in drug and gene delivery.

Absorbable Implants↗
PubMed2006

The use of low dose methotrexate in rheumatoid arthritis - are we entering a new era of therapeutic drug monitoring and pharmacogenomics?

Methotrexate (MTX) is one of the most commonly used medications in the treatment of rheumatoid arthritis (RA). It has proven efficacy as a sole agent as well as in combination with other disease modifying anti-rheumatic agents (DMARDs) including the newer biological agents. MTX is generally well tolerated although there are a number of potentially serious adverse effects. Of these, haematopoietic suppression, hepatotoxicity and pulmonary toxicity are the more severe and patients are therefore required to have appropriate monitoring while they remain on MTX. In the past, attempts at therapeutic drug monitoring using serum MTX concentrations have been unsuccessful. However, MTX is taken into red blood cells (RBC) where up to four glutamates are added to form MTX polyglutamates (MTXPG(n)). More recently it has been suggested that higher RBC MTXPG(3-5) concentrations may be associated with improved disease control. Genetic variations in enzymes involved in the uptake of MTX into cells and its metabolism are also being examined for their ability to predict drug response and potential for adverse events. While it is unlikely that a single genetic variant will predict efficacy or toxicity there is preliminary evidence that a "pharmacogenetic index" that takes into account the effects of multiple genetic variants maybe useful. Although in their infancy at present, both therapeutic drug monitoring using MTXPG concentrations and pharmacogenomics of MTX may prove useful in the future and are worthy of further investigation.

Antirheumatic Agents↗
PubMed2006

Toward intrinsically fluorescent proteomimetics: fluorescent probe response to alpha helix structure of poly-gamma-benzyl-L-glutamate.

A fluorescent probe (1), developed for recognition of alpha helical secondary structure, shows a large fluorescence change upon titration with the synthetic protein PBLG. Compared to fluorophores of similar size and shape, 1 displayed the smallest dissociation constant (K(D)=80microM) when titrated with PBLG. These preliminary studies are directed toward developing small molecule proteomimetics that have intrinsic fluorescence and are specific for helical-protein binding-sites.

Fluorescent Dyes↗
PubMed2004

Mechanisms of cell death in polyglutamine expansion diseases.

Abnormal protein aggregation is a hallmark of many neurodegenerative diseases. However, the mechanism by which protein aggregates induce neurodegneration remains controversial. Recently proposed mechanisms of neuronal death in polyglutamine expansion diseases include activation of caspases and associated cell death pathways, interference with transcriptional regulation, downregulation of survival pathways and obstruction of axonal transport. Because the expression of expanded polyglutamine in selected neuronal populations can adversely affect multiple aspects of neuronal survival and function, we propose that effective therapeutic approaches might have to target the upstream mechanism of neurotoxicity by selectively inhibiting the formation of intraneuronal aggregates and increasing the degradation of mutant proteins.

Animals↗
PubMed2005

Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly(gamma-benzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety.

Poly(gamma-benzyl L-glutamate) (PBLG)/poly(ethylene glycol) (PEG) diblock copolymer endcapped with galactose moiety (abbreviated as GEG) was synthesized and characterized for study of liver-specific targeting. From dynamic light scattering measurement, particle sizes of copolymeric nanoparticles were decreased with an increase of PEG in the copolymer. The morphology of GEG-3 nanoparticles observed by transmission electron micrograph was observed as almost spherical shapes and ranged about 50-300 nm. From the structural characterization using 1H nuclear magnetic resonance, both characteristic peaks of PBLG and PEG were visible in CDCl3 but the characteristic peaks of PBLG were invisible in D2O, indicating that GEG block copolymers are found to the core-shell type nanoparticles in water with PBLG innercore and PEG outershell, exposing that galactose moiety of GEG block copolymers are outerwards oriented on the nanoparticle surfaces. By galactose-specific aggregation test of particles using beta-galactose specific lectin, and flow cytometry measurement, specific interaction between asialoglycoprotein receptors (ASGPR) of HepG2, human hepatoma cell line, and galactose moieties of the GEG nanoparticles was confirmed. From cell cytotoxicity test, HepG2 cells with ASGPR are more sensitive to paclitaxel (TX)-loaded nanoparticles than free TX whereas, P388 cells, murine leukemia cell line, and SK-Hep 01, human hepatoma cell line, without ASGPR is less sensitive to TX-loaded nanoparticles than free TX, suggesting that specific interaction between HepG2 cells and galactose moiety of the nanoparticles occurred.

