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PubMedDate not supplied

Evaluation of acrylate-based block copolymers prepared by atom transfer radical polymerization as matrices for paclitaxel delivery from coronary stents.

Acrylate-based block copolymers, synthesized by atom transfer radical polymerization (ATRP) processes, were evaluated as drug delivery matrices for the controlled release of paclitaxel from coronary stents. The polymers were multiblock copolymers consisting of poly(butyl acrylate) or poly(lauryl acrylate) soft blocks and hard blocks composed of poly(methyl methacrylate), poly(isobornyl acrylate), or poly(styrene) homo- or copolymers. Depending on the ratio of hard to soft blocks in the copolymers, coating formulations were produced that possessed variable elastomeric properties, resulting in stent coatings that maintained their integrity when assessed by scanning electron microscopy (SEM) imaging of overexpanded stents. In vitro paclitaxel release kinetics from coronary stents coated with these copolymers typically showed an early burst followed by sustained release behavior, which permitted the elution of the majority of the paclitaxel over a 10-day time period. It was determined that neither the nature of the polyacrylate (n-butyl or lauryl) nor that of the hard block appeared to affect the release kinetics of paclitaxel at a loading of 25% drug by weight, whereas some effects were observed at lower drug loading levels. Differential scanning calorimetry (DSC) analysis indicated that the paclitaxel was at least partially miscible with the poly(n-butyl acrylate) phase of those block copolymers. The copolymers were also evaluated for sterilization stability by exposing both the copolymer alone and copolymer/paclitaxel coated stents to e-beam radiation at doses of 1-3 times the nominal dose used for medical device sterilization (25 kGy). It was found that the copolymers containing blocks bearing quaternary carbons within the polymer backbone were less stable to the radiation and showed a decrease in molecular weight as determined by gel-permeation chromatography. Conversely, those without quaternary carbons showed no significant change in molecular weight when exposed to 3 times the standard radiation dose. There was no significant change in drug release profile from any of the acrylate-based copolymers after exposure to 75 kGy of e-beam radiation, and this was attributed to the inherent radiation stability of the poly(n-butyl acrylate) center block.

Acrylates↗
PubMed1997

Structure of a viral procapsid with molecular scaffolding.

The assembly of a macromolecular structure proceeds along an ordered morphogenetic pathway, and is accomplished by the switching of proteins between discrete conformations as they are added to the nascent assembly. Scaffolding proteins often play a catalytic role in the assembly process, rather like molecular chaperones. Although macromolecular assembly processes are fundamental to all biological systems, they have been characterized most thoroughly in viral systems, such as the icosahedral Escherichia coli bacteriophage phiX174. The phiX174 virion contains the proteins F, G, H and J. During assembly, two scaffoldingproteins B and D are required for the formation of a 108S, 360-A-diameter procapsid from pentameric precursors containing the F, G and H proteins. The procapsid contains 240 copies of protein D, forming an external scaffold, and 60 copies each of the internal scaffolding protein B, the capsid protein F, and the spike protein G. Maturation involves packaging of DNA and J proteins and loss of protein B, producing a 132S intermediate. Subsequent removal of the external scaffold yields the mature virion. Both the F and G proteins have the eight-stranded antiparallel beta-sandwich motif common to many plant and animal viruses. Here we describe the structure of a procapsid-like particle at 3.5-A resolution, showing how the scaffolding proteins coordinate assembly of the virus by interactions with the F and G proteins, and showing that the F protein undergoes conformational changes during capsid maturation.

Bacteriophage phi X 174↗
PubMed2004

Self-immolative dendrimer biodegradability by multi-enzymatic triggering.

New self-immolative dendritic molecules have been designed and synthesized. The dendrons are built with a multi-enzymatic triggering mechanism, which initiates their biodegradation through a self-immolative chain fragmentation to release a reporter group from the focal point. The dendritic backbone is constructed from polycarbamate linkages, which are stable to hydrolysis and enhance the dendrons' solubility in water. The degradation can readily take place under physiological conditions on enzymatic triggering.

Biocompatible Materials↗
PubMed2006

Functionalization of polyoxometalates by carboxylato and azido ligands: macromolecular complexes and extended compounds.

Polyoxometalate compounds continue to be widely studied due to their relevance in various fields such as catalysis or magnetochemistry. In this article, we will focus on two topics we recently developed, the functionalization of rare earth polyoxometalates by organic ligands, which has led to compounds ranging from magnetic macromolecular complexes to a 3D open-framework system, and the functionalization of first row transition metal substituted polyoxometalates by azido ligands, which has allowed the isolation of complexes exhibiting the largest ferromagnetic exchange couplings observed to date in polyoxometalate chemistry.

