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PubMed1997

Mechanism of macromolecule concentration in collecting lymphatics in rat mesentery.

The mechanism by which macromolecular contents are concentrated during lymph transport was investigated in the collecting lymphatics of the mesentery of the rat. To examine changes in the concentration of lymph macromolecular tracer (fluorescein isothiocyanate-tagged dextran, MW 148,900) in the rhythmically contractile lymphatics, we quantified the fluorescence intensity of the lymph tracer using an intravital microscopy system with single slit-laser (20 microns in thickness) epi-illumination, regardless of the vasomotion of the lymph vessel. The results for the fluorescence intensity measurement at different sites at distances of about 300-1000 microns along unbranched collecting lymphatics revealed that the concentration of the lymph macromolecular contents was significantly increased during their passage from upstream to downstream (P < 0.05). The fluorescence intensity of lymph tracer in the occluded segment of collecting lymphatics around 1000 microns in length was enhanced during the contraction phase and reduced during the relaxation phase. These results suggest that the filtration of macromolecule-free fluid from the lymph across the lymphatic wall during its contraction plays an important role in the lymph concentration mechanism in the collecting lymphatics, probably due to the Starling forces acting across the lymphatic wall.

Animals↗
PubMed2003

Recent trends in the use of polysaccharides for improved delivery of therapeutic agents: pharmacokinetic and pharmacodynamic perspectives.

New and innovative methods of delivery of therapeutic agents using polysaccharides have been recently developed, which target site of action, increase the intensity and/or prolong pharmacologic action, and/or reduce toxicity of small molecule drugs, proteins, or enzymes. This review is focused on the role of dextran, pullulan, and mannan polysaccharides in such applications. While dextran and pullulan are glucose polymers with different glucosidic linkages, mannan is composed of mannose units. In terms of pharmacokinetics of the carriers themselves, molecular weight (MW), electric charge, various chemical modifications, and degree of polydispersity and/or branching would mostly determine their fate in vivo. Generally, large MW polysaccharides (MWs > or = 40 kD) have low clearance and relatively long plasma half life, resulting in accumulation in reticuloendothelial or tumor tissues. The tumor accumulation in most cases is a passive targeting due to "enhanced permeation and retention" of macromolecules by tumors. Additionally, drugs such as anticancer agents may be actively targeted to specific cells by polysaccharides to which appropriate ligands are attached. In terms of mode of use, polysaccharides have been utilized in a variety of innovative ways for improvement of drug delivery. Their most important application has been as carriers for preparation of macromolecular prodrugs that are normally inactive and need to release the active drug at the site(s) of interest. Also, they have been used for preparation of macromolecule-protein conjugates, which may retain the activity of the proteins, in order to increase the duration of effect and decrease the immunogenicity of proteins. Several other new applications, such as polysaccharide-anchored liposomal formulations, have also been gained attention recently and are briefly reviewed here. Finally, four recent examples of polysaccharide-based delivery systems involving specific drugs/imaging agents are reviewed in detail in terms of their development, pharmacokinetics, and pharmacodynamics. Collectively, these data suggest that macromolecular polysaccharides are promising agents for improving drug delivery.

Animals↗
PubMed2002

Understanding salt or PEG induced attractive interactions to crystallize biological macromolecules.

Phase diagrams of biological macromolecules are governed by an appropriate combination of interaction potentials in solution. Repulsive regimes favor solubility, whereas the presence of attractive potentials may induce a variety of phase transitions, including the desired macromolecular crystallization. The forces at work may be analyzed with a combination of small angle X-ray scattering and of numerical treatments. From the results obtained with a variety of model systems, the respective advantages and drawbacks of using monovalent salts or PEGs as crystallizing agents are discussed.

Crystallization↗
PubMed1988

The DNA intermediate in yeast Ty1 element transposition copurifies with virus-like particles: cell-free Ty1 transposition.

