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At least 1,423 records · Page 79Linked to original sources
PubMed2002

Liposome-based drug delivery in breast cancer treatment.

Drug delivery systems can in principle provide enhanced efficacy and/or reduced toxicity for anticancer agents. Long circulating macromolecular carriers such as liposomes can exploit the 'enhanced permeability and retention' effect for preferential extravasation from tumor vessels. Liposomal anthracyclines have achieved highly efficient drug encapsulation, resulting in significant anticancer activity with reduced cardiotoxicity, and include versions with greatly prolonged circulation such as liposomal daunorubicin and pegylated liposomal doxorubicin. Pegylated liposomal doxorubucin has shown substantial efficacy in breast cancer treatment both as monotherapy and in combination with other chemotherapeutics. Additional liposome constructs are being developed for the delivery of other drugs. The next generation of delivery systems will include true molecular targeting; immunoliposomes and other ligand-directed constructs represent an integration of biological components capable of tumor recognition with delivery technologies.

Antineoplastic Agents↗
PubMed1992

The Rex system of bacteriophage lambda: tolerance and altruistic cell death.

The rexA and rexB genes of bacteriophage lambda encode a two-component system that aborts lytic growth of bacterial viruses. Rex exclusion is characterized by termination of macromolecular synthesis, loss of active transport, the hydrolysis of ATP, and cell death. By analogy to colicins E1 and K, these results can be explained by depolarization of the cytoplasmic membrane. We have fractionated cells to determine the intracellular location of the RexB protein and made RexB-alkaline phosphatase fusions to analyze its membrane topology. The RexB protein appears to be a polytopic transmembrane protein. We suggest that RexB proteins form ion channels that, in response to lytic growth of bacteriophages, depolarize the cytoplasmic membrane. The Rex system requires a mechanism to prevent lambda itself from being excluded during lytic growth. We have determined that overexpression of RexB in lambda lysogens prevents the exclusion of both T4 rII mutants and lambda ren mutants. We suspect that overexpression of RexB is the basis for preventing self-exclusion following the induction of a lambda lysogen and that RexB overexpression is accomplished through transcriptional regulation.

Adenosine Triphosphate↗
PubMed2003

BioEditor-simplifying macromolecular structure annotation.

SUMMARY: BioEditor is an application to enable scientists and educators to prepare and present structure annotations containing formatted text, graphics, sequence data, and interactive molecular views. It is intended to bridge the gap between printed journal articles and Internet presentation formats. BioEditor is relevant in the era of structural genomics, where annotation and publication could become the rate determining step in structure determination. AVAILABILITY: BioEditor is available at http://bioeditor.sdsc.edu. The Web site includes the latest version of the software for Microsoft Windows, including documentation, the opportunity to submit bug reports and suggestions, example documentaries prepared with BioEditor and a repository where users can submit documentaries for posting to the site.

Biopolymers↗
PubMed2003

PDB file parser and structure class implemented in Python.

UNLABELLED: The biopython project provides a set of bioinformatics tools implemented in Python. Recently, biopython was extended with a set of modules that deal with macromolecular structure. Biopython now contains a parser for PDB files that makes the atomic information available in an easy-to-use but powerful data structure. The parser and data structure deal with features that are often left out or handled inadequately by other packages, e.g. atom and residue disorder (if point mutants are present in the crystal), anisotropic B factors, multiple models and insertion codes. In addition, the parser performs some sanity checking to detect obvious errors. AVAILABILITY: The Biopython distribution (including source code and documentation) is freely available (under the Biopython license) from http://www.biopython.org

Computer Simulation↗
PubMed1999

The proopiomelanocortin system.

