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At least 919 records · Page 51Linked to original sources
PubMed1997

Lymph vessel expansion and function in the development of hepatic fibrosis and cirrhosis.

The process of lymph vessel expansion and function in the development of CCl4-induced hepatic fibrosis and cirrhosis was studied using intravital fluorescence microscopy of the rat liver. The unique aspect of our approach was the use of high molecular fluorescein-isothiocyanate-labeled dextran (MW, 150,000) as fluorescent marker, which allowed for simultaneous assessment of both 1) the macromolecular blood hepatocytic exchange from the sinusoidal microvasculature (extra-/intrasinusoidal gray level intensity at 1, 3, 5, and 10 minutes after intravenous injection) and 2) the hepatic lymph system. In animals exposed with CCl4 up to 4 weeks, macromolecular trans-sinusoidal exchange was found progressively delayed. This was strongly associated with lymph vessel expansion and function, as indicated by a continuous increase of lymph vessel density and area. Delay of macromolecular exchange and lymph vessel expansion was found not further enhanced at fibrotic and cirrhotic stages of 8- and 12-week CCl4-exposed livers. Linear regression analysis revealed a strong negative correlation between lymphatic network density development and macromolecular trans-sinusoidal exchange (r2 = 0.99; P < 0.01). Thus, our study provides for the first time direct evidence for the pivotal role of lymphatic function for macromolecular transport in case of deteriorated sinusoidal hepatocellular exchange capacity.

Animals↗
PubMed1996

Symmetry, stability, and dynamics of multidomain and multicomponent protein systems.

Symmetry is commonly observed in many biological systems. Here we discuss representative examples of the role of symmetry in structural molecular biology. Point group symmetries are observed in many protein oligomers whose three-dimensional atomic structures have been elucidated by x-ray crystallography. Approximate symmetry also occurs in multidomain proteins. Symmetry often confers stability on the molecular system and results in economical usage of basic components to build the macromolecular structure. Symmetry is also associated with cooperativity. Mild perturbation from perfect symmetry may be essential in some systems for dynamic functions.

Protein Conformation↗
PubMed1999

Yeast cells as tools for target-oriented screening.

Information about biomolecular interaction networks is crucial for understanding cellular functions and the development of disease processes. Many diseases are known to be based on aberrations of DNA sequences encoding proteins with key functions in the cellular metabolism. Alterations in the respective proteins often lead to disturbances in biomolecular interactions caused by unbalanced stoichiometries, and thus result in alterations of molecule fluxes, cell architecture and signalling pathways. Drug discovery programmes have been designed to find promising chemical lead structures with the help of target-oriented bioassay systems. These are, in most cases, based upon the interaction of small molecules to specific macromolecular targets in vivo or in vitro, as exemplified by enzyme assays or small-ligand-based receptor systems. In addition, interactions between large biomolecules, such as proteins or nucleic acids, offer a huge arsenal of potential drug targets that can be addressed by small chemical compounds. This latter approach is gaining considerable attention because many potential target structures are becoming available through genomic research. Funnelling these new targets into high-throughput screening programs represents a major challenge for today's pharmaceutical research. An important outcome of the ongoing genome projects is the fact that the basic cellular structures, pathways and signalling principles show a high degree of conservation. Model organisms that are easily approachable by genetic, biochemical and physiological means can thus play an important role in the design of target-oriented screening systems. They offer the possibility to express individual proteins, nucleic acids or even more complex aggregates of biomolecules such as protein-interaction networks or transcription-initiation complexes, which can be addressed by small effector molecules in vivo. Combining these targets with biological signalling systems is an attractive way of creating robust cellular assay systems.

Animals↗
PubMed1984

Thermodynamic nonideality as a probe of macromolecular isomerizations: application to the acid expansion of bovine serum albumin.