Yeast Ty1 elements are retrotransposons that transpose via an RNA intermediate found in a virus-like particle (Ty-VLP). A Ty-encoded reverse transcriptase activity found inside the particles is capable of giving rise to full-length reverse transcripts. The predominant form of these reverse transcripts is a full-length linear duplex DNA. We have developed a cell-free system for transposition of Ty1 DNA molecules into a bacteriophage lambda target. Purified Ty-VLPs and target DNA are the only macromolecular components required for the transposition reaction. A TYB-encoded protein, p90-TYB, contains amino acid sequences that are similar to those of retroviral integrase proteins. Mutations in the integrase coding region abolish transposition both in vivo and in vitro.

Antibodies, Monoclonal↗
PubMed2004

Human septin-septin interactions as a prerequisite for targeting septin complexes in the cytosol.

Septins are a cytosolic GTP-binding protein family first characterized in yeast, but gaining increasing recognition as critical protagonists in higher eukaryotic cellular events. Mammalian septins have been associated with cytokinesis and exocytosis, along with contributing to the development of neurological disorders. Ten different septins, divided into four groups, have been identified in mammals, and individual septins are capable of interacting with each other to form macromolecular complexes. The present study characterizes the structural requirements for human septin-septin interactions using a yeast two-hybrid system. We focus on three septins that are highly expressed in platelets and neurons, SEPT4 [previously designated H5, CDCrel-2 (cell-division-control-related-2), PNUTL2], SEPT5 (CDCrel-1, PNUTL1) and SEPT8 (KIAA0202). Each of these three septins contains a characteristic domain structure consisting of unique N- and C-termini, and a central core domain conserved among the family of proteins. The yeast two-hybrid system yielded data consistent with a model where each of the three septins can interact with itself (homotypic assembly) or with one of the other septins (heterotypic assembly). For SEPT5 and SEPT8, the results illustrate a model whereby heterotypic septin assembly is dependent on the conserved central core domain and homotypic interactions require the N- and C-termini of each protein. We also characterized a model in which the proper cellular localization of SEPT5 and SEPT8 requires concomitant expression of both proteins. Co-transfection of SEPT5 and SEPT8 results in both proteins targeted to a vesicular-like location. Therefore the cellular repertoire of human septins has an impact on function by targeting septin macromolecular complexes to specific cellular locations.

Amino Acid Sequence↗
PubMedDate not supplied

The esterolytic activity of poly(1-methyl-4- and -5-vinylimidazole) in water.

The water solubility of poly(1-Me-5-VIm) has made it possible to achieve phenomenal rate enhancements and to gain even greater insight into the mechanism of catalysis by polymeric imidazoles. The poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- exhibited saturation in excess catalyst nad in excess substrate. Inhibition of the poly(1-Me-5-Vim) catalyzed hydrolysis of Sn- type substrates by analog inhibitors was also observed. The saturation apparently did not follow a simple Michaelis-Menten mechanism; however, the results could be rationalized by analogy to certain enzymatic systems. Multisite enzymes have long been known to display kinetic patterns different from that exhibited by enzymes with only one active site, i.e. such phenomena as sigmoidal rate vs [S] plots. These phenomena may arise entirely as a result of the multisite nature of the enzyme. Consequently, a synthetic macromolecular catalyst with multiple sites might also be expected to display such characteristics. The poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- is apparently the first synthetic system in which such phenomena have been observed. The intermediacy of an apolar polymer substrate complex for the poly(1-Me-5-VIm)-catalyzed hydrolysis of S12- in water was given support by studies of the effect of temperature on the rate of hydrolysis. Activation parameters were determined for catalysis by 1,5-DMIm and by poly(1-Me-5-VIm). These results showed that the rate enhancement exhibited by the polymer was due entirely to a favorable entropy term.

Chemical Phenomena↗
PubMed2005

Preparation and in vitro evaluation of thiolated chitosan microparticles.