Journal Article↗
PubMed1988

Effect of serum proteins on haem uptake and metabolism in primary cultures of liver cells.

A role of haemopexin in transporting haem to hepatocytes for degradation has been inferred from the high affinity of haemopexin for haem. We have examined this question in primary cultures of chick-embryo and adult rat liver cells. We present here the results of four sets of experiments which indicate that haemopexin retarded haem uptake by hepatocytes in culture. (1) Haem bound to bovine serum albumin is known to repress the activity of delta-aminolaevulinate synthase in chick cultures as indicated by decreased porphyrin accumulation. When haem-albumin was added in the presence of excess purified or freshly secreted chicken haemopexin, no haem-mediated repression of porphyrin production was observed. The haem-mediated repression of porphyrin accumulation was partially prevented when human, but not chicken, albumin was added to cultures. This finding reflected the higher affinity of human albumin for haem compared with that of chicken albumin. (2) Haemopexin inhibited the ability of haem to be incorporated into cytochrome P-450 induced in the chick cultures in the presence of the iron chelator desferrioxamine. (3) The rate of association of [55Fe]haem with cultured rat hepatocytes when [55Fe]haem-haemopexin was added was one-eighth of the rate observed when [55Fe]haem-bovine serum albumin was used as the haem donor. (4) The presence of haemopexin also diminished the catabolism of haem by both rat and chick-embryo liver cell cultures. It is concluded that the uptake and subsequent metabolic effects of haem are inhibited in cultured hepatocytes by proteins such as haemopexin which have a high affinity for haem.

5-Aminolevulinate Synthetase↗
PubMed2002

Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis.

Nuclear pore complexes (NPCs) are elaborate macromolecular structures that regulate the bidirectional nucleocytoplasmic traffic system. In vertebrate cells, NPCs include a family of 50 to 100 proteins termed nucleoporins (Nups). The 88-kD Nup has been found to be linked in a dynamic subcomplex with the oncogenic CAN/Nup214. Applying a polyclonal antiserum to Nup88 on paraffin sections, we found that it immunoreacts with numerous malignant neoplasms. All carcinomas reacted irrespective of site, type, or degree of differentiation; often, high-grade carcinomas stained more strongly and extensively. Some sarcomas (e.g., fibrosarcomas, leiomyosarcomas, liposarcomas, and rhabdomyosarcomas) reacted intensely; melanomas, gliomas, mesotheliomas, and malignant lymphomas also stained. In situ carcinomas of the colon, stomach, breast, and prostate stained convincingly, as did in situ melanomas; some samples of fetal tissues also reacted. Cytologic smears of some of the aforementioned tumors also stained. In selected samples, enhanced immunostaining of tissue sections and cytologic smears correlated strongly and consistently with immunoblot data. Immunoblots of the same tumors with antibodies to 2 other Nups (Nup214 and Nup153) showed no comparable enhancement. Therefore, it seems that in some malignant tumors, Nup88 overexpression is not parallelled by an overexpression of other Nups. Benign tumors, hyperplasias, and normal tissues showed weak and sporadic staining or absence of staining; immunoblots of the same samples yielded weak signals. Occasional highly proliferative hyperplastic-reactive processes showed focal staining. Thus, our correlative histologic, cytologic, and molecular data indicate that Nup88 may be viewed as a potentially useful, broadly based histodiagnostic and molecular marker of many malignancies and premalignant dysplasias, and further suggest that in some malignant tumors, Nup88 may be selectively overexpressed as compared with other Nups. Thus, we propose that Nup88 be designated as karyoporin.

Biomarkers, Tumor↗
PubMed1980

A proposed comprehensive pathophysiology of thrombotic thrombocytopenic purpura with implicit novel tests and therapies.

The first detailed comprehensive hypothesis for the pathophysiology of TTP is proposed which accounts for all of the features of TTP at several levels of reference: clinical, physiologic, biochemical, hematologic, and tissue pathology. From the proposed pathophysiology, by deduction, a number of novel diagnostic tests and several rational, promising therapeutic modalities.

Blood Transfusion↗
PubMed1979

Correlation of polypeptide composition with functional events in acetylcholine receptor-enriched membranes from Torpedo californica.