Animals↗
PubMed2006

Micelle formation and drug release behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer.

Self-association behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer and drug carrier capability of the formed micelles was examined. The results gained through fluorescence spectroscopy, transmission electron microscopy and nuclear magnetic resonance spectroscopy revealed that both polypeptide graft copolymer and its mixture with polypeptide block copolymer can self-assemble to form polymeric micelles in aqueous media. The molecular structure of the graft copolymer and blending the graft with block copolymer exert marked effects on the critical micelle concentration and the shape of formed micelles. It was found that the hydrophobic inner core of the micelles formed either by graft copolymer or mixture of graft and block copolymers can act as an incorporation site for the hydrophobic drugs. The drug loading content of the graft copolymer micelles tends to be larger when the content of the polypeptide segments in the copolymer increases. The results obtained from the drug-release studies showed that the drug-release rates are dependent on the chemical nature of the graft copolymer, the composition of the graft and block copolymer mixture, and also the pH value of the release media.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

A nanocompartment system (Synthosome) designed for biotechnological applications.

A nanocompartment system based on two deletion mutants of the large channel protein FhuA (FhuA Delta1-129; FhuA Delta1-160) and an ABA triblock copolymer (PMOXA-PDMS-PMOXA) has been developed for putative biotechnological applications. FhuA is ideally suited for applications in biotechnology due to its monomeric structure, large pore diameter (39-46 A elliptical cross-section) that ensures rapid compound flux, and solved crystallographic structure. Two areas of application were targeted as proof of principle: (A) selective product recovery in nanocompartments and (B) enzymatic conversion in nanocompartments. Selective recovery of negatively charged compounds has been achieved on the example of sulforhodamine B by using positively charged polylysine molecules as trap inside the nanocompartment. Conversion in nanocompartments has been achieved by 3,3',5,5'-tetramethylbenzidine oxidation employing horseradish peroxidase (HRP).

Bacterial Outer Membrane Proteins↗
PubMed2005

Monolayer formation of PBLG-PEO block copolymers at the air-water interface.

Physicochemical properties of PBLG (poly(gamma-benzyl-l-glutamate))-PEO (poly(ethylene oxide)) diblock copolymers composed of PBLG as the hydrophobic rod component and PEO as the hydrophilic component were investigated at the air-water interface. Surface pressure-area isotherms obtained by the Wilhelmy plate method provide several variables such as molecular size, compressibility of PEO, and the free energy change of the PBLG-PEO block copolymer. GE-1 (M(w) of PBLG:PEO=103,700:12,000), with a relatively longer rod, has negative temperature effects and GE-3 (M(w) of PBLG:PEO=8400:12,000), with a relatively shorter rod, shows a positive temperature effect because of the large entropy loss. These competitions were based on the block size of PBLG and PEO and were affected by various microstructures of the PBLG-PEO diblock copolymer. Monolayer aggregations transferred onto mica from the air-water interface were analyzed with AFM. AFM images of GE-1 monolayers show cylindrical micelles, but the self-assembled structure has many large domains. The monolayer of GE-2 (M(w) of PBLG:PEO=39,800:12,000), which has a medium size rod, forms a spherical structure at the air-water interface. Monolayers of GE-3, with a short rod length, form bilayer structures. These results demonstrate that the microstructures of PBLG-PEO diblock copolymers are related to free energy changes between rod and coil blocks.

Air↗
PubMed2004

Modified z-gradient filtering as a mean to obtain phased deuterium autocorrelation 2D NMR spectra in oriented solvents.

We describe a modified z-gradient filter scheme specifically designed to obtain pure absorption mode deuterium 2D NMR spectra recorded in oriented solvents. The proposed technique is investigated by analysing the evolution of the density operator for a spin I=1. The method is applied to the recently designed Q-COSY and Q-resolved 2D experiments to simplify the analysis of chiral molecules dissolved in weakly orienting chiral liquid crystals. The efficiency of this z-gradient filtering technique is illustrated using the perdeuterated 1-butanol, a prochiral molecule of average Cs symmetry, dissolved in an organic solution of poly-gamma-benzyl-L-glutamate (PBLG). The experimental results as well as the advantages of the new experiments compared with the previous ones are described and discussed.