The potential use of thermodynamic nonideality as an index of the coexistence of two isomeric protein states in equilibrium is explored in relation to the effect of inert space-filling macromolecular solutes on the gel chromatographic behavior of the system. Frontal gel chromatography, on Sephadex G-100, of bovine serum albumin at pH 3.2 in the presence and absence of a moderately high (15 g/liter) concentration of either Dextran T70 or Dextran T10 is then employed to establish that the progressive increase in the Stokes radius of albumin as the pH is lowered from 5 to 2 should not be viewed as a pH-dependent isomerization equilibrium between native and acid-expanded states. In addition, calculations based on parameters for the aspartate transcarbamoylase system point to the possible use of the present methodology to distinguish between preexistence and ligand induction of an isomerization equilibrium as the source of a sigmoidal effect in allosteric systems.

Allosteric Regulation↗
PubMed2001

Conjugative plasmid protein TrwB, an integral membrane type IV secretion system coupling protein. Detailed structural features and mapping of the active site cleft.

Bacterial conjugation is an example of macromolecular trafficking between cells and responsible for the spreading of antibiotic resistance among bacteria. It involves translocation of single-stranded DNA across membranes through a type IV secretion system. A coupling protein links the DNA-processing nucleoprotein complex, the relaxosome, with the transport apparatus during cell mating. In Escherichia coli plasmid R388 such a protein is TrwB, a basic integral inner-membrane nucleoside-triphosphate-binding protein. TrwB is the structural prototype for the type IV secretion system coupling proteins, a family of proteins essential for macromolecular transport between cells and export. The structure of a soluble TrwB variant unveils an elongated molecule with six equivalent protein units featuring a spherical quaternary structure, leaving a central channel. The structures of the non-liganded protein and four different complexes with substrate analogues and products allow the precise description of the active site architecture. The active sites are located at the interface between protomers, each of them shaped mainly by residues of one monomer, but including two crucial arginine residues belonging to the adjacent molecule. Upon substrate binding and putative hydrolysis, conformational changes are transferred from the external surface to the interior central channel.

Anions↗
PubMed2001

Design and implementation of a collaborative molecular graphics environment.

During the determination of macromolecular structures, scientists routinely use complex graphics software to display various representations of the molecule of interest. Once the structure determination is complete, coordinates are deposited in the Protein Data Bank (PDB), from where anyone with an Internet connection may download and view them or request them on CD-ROM. However, the currently available visualization software is such that causal users, whose expertise may not be in structure determination, often cannot obtain useful images of interesting molecules without expending considerable time and effort. Existing visualization software is generally very complex, requiring a high degree of familiarity to obtain the best results, or else it is too simplistic to provide users with the level of customizability needed to get the most out of the atomic coordinates. Few of the existing software packages have the capability for collaborative visualization via the Internet. These and other issuses are being addressed by the Molecular Interactive Collaborative Environment (MICE) project (http://mice.sdsc.edu/). The core of the MICE project is the MICE application, an interactive molecular structure viewer with built-in collaborative capabilities. MICE not only addresses the issues of usability and flexibility but also extends the role of traditional visualization tools by allowing multiple users to view, manipulate, and interact with a single representation of a macromolecular structure. MICE is written entirely in Java, using the Java3D extensions for rendering and manipulation of the three-dimensional scene, and the Common Object Request Broker Architecture (CORBA) communications suite to enable collaborative manipulation of that scene.

Animals↗
PubMed1996

[The effect of a protein concentrate from milk whey and its fractions on the macromolecular permeability of the intestinal barrier in rats with experimental food anaphylaxis].

Rats received dietary supplement of milk whey concentrate (KSP) being manufactured from skimmed milk by addition of apple pectin (Pec), KSP ultrafiltrated fractions and pure Pec during 21 day. A part of animals were sensitized i/p with chicken ovalbumin and finally subjected to systemic anaphylaxis (SA) by i/v antigen challenge. Gastrointestinal barrier macromolecular permeability (MP) for polyethylene glycol 4000 (PEG-4000) was measured by its urinary excretion after an intragastric load. MP increased significantly in nonsensitized rats after feeding with KSP and its high molecular (HM) fraction but not after feeding with low molecular (LM) KSP fraction compared to NaCl fed group. Feeding with Pec dramatically (5-fold) increased permeability. On the contrary the permeability decreased in sensitized rats subjected to SA when fed with KSP, its LM and particularly HM fraction the later group permeability being normalized down to normal value found in nonsensitized animals. It's concluded that KSP whey protein may be recommended for incorporation into specialized foods for patients with impaired gastrointestinal function.