Membrane vesicles containing partially inactivated acetylcholine receptor (AcChoR) channels may produce a full 22Na+ flux response because an excess of channels may exist above the level needed to completely empty the vesicles of ions. Therefore, attempts to use ion flux amplitudes as indicators of AcChoR function may fail due to the presence of these excess AcChoR channels. Random inactivation of variable fractions of AcChoR channels in vesicles by the irreversible binding of the neurotoxin alpha-bungarotoxin provides a tool for assessing the size of the excess receptor population. Using this approach, we predict that the dependence of the flux response on partial inactivation by alpha-bungarotoxin will drastically change if an essential AcChoR component is substantially removed from the membranes. Membranes from which Mr 43,000, Mr 90,000, and other polypeptides had been substantially removed by base extraction exhibited a flux response after random inactivation that was indistinguishable from that of untreated membranes. Therefore, those components which are substantially removed by base extraction do not appear to be essential for AcChoR-mediated ion flux.

Animals↗
PubMed1979

Cell-free translation of the mRNAs for the heavy and light chains of HLA-A and HLA-B antigens.

Cell-free translation of poly(A)-containing RNA from the JY lymphoblastoid cell line followed by immunoprecipitation has indicated the presence of mRNAs for both the heavy and light chains of HLA-A and HLA-B antigens in these preparations. Both chains are synthesized with an NH2-terminal extension, approximately 20 residues in length for the light chain, and 20 or 24 residues for the heavy chains. The precursors can be processed by dog pancreatic microsomes to products similar to those obtained in vivo. Immunoprecipitation of the cell-free products has been employed as an assay for partial purification of the mRNAs. Investigation of the Daudi cell line, which cannot synthesize the small subunit, beta 2-microglobin, has indicated that the heavy chains of HLA-A and HLA-B antigens are synthesized intracellularly in vivo and can also be translated from their cognate RNAs in vitro. The implications of these findings for biosynthesis of membrane proteins in general and multimeric membrane proteins in particular, as well as the role of beta 2-microglobulin in expression of HLA-A and HLA-B antigens, are discussed.

Amino Acid Sequence↗
PubMed1985

Thyroid hormone regulation of thyrotropin alpha- and beta-subunit gene transcription.

We studied the effect of thyroid hormone on the transcription of the genes for the alpha- and beta-subunits of thyrotropin (TSH) in thyrotropic tumors (IAK 109D and 109F) carried in hypothyroid mice. Gene transcription was measured in isolated nuclei by allowing completion of RNA chains initiated in vivo in the presence of [alpha-32P]UTP and by hybridization of labeled RNA transcripts to filter-bound plasmids containing alpha or TSH-beta cDNA sequences. Treatment of animals carrying tumor IAK 109D with 3,5,3'-triiodo-L-thyronine (T3) (5 micrograms/100 g body weight) for 2 hr reduced TSH-beta gene transcription to less than 10% of control levels, whereas alpha RNA synthesis was reduced to 59% of control. The inhibition of TSH-beta gene activity was maintained after 6 hr of T3 treatment, whereas alpha gene transcription rose slightly to 77% of control. The tumor content of alpha and TSH-beta mRNA, determined by dot blot hybridization with 32P-labeled plasmid probes containing alpha or TSH-beta cDNAs, was unchanged after 2 hr of T3 treatment, and each was reduced by approximately 25% at 6 hr. These untreated tumors contained approximately equal amounts of alpha and TSH-beta mRNA. However, the basal rate of TSH-beta gene transcription was threefold greater than that of alpha gene transcription. Treatment of animals bearing tumor IAK 109F with the same dose of T3 for 30 min did not significantly affect alpha or TSH-beta gene transcription, but at 2 hr alpha and TSH-beta RNA synthesis had decreased to 50% and 10% of control values, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Predictome: a database of putative functional links between proteins.

The current deluge of genomic sequences has spawned the creation of tools capable of making sense of the data. Computational and high-throughput experimental methods for generating links between proteins have recently been emerging. These methods effectively act as hypothesis machines, allowing researchers to screen large sets of data to detect interesting patterns that can then be studied in greater detail. Although the potential use of these putative links in predicting gene function has been demonstrated, a central repository for all such links for many genomes would maximize their usefulness. Here we present Predictome, a database of predicted links between the proteins of 44 genomes based on the implementation of three computational methods--chromosomal proximity, phylogenetic profiling and domain fusion--and large-scale experimental screenings of protein-protein interaction data. The combination of data from various predictive methods in one database allows for their comparison with each other, as well as visualization of their correlation with known pathway information. As a repository for such data, Predictome is an ongoing resource for the community, providing functional relationships among proteins as new genomic data emerges. Predictome is available at http://predictome.bu.edu.