POMC (31,000 MW) is localized to the pituitary, brain, skin, and other peripheral sites. The particular enzyme profile present within a cell dictates the nature of the hormonal ligand (melanocortin) synthesized and secreted: melanotropic peptides (alpha-MSH beta-lipotropin, lambda-MSH), corticotropin (ACTH), several endorphins (e.g., met-enkephalin). These POMC-derived peptides mediate their actions through typical seven-spanning membrane receptors (MCRs; MCR1, 2, 3, 4, and 5). A specific melanocortin acting on a specific MCR regulates a particular biological response; for example, alpha-MSH on MCR1 increases melanogenesis within melanocytes, ACTH on MCR2 increases cortisol production within adrenal zona fasciculata cells. Within the brain melanocortins regulate satiety (MCR4) and erectile activity (MCR?). MCRs have been localized by melanocortin macromolecular probes, for example, fluorescent to human epidermal melanocytes and also to keratinocytes, suggesting that systemic melanocortins or localized POMC products might regulate these integumental cellular elements in synchrony to enhance skin pigmentation and/or immunological responses. Superpotent, prolonged acting melanotropic peptides have been synthesized and their application in clinical medicine has been demonstrated. MCR antagonists have been used to discover and further delineate other roles of melanocortin ligands. For example, melanocortin-induced satiety can be antagonized by a melanocortin antagonist. Defects in melanocortin ligand biosynthesis, secretion, and melanocortin receptor function can lead to a diverse number of pathological states.

Adrenocorticotropic Hormone↗
PubMed2000

Potential use of non-classical pathways for the transport of macromolecular drugs.

Since an increasing number of drug delivery strategies utilising proteins and peptides exhibiting 'non-classical' transport activities have been proposed, studies have begun to establish underlying functional relationships between different vectors. These attempts to find common factors have been hampered by a lack of biophysical data for the various potential protein and peptide transporters, as well as by the structural and functional diversity of the group as a whole. We describe the various types of vectors being considered for use and the preliminary therapeutic successes that have been achieved. Additionally, the various models that have been proposed for non-classical import and export are outlined and discussed in relation to therapeutic delivery. Possible future developments are also discussed.

Animals↗
PubMed2003

Yeast two-hybrid system survey of interactions between LEE-encoded proteins of enteropathogenic Escherichia coli.

Many Gram-negative pathogens employ a specific secretion pathway, termed type III secretion, to deliver virulence effector proteins directly to the membranes and cytosol of host eukaryotic cells. Subsequent functions of many effector proteins delivered in this manner result in subversion of host-signalling pathways to facilitate bacterial entry, survival and dissemination to neighbouring cells and tissues. Whereas the secreted components of type III secretion systems (TTSSs) from different pathogens are structurally and functionally diverse, the structural components and the secretion apparatus itself are largely conserved. TTSSs are large macromolecular assemblies built through interactions between protein components of hundreds of individual subunits. The goal of this project was to screen, using the standard yeast two-hybrid system, pair-wise interactions between components of the enteropathogenic Escherichia coli TTSS. To this end 37 of the 41 genes encoded by the LEE pathogenicity island were cloned into both yeast two-hybrid system vectors and all possible permutations of interacting protein pairs were screened for. This paper reports the identification of 22 novel interactions, including interactions between inner-membrane structural TTSS proteins; between the type III secreted translocator protein EspD and structural TTSS proteins; between established and putative chaperones and their cognate secreted proteins; and between proteins of undefined function.

Bacterial Proteins↗
PubMed1995

Hydrogen bonding motifs of protein side chains: descriptions of binding of arginine and amide groups.

The modes of hydrogen bonding of arginine, asparagine, and glutamine side chains and of urea have been examined in small-molecule crystal structures in the Cambridge Structural Database and in crystal structures of protein-nucleic acid and protein-protein complexes. Analysis of the hydrogen bonding patterns of each by graph-set theory shows three patterns of rings (R) with one or two hydrogen bond acceptors and two donors and with eight, nine, or six atoms in the ring, designated R2(2)(8), R2(2)(9), and R1(2)(6). These three patterns are found for arginine-like groups and for urea, whereas only the first two patterns R2(2)(8) and R2(2)(9) are found for asparagine- and glutamine-like groups. In each case, the entire system is planar within 0.7 A or less. On the other hand, in macromolecular crystal structures, the hydrogen bonding patterns in protein-nucleic acid complexes between the nucleic acid base and the protein are all R2(2)(9), whereas hydrogen bonding between Watson-Crick-like pairs of nucleic acid bases is R2(2)(8). These two hydrogen bonding arrangements [R2(2)(9)] and R2(2)(8)] are predetermined by the nature of the groups available for hydrogen bonding. The third motif identified, R1(2)(6), involves hydrogen bonds that are less linear than in the other two motifs and is found in proteins.