Deuterium↗
PubMed2006

Resolution enhancement in spectra of natural products dissolved in weakly orienting media with the help of 1H homonuclear dipolar decoupling during acquisition: application to 1H-13C dipolar couplings measurements.

In weakly orienting media such as poly-gamma-benzyl-L-glutamate (PBLG) a polymer that forms a chiral liquid crystal in organic solvents, the spectral resolution for embedded molecules is usually poor because of numerous (1)H, (1)H dipolar couplings that generally broaden proton spectra. Therefore (1)H, (13)C dipolar couplings are difficult or impossible to measure. Here, we incorporate Flip-Flop decoupling during detection into an HSQC experiment. Flip-Flop removes the (1)H, (1)H dipolar couplings and scales the chemical shifts of the protons as well as the (1)H, (13)C dipolar couplings during detection. A resolution gain by a factor 1.5-4.2 and improved signal intensity by an average factor of 1.6-1.7 have been obtained. This technique is demonstrated on (+)-menthol dissolved in a PBLG/CDCl(3) phase.

Anisotropy↗
PubMed2002

Interaction of STOP with neuronal tubulin is independent of polyglutamylation.

In eukaryotes, the coordinated progress of the various cellular tasks along with the assembly of adapted cytoskeletal networks requires a tight regulation of the interactions between microtubules and their associated proteins. Polyglutamylation is the major post-translational modification of neuronal tubulin. Due to its oligomeric structure, polyglutamylation can serve as a potentiometer to modulate binding of diverse MAPs. In addition, it can exert a differential mode of regulation towards distinct microtubule protein partners. To find out to what extent polyglutamylation is a general regulator, we have analyzed its ability to affect the binding of STOPs, the major factors that confer cold- and nocodazole-resistance to microtubules. We have shown by blot overlay experiments that binding of STOP does not depend on the length of the polyglutamyl chains carried by tubulins. And contrary to the other microtubule-associated proteins tested so far, STOP can bind quantitatively to any tubulin isoform whatever its degree of polyglutamylation.

Animals↗
PubMed2000

Orientation of the infrared transition moments for an alpha-helix.

Appropriate values for the orientation of the amide transition dipoles are essential to the growing use of isotopically edited vibrational spectroscopy generally in structural biology and to infrared dichroism measurements on membrane-associated alpha-helices, in particular. The orientations of the transition moments for the amide vibrations of an alpha-helix have been determined from the ratio of intensities of the A- and E(1)-symmetry modes in the infrared spectra of poly(gamma-methyl-L-glutamate)(x)-co-(gamma-n-octadecyl-L-glutamate)( y) oriented on silicon substrates. Samples possessing a high degree of alignment were used to facilitate band fitting. Consistent results were obtained from both attenuated total reflection and transmission experiments with polarized radiation, yielding values of Theta(I) = 38 degrees, Theta(II) = 73 degrees, and Theta(A) = 29 degrees, relative to the helix axis, for the amide I, amide II, and amide A bands, respectively. The measurements are discussed both in the context of the somewhat divergent older determinations, and in relation to the helix geometry and results on model amide compounds, to resolve current uncertainties in the literature.

Biophysical Phenomena↗
PubMed1996

Determination of molecular order in supported lipid membranes by internal reflection Fourier transform infrared spectroscopy.

When polarized internal reflection infrared spectroscopy is used to determine molecular order in supported lipid membranes, the results are critically dependent on the accuracy of assumptions made about the evanescent electric field amplitudes in the membrane. In this work, we examine several expressions used for calculating evanescent electric field amplitudes in supported lipid monolayers and bilayers, and test their validity by measuring the infrared dichroism of poly-gamma-benzyl-L-glutamate and poly-beta-benzyl-L-aspartate under conditions in which their molecular order is known. Our results indicate that treating such systems as a simple single interface between two semi-infinite bulk phases is more accurate than the commonly employed thin-film approximation. This implies that earlier conclusions about molecular order in supported lipid membranes may require substantial revision.

Liposomes↗