Animals↗
PubMed2002

S/MARt DB: a database on scaffold/matrix attached regions.

S/MARt DB, the S/MAR transaction database, is a relational database covering scaffold/matrix attached regions (S/MARs) and nuclear matrix proteins that are involved in the chromosomal attachment to the nuclear scaffold. The data are mainly extracted from original publications, but a World Wide Web interface for direct submissions is also available. S/MARt DB is closely linked to the TRANSFAC database on transcription factors and their binding sites. It is freely accessible through the World Wide Web (http://transfac.gbf.de/SMARtDB/) for non-profit research.

Animals↗
PubMed1994

Determination of fostriecin pharmacokinetics in plasma using high-pressure liquid chromatography assay.

Fostriecin is an antitumor antibiotic with marked activity against ovarian, breast, and lung cancer cell lines in the human tumor clonogenic assay. The mechanism of cytotoxicity in vivo is unknown; in vitro it has been shown to inhibit macromolecular synthesis, interact with the reduced folate carrier system, and inhibit topoisomerase II. Phase I testing of fostriecin in a daily for 5 days schedule has begun in cancer patients. A high-pressure liquid chromatographic method to measure fostriecin in plasma samples was developed using sulfaquinoxaline as an internal standard and ultraviolet detection (268 nm). The extraction efficiency is 70% and the sensitivity limit is 100 ng/ml. The pharmacokinetics of fostriecin were determined in six rabbits following intravenous injection of 12 mg/m2. The mean distribution space was 4.44 L/m2 and the mean plasma clearance was 302 ml/min/m2. The elimination half-life was 11.95 +/- 8.55 min. All rabbits exhibited a 10-60-fold increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that resolved within 48 h of drug administration.

Alkenes↗
PubMed2004

Protein self-association in crowded protein solutions: a time-resolved fluorescence polarization study.

The self-association equilibrium of a tracer protein, apomyoglobin (apoMb), in highly concentrated crowded solutions of ribonuclease A (RNase A) and human serum albumin (HSA), has been studied as a model system of protein interactions that occur in crowded macromolecular environments. The rotational diffusion of the tracer protein labeled with two different fluorescent dyes, 8-anilinonaphthalene-1-sulfonate and fluorescein isothiocyanate, was successfully recorded as a function of the two crowder concentrations in the 50-200 mg/mL range, using picosecond-resolved fluorescence anisotropy methods. It was found that apoMb molecules self-associate at high RNase A concentration to yield a flexible dimer. The apparent dimerization constant, which increases with RNase A concentration, could also be estimated from the fractional contribution of monomeric and dimeric species to the total fluorescence anisotropy of the samples. In contrast, an equivalent mass concentration of HSA does not result in tracer dimerization. This different effect of RNase A and HSA is much larger than that predicted from simple models based only on the free volume available to apoMb, indicating that additional, nonspecific interactions between tracer and crowder should come into play. The time-resolved fluorescence polarization methods described here are expected to be of general applicability to the detection and quantification of crowding effects in a variety of macromolecules of biological relevance.

Animals↗
PubMed1994

Light and biological rhythms.

Chronobiology--derived from chronos (time), bios (life), and logos (study of)--is the objective description of biological time structures and plays an important role in medicine. Circadian rhythms regulate the behaviour, physiology and function of living organisms at many biochemical levels. The influence of the rhythmic manifestation of life may be shown in the constructive effects of growth, development and maturation and is named anachronobiology. In contrast catachronobiology denotes deleterious effects of time and rhythm which may lead to a diseased state. This article summarizes some new data about light as a synchronizer of biological rhythms. A time-keeper--biological clock--is used by the body for readjustment of rhythms when this is desirable. More recently, light has been used to adjust the biological clock following changes of circadian rhythms during shift work or jet lag occurring when flying from one time zone to another. Light may be used to treat depression, sleep disorders, menstrual dysregulations and other illnesses with disturbed circadian and seasonal rhythms. Examples of the importance of chronopharmacology (time-dependent changes in drug metabolism and drug effect) are also presented. New findings indicate that circadian oscillators are under genetic control; a light-influenced regulatory role for cellular immediate-early genes in circadian behaviour has been discovered. This suggests that light is of importance in regulation of macromolecular synthesis at all levels of the circadian system.

Chronobiology Phenomena↗