Adenine↗
PubMed1994

Anaphylaxis models in the guinea-pig.

Immediate hypersensitivity (or anaphylactic) reactions can be caused by large molecules which are directly immunogenic or by smaller molecules which bind to macromolecular carriers and act as haptens. To reproduce these reactions in animals, either systemic or local models are used in actively or passively sensitized animals, respectively. Several attempts have been made to detect the potential of new drugs and chemicals to induce anaphylactic reactions. Protocols using the inhalation of reactive low-molecular-weight compounds produced clinical symptoms in the guinea-pig. An intralaboratory validation study was initiated using a panel of six positive and one negative model compounds in a guinea-pig model combining systemic and local anaphylaxis. Anaphylactic reactions to positive model compounds were obtained only when the molecular weight was approximately 3000 or more. Overall, published results indicate that the potential to induce immediate hypersensitivity reactions can be detected as far as large-molecular-weight molecules are concerned--in contrast to the majority of low-molecular-weight drugs and chemicals.

Administration, Cutaneous↗
PubMedDate not supplied

The relationship of problems in biomedical MRI to the study of porous media.

The NMR methods that are used to characterize inanimate porous media measure relaxation times and related phenomena and material transport, fluid displacement and flow. Biological tissues are comprised of multiple small, fluid-filled compartments, such as cells, that restrict the movement of the bulk solvent water and whose constituents influence water proton relaxation times via numerous interactions with macromolecular surfaces. Several of the methods and concepts that have been developed in one field of application are also of great value in the other, and it may be expected that technical developments that have been spurred by biomedical applications of MR imaging will be used in the continuing study of porous media. Some recent specific studies from our laboratory include the development of multiple quantum coherence methods for studies of ordered water in anisotropic macromolecular assemblies, studies of the degree of restriction of water diffusion in cellular systems, multiple selective inversion imaging to depict the ratios of proton pool sizes and rates of magnetization transfer between proton populations, and diffusion tensor imaging to depict tissue anisotropies. These illustrate how approaches to obtain structural information from biological media are also relevant to porous media. For example, the recent development of oscillating gradient spin echo techniques (OGSE), an approach that extends our ability to resolve apparent diffusion changes over different time scales in tissues, has also been used to compute surface to volume measurements in assemblies of pores. Each of the new methods can be adapted to provide spatially resolved quantitative measurements of properties of interest, and these can be efficiently acquired with good accuracy using fast imaging methods such as echo planar imaging. The community of NMR scientists focused on applications to porous media should remain in close communication with those who use MRI to study problems in biomedicine, to their mutual benefits.

Animals↗
PubMed2003

Mammalian longevity under the protection of PARP-1's multi-facets.

Given the presence of continuous endogenous and exogenous sources of stress, mammalian species have evolved complex systems of protection, detoxification and repair, in order to maintain homeostasis during development and until reproductive maturity for the sake of the species. However, since no system is perfect, complete prevention of damage is unlikely to occur. Accumulation of macromolecular damage, including damage to DNA and genomic instability, is considered a driving force for the ageing process and age-related diseases. One of the immediate eukaryotic cellular responses to DNA breakage is the covalent post-translational modification of nuclear proteins with poly(ADP-ribose) from NAD+ as precursor, mostly catalysed by poly(ADP-ribose) polymerase-1 (PARP-1). Poly(ADP-ribosyl)ation is involved in DNA base-excision repair (BER), DNA-damage signalling and regulation of genomic stability. In recent years, many groups have become involved in PARP field, shedding light on new partners for PARP-1, new members of the PARP family and new physiological and pathophysiological properties for the founding member of the poly(ADP-ribose) polymerase super family. The present review focuses on PARP-1 and its role in the maintenance of genome stability and in mammalian longevity.