The objective of this study was to prepare a microparticulate drug delivery system being based on a new thiomer, namely a chitosan 2-iminothiolane conjugate (chitosan-TBA conjugate). Due to thiol groups being immobilized on chitosan, chitosan-TBA conjugate exhibits improved mucoadhesive and permeation enhancing properties. Because of these features microparticulate drug delivery systems based on chitosan-TBA conjugate might be a promising tool for the non-invasive administration of hydrophilic macromolecular drugs. Chitosan-TBA conjugate microspheres were prepared by the emulsification/solvent evaporation method. Fluorescein-isothiocyanate labelled dextran (FITC-dextran) was chosen as a model hydrophilic drug. Microspheres have been characterized by morphological analysis, thiol group content, swelling behaviour, polymer degradation drug load determination, dissolution test and mucoadhesion studies. Results reported in this work demonstrated the possibility to obtain stable microspheres without cross-linking agents. Thiolated chitosan microspheres seem to be more stable in aqueous media with respect to unmodified chitosan. The degradability by lysozyme appears quite similar for both polymers, showing that chemical modification does not influence the biodegradable properties of chitosan. Microspheres were able to control the drug release for at least 1 h, exhibiting comparatively strong mucoadhesive properties. The chitosan-TBA conjugate microparticles remain on the mucosa in a 2.5-fold higher concentration with respect to unmodified chitosan microparticles. These data suggest that chitosan-TBA conjugate microspheres have the potential to be used as a mucoadhesive drug delivery system.

Adhesiveness↗
PubMed2000

Quantitative characterization of reversible macromolecular associations via sedimentation equilibrium: an introduction.

The measurement and analysis of sedimentation equilibrium provides one of the most powerful and widely applicable methods for the characterization of reversible associations of macromolecules in solution. Recent developments in instrumentation, experimental design, and data analysis have substantially broadened the range of systems to which this technique may be applied, simplified its application, and reduced the cost of acquiring analytical capability.

Animals↗
PubMed1984

Drug absorption from the gastrointestinal tract and immunity: the mechanism of the decreased absorption of salicylic acid during systemic anaphylaxis. I.

Previous studies have demonstrated the decrease of intestinal salicylic acid absorption in ovalbumin-immunized rats during systemic anaphylaxis. In the present study, the mechanism whereby systemic anaphylaxis interferes with the intestinal absorption of salicylic acid was studied. The pH of the luminal solution was not affected by the intravenous challenge with ovalbumin. A significant increase of the intraluminal protein was observed in rats under systemic anaphylaxis. However, there was no significant difference between ovalbumin-treated rats and saline-treated ones on the binding of salicylic acid with intraluminal macromolecular substances. Enhanced mucus release in the perfusate was also observed in sensitized rats but the extent of decrease in absorption of salicylic acid did not correlate with the increase in amount of the intraluminal mucus in the same animals. In addition, no significant effect was observed on the uptake by the intestinal everted sac of rats with systemic anaphylaxis. These findings suggested that mucus as well as protein is not responsible for the decrease of absorption of salicylic acid induced by systemic anaphylaxis. From these observations, it would appear that the circulatory changes in the gastrointestinal tract may play an important role in the decreased absorption of salicylic acid during systemic anaphylaxis.

Anaphylaxis↗
PubMed2004

Ground-based diffusion experiments on liquid Sn-In systems using the shear cell technique of the satellite mission Foton-M1.

This study reported in this paper was aimed at testing the shear cell that was developed for the satellite mission Foton-M1 to measure diffusion coefficients in liquid metals under microgravity (microg)-conditions. Thick Layer diffusion experiments were performed in the system Sn90In10 versus Sn under 1 g-conditions. For this system several microg-diffusion results are available as reference data. This combination provides a low, but sufficiently stable, density layering throughout the entire experiment, which is important to avoid buoyancy-driven convection. The experimental results were corrected for the influences of the shear-induced convection and mixing after the final shearing, both of which are typical for the shear cell technique. As the result, the reproducibility and the reliability of the diffusion coefficients in the ground-based experiments were within the limits of error of microg-data. Based on our results we discuss the necessary conditions to avoid buoyancy-driven convection.

Capillaries↗
PubMed1984

Lymphokine/monokine inhibition of fibroblast proliferation and collagen production: role in progressive systemic sclerosis (PSS).