Anaphylaxis↗
PubMed2005

Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.

Low molecular weight heparin (LMWH) is an agent of choice in the anti-coagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, the therapeutic use is partially limited due to a poor oral bioavailability. It was therefore the aim of this study to design and evaluate a highly efficient stomach-targeted oral delivery system for LMWH. In order to appraise the influence of the molecular weight on the oral bioavailability, mini-tablets comprising 3 kDa (279 IU) and 6 kDa (300 IU) LMWH, respectively, were generated and tested in vivo in rats. The potential of the test formulations based on thiolated polycarbophil, was evaluated in comparison to hydroxyethylcellulose (HEC) as control carrier matrix. The plasma levels of LMWH after oral versus subcutaneous administration were determined in order to calculate the relative bioavailability. With the delivery system containing 3 kDa LMWH (279 IU) a relative bioavailability of 19.1% was achieved, offering a significantly (p < 0.05) better bioavailability than the control system displaying a relative bioavailability of 8.1% The 6 kDa LMWH (300 IU) formulation displayed a relative bioavailability of 10.7% in contrast to the control displaying a relative bioavailability of 2.1%. In conclusion, these results suggest that mucoadhesive thiolated polymers are a promising tool for the non-invasive stomach-targeted systemic delivery of LMWH as model for a hydrophilic macromolecular polysaccharide.

Acrylic Resins↗
PubMed1991

Carcinogen-macromolecular adducts as biomarkers in human cancer risk assessment.

Substantial data have been generated during the past 5 years in both experimental systems and human populations which shed light on the potential role of carcinogen-macromolecular adducts in human cancer risk assessment. The use of DNA and protein adducts is based on the fundamental concept in chemical carcinogenesis that most genotoxins are metabolized to electrophilic "ultimate" carcinogens that are capable of forming covalent adducts with cellular macromolecules. This report examines the relative usefulness and limitations of using DNA and protein adducts and related techniques for assessing human exposure to genotoxic carcinogens. Data discussed in this report clearly demonstrate that these biomarkers not only allow early detection of potential cancer hazard in humans, but they can also significantly increase the power of conventional cancer epidemiological studies in determining true causal relationships. In addition, such biomarkers can improve extrapolation of cancer risks from laboratory animals to humans or from one human population to another.

Biomarkers↗
PubMed1990

The inflammatory actions of platelet activating factor are blocked by levorotatory terbutaline.

Platelet activating factor (PAF), a potent vasoactive lipid, may play an important role in the inflammatory process. In this study, we infused PAF intra-arterially to characterize its edematogenic potency in the canine forelimb. We have also assessed the ability of the beta 2-receptor agonist l-terbutaline to block PAF-mediated edema formation. The infusion of PAF at .25 micrograms/min, .5 micrograms/min and 1 micrograms/min increased forelimb arterial pressures and, at the two higher dosages, significantly decreased systemic arterial pressure. PAF infusions increased transvascular fluid and macromolecular flux as indicated by significant increases in skin lymph flow, protein concentration and protein transport. The intra-arterial infusion of l-terbutaline at 1 micrograms/min significantly decreased forelimb arterial pressures but did not affect small vein pressure, systemic pressure or forelimb lymph parameters. The subsequent infusion of PAF at .5 micrograms/min, during the continued infusion of l-terbutaline, failed to significantly affect forelimb lymph parameters. These data indicate that PAF is significantly more potent as an edematogenic agent in the forelimb than histamine or bradykinin. Furthermore, the blockade of PAF-mediated edema formation by l-terbutaline suggests that beta 2-receptor agonists may be capable of antagonizing the inflammatory actions of a wide variety of putative inflammatory mediators.

Animals↗
PubMed1992

[The permeability of the barrier of the gastrointestinal tract for the macromolecules of polyethylene glycol-4000: an assessment of the mechanism and its reproducibility].

Polyethylene glycol (PEG)-4000 is proposed as a tracer of intestinal macromolecular permeability. The reproducibility of permeability testing with PEG-4000 and the mechanism of its penetration through intestinal mucosa were studied in adult rats. Permeability measurement for PEG-4000 was reproducible when repeated twice for 2 days. This makes it possible to repeat PEG-4000 permeability testing before and after any experimental impact on the intestine. I.p. administration of colchicine to rats (125 micrograms/100 g b. w.) significantly inhibited intestinal absorption of PEG-4000 fed to the animals 3 hours later. Hence, PEG-4000 penetration through the intestinal mucosa is mediated by the system of enterocyte cytoplasmic microtubules. Mucosal permeability for PEG-4000 may be consequently considered as a valuable model of permeability for protein macromolecules.

Animals↗
PubMed2004

Nanotechnology and biomimetic methods in therapeutics: molecular scale control with some help from nature.

Nanoscale science and engineering has provided new avenues for engineering materials with macromolecular and even molecular precision. In particular, researchers are beginning to mimic biological systems, achieving molecular scale control via self-assembly and directed assembly techniques. Fabrication and manipulation with macromolecular and molecular precision have led and will lead to the development of novel materials, and these materials will facilitate the fabrication of micro- and nanoscale devices, such as self-regulated micro- and nanoscale drug delivery devices that combine diagnostic and therapeutic actions for instantaneous administration of therapy. As the field of nanoscale science and engineering matures, technologies that will revolutionize the way health care is administered will continue to be developed.

Biomimetic Materials↗
PubMed2001

Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging.

Three novel Mn(II) complexes bearing benzyloxymethyl functionalities are reported and their ability to enhance water (1H and 17O) relaxation times is investigated in detail. Two of them contain one coordinated water molecule and display relaxivity values only slightly smaller than those shown by the most clinically used contrast agents (e.g. [Gd(DTPA)(H2O)]2-). Moreover, in these Mn(II) chelates the exchange rate of the coordinated water is ca. one order of magnitude higher if compared to the exchange rates previously reported for Gd(III) complexes with octadentate ligands. The occurrence of such fast exchange rates of the coordinated water is exploited in the formation of macromolecular adducts with human serum albumin to attain systems displaying relaxivity values in the upper range of those so far reported for analogous Gd(III) systems. These results strongly support the view that Mn(II) complexes, in spite of the lower effective magnetic moment, can be considered as viable alternatives to the currently used Gd(III) complexes as contrast agents for MRI applications.

Chelating Agents↗
PubMed1984

Development of a mouse embryo limb bud cell culture system for the estimation of chemical teratogenic potential.

High-density cultures of mouse embryo limb bud cells differentiate and synthesize an extracellular matrix containing sulfated proteoglycans. Since these in vitro events are related to those that occur during fetal development, we have investigated the use of cultured limb bud cells for the analysis of the activities of chemical teratogens. We have established the conditions for the use of the radiochemicals 35SO=4 and 3H-thymidine for the assessment of chemical effects on sulfated proteoglycan and DNA synthesis, respectively, in mouse limb bud cells. By performing double-labeling experiments in the presence of test chemicals, the preferential inhibition of either proteoglycan synthesis or DNA synthesis could be demonstrated for 19 of 22 known mouse teratogens tested. The five nonteratogens tested did not cause significant differences in the inhibition of either macromolecular class. The overall predictive accuracy of the system was approximately 89%, and the false-negative rate was approximately 14.8%. No false positives were observed. These data showed that this cell culture system differentiated between the activities of a limited set of selected mouse teratogens and nonteratogens, suggesting that cultured mouse embryo limb bud cells may constitute the basis for the development of a powerful tool for analyses of chemical teratogenic potential.

Animals↗