Aging↗
PubMedDate not supplied

Tat-conjugated synthetic macromolecules facilitate cytoplasmic drug delivery to human ovarian carcinoma cells.

We have synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-cell penetrating peptide Tat conjugates and evaluated their subcellular distribution in A2780 human ovarian carcinoma cells by confocal fluorescence microscopy and subcellular fractionation. Our data indicate the transport of these conjugates by a single Tat molecule to both the cytoplasm and nucleus via a nonendocytotic and concentration independent process. The uptake was observed to occur within 3 min, as confirmed by live cell microscopy. In contrast, HPMA copolymers lacking the Tat peptide were internalized solely by endocytosis. For the first time, Tat-mediated cytoplasmic delivery of a polymer bound anticancer drug, doxorubicin, was also demonstrated. These findings establish the feasibility of overcoming major cellular and subcellular obstacles to intracellular macromolecular delivery and hold great promise for the development of polymer-based systems for the cytoplasmic delivery of therapeutic molecules.

Cell Nucleus↗
PubMed1977

Association products and conformations of salt-dissociated and acid-extracted histones. A two-phase procedure for isolating salt-dissociated histones.

We present an extremely rapid and efficient method for the separation of salt-dissociated histones from DNA in which the macromolecular components of chicken erythrocyte chromatin are partitioned in a two-phase system of the water-soluble, nonionic polymers, poly(ethylene glycol) and dextran. We have compared the association products and conformations of salt-dissociated histones purified with the two-phase procedure and histones that had been extracted with 0.4 M H2SO4. In the gel chromatography system of D. R. vander Westhuyzen and C. von Holt (1971), FEBS Lett. 14, 333-337] the association products of salt-dissociated and acid-extracted histones are indistinguishable. Furthermore, the circular dichroism spectra of histones prepared with the two methods are identical within experimental error. These results indicate that histones extracted, with sulfuric acid can adopt conformations at least very similar to those of salt-dissociated preperties of total erythrocyte histones are the same in 2 M NaCl as those of these histones bound to DNA in chromatin in 1 mM Tris-Cl (pH 7.5). This result and the studies of Weintraub et al. [Weintraub, H., Palter, K., and Van Lente, F. (1975), Cell 6, 68-110] on the patterns of tryptic digest products of histones strongly suggest that in 2 M NaCl the histones exist in conformations very similar to their conformations when bound to DNA. The concept of native histone conformations is discussed in light of our results.

Animals↗
PubMed2005

Amphiphilic hydrogel nanoparticles. Preparation, characterization, and preliminary assessment as new colloidal drug carriers.

Inverse emulsion photopolymerization of acrylated poly(ethylene glycol)-bl-poly(propylene glycol)-bl-poly(ethylene glycol) and poly(ethylene glycol) was successfully employed to prepare stable, cross-linked, amphiphilic nanoparticles. Even at low emulsifier concentrations (2%) and high water-to-hexane weight ratios (35/65), the stability of the inverse emulsion allowed for the formation of well-defined colloidal material. Inverse emulsion characteristics and polymerization conditions could be controlled to vary the size of the nanoparticles between 50 and 500 nm. The presence of hydrophobic nanodomains within these otherwise hydrophilic nanoparticles was verified by using pyrene as a microenvironmentally sensitive probe. The hydrophobic poly(propylene glycol)-rich domains appear to be suitable for incorporation of hydrophobic drugs, encapsulating Doxorubicin up to 9.8% (w/w). We believe that the complex nano-architecture of these materials makes them a potentially interesting colloidal drug delivery carrier system and that the method should be useful for a number of amphiphilic macromolecular precursors.