A normal fibrotic response to inflammatory stimuli appears to be dependent on the balanced production of a number of stimulatory and inhibitory fibroblast-regulatory mediators by activated mononuclear cells (MNL). To investigate whether altered mediator production contributes to the fibrosis observed in progressive systemic sclerosis (PSS), we stimulated human peripheral blood MNL with concanavalin A (Con A) and lipopolysaccharide (LPS) to produce macromolecular mediators that inhibit the proliferation and the collagen production of cultured normal human fibroblasts. The two Con A-induced mediators were lymphokines (LK) as they were exclusively produced by activated T cells and they coeluted from a Sephacryl S-200 column with a Mr of 50,000. In contrast, the two LPS-induced mediators were monokines (MK) as they were exclusively produced by activated monocytes, and they coeluted in the Mr 20,000 range. Each pair of inhibitory LK and MK may also be distinct as inhibition of collagen production still occurred in proliferatively quiescent cultures. A quantitative comparison of the levels of fibroblast-inhibitory LK/MK produced by normal volunteers and long-term PSS patients revealed that although PSS MNL produced normal levels of both collagen production inhibitory mediators, they were aberrant producers of both proliferation inhibitory mediators, being hypo-producers (-49%) of the LK and hyper-producers (+196%) of the MK. These results suggest that reduced production of proliferation inhibitory LK may allow stimulatory mediators to induce the unrestricted fibroblast proliferation observed in early active PSS, which then may be stabilized in long-term PSS by the increased production of proliferation inhibitory MK.

Adult↗
PubMed2003

A reversible hydrogel membrane for controlling the delivery of macromolecules.

Glucose-sensitive hydrogel membranes have been synthesized and characterized for their rate-of-delivery of macromolecules. The mechanism for changing this rate is based on variable displacement of the affinity interaction between dextran and concanavalin A (con A). Our main objective was to characterize the diffusion of model proteins (insulin, lysozyme, and BSA) through the membrane, in response to changes in environmental glucose concentrations. Membranes were constructed from crosslinked dextrans to which con A was coupled via a spacer arm. Changes in the porosity of the resulting hydrogel in the presence of glucose led to changes in the diffusion rate observed for a range of proteins. Gels of specified thickness were cast around to nylon gauze support (pore size, 0.1 mm) to improve mechanical strength. Diffusion of proteins through the gel membrane was determined using a twin-chamber diffusion cell with the concentrations being continuously monitored using a UV-spectrophotometer. Changes in the transport properties of the membranes in response to glucose were explored and it was found that, while 0.1M D-glucose caused a substantial, but saturateable, increase in the rates of diffusion of both insulin and lysozyme, controls using glycerol or L-glucose (0.1M) had no significant effect. Sequential addition and removal of external glucose in a stepwise manner showed that permeability changes were reversible. As expected, diffusion rates were inversely proportional to membrane thickness. A maximum increase in permeability was observed at pH 7.4 and at 37 degrees C. The results demonstrate that this hydrogel membrane functions as a smart material allowing control of solute delivery in response to specific changes in its external environment.

Anti-Bacterial Agents↗
PubMed1992

The methionine-rich domain of the 54 kDa subunit of signal recognition particle is sufficient for the interaction with signal sequences.

The signal recognition particle (SRP) binds to signal sequences when they emerge from a translating ribosome and targets the complex of ribosome, nascent chain and SRP to the membrane of the rough endoplasmic reticulum (rER) allowing the co-translational translocation of the nascent chain. By photo-crosslinking it has been shown that the signal sequence of preprolactin (PPL) only interacts with the methionine-rich (M) domain of the 54 kDa protein subunit (SRP54) of SRP. Here we show that (i) a signal-anchor sequence is likewise crosslinked only to the methionine-rich domain of SRP54, (ii) free SRP54 can interact with signal sequences independently of the other components of SRP, (iii) its M domain suffices to perform this function, and (iv) an essentially intact M domain is required for signal sequence recognition. Alkylation of the N+G domain in intact SRP54 with N-ethyl maleimide (NEM), but not after cleavage with V8 protease, prevents the binding of a signal sequence to the M domain. This suggests a proximity between the N+G and M domains of SRP54 and raises the possibility that the role of the N+G domain may be to regulate the binding