Antineoplastic Agents↗
PubMed1989

Vaccine engineering: enhancement of immunogenicity of synthetic peptide vaccines related to hepatitis in chemically defined models consisting of T- and B-cell epitopes.

We report the development of two models for synthetic hepatitis B vaccines. The models were based on the multiple antigen peptide (MAP) system and contained the relevant B- and T-cell epitopes without any macromolecular carrier. Two peptides, representing the a determinant of the S region (S protein) of hepatitis B surface antigen, a dominant serotype of hepatitis B virus infection found in humans, and residues 12-26 of the pre-S(2) region of the middle protein were incorporated as either monoepitope or diepitope MAP models. Immunizations of outbred rabbits with the monoepitope MAP that contains the pre-S(2) antigen resulted in high-titered antibody response to the middle protein, but the other monoepitope, containing only the a-determinant peptide antigen, resulted in poor immune responses to either the peptide antigens or to the S protein. The diepitope MAPs containing both the a and the pre-S(2) determinants produced high-titer antibodies reactive to the a-synthetic peptide and the S protein, as well as to the middle proteins. Thus, our results show that the diepitope MAP models eliminate the need for a protein carrier and that the pre-S(2) peptide determinant serves as a T-helper cell epitope that enhances the immune response of the S region and overcomes the poor immunogenicity encountered with a single epitope of the S region.

Amino Acid Sequence↗
PubMed2002

The glycoforms of a Trypanosoma brucei variant surface glycoprotein and molecular modeling of a glycosylated surface coat.

The plasma membrane of the African sleeping sickness parasite Trypanosoma brucei is covered with a dense, protective surface coat. This surface coat is a monolayer of five million variant surface glycoprotein (VSG) dimers that form a macromolecular diffusion barrier. The surface coat protects the parasite from the innate immune system and, through antigenic variation, the specific host immune response. There are several hundred VSG genes per parasite, and they encode glycoproteins that vary in primary amino acid sequence, the number of N-glycosylation sites, and the types of N-linked oligosaccharides and glycosylphosphatidylinositol membrane anchors they contain. In this study, we show that VSG MITat.1.5 is glycosylated at all three potential N-glycosylation sites, and we assign the oligosaccharides present at each site. Using the most abundant oligosaccharides at each site, we construct a molecular model of the glycoprotein to assess the role of N-linked oligosaccharides in the architecture of the surface coat.

Amino Acid Sequence↗
PubMed1997

Different tools to study interaction potentials in gamma-crystallin solutions: relevance to crystal growth.

Osmotic pressure, small-angle X-ray scattering and quasi-elastic light scattering were used to study the medium-range interaction potentials between macromolecules in solution. These potentials determine macromolecular crystallization. Calf eye lens gamma-crystallins were used as a model system with the charge, and therefore the interactions, varied with pH. The second virial coefficient was determined under the same conditions with each of the three techniques. Osmotic pressure and quasi-elastic light scattering can be used conveniently in the laboratory to rapidly test the type of interactions (either attractive or repulsive) present in the solution. The measurement is direct with osmotic pressure, whereas with quasi-elastic light scattering, the directly measured coefficient is a combination of thermodynamic and hydrodynamic terms. X-rays, which require more sophisticated equipment such as synchrotron radiation facilities, can provide more detailed information on the interparticle potentials when models are used. At low ionic strength, two potentials were found necessary to account for the temperature and pH phase diagram as a function of protein concentration. The first potential is the van der Waals attractive potential that was previously shown to account for the fluid-fluid phase separation at low temperature. The second potential is an electrostatic coulombic repulsive potential which is a function of the protein charge and thus of the pH. The interaction trail could be followed at protein concentrations as low as 10 mg ml(-1). The results as a whole are expected to be valid for all compact low molecular weight proteins at low ionic strength.

Journal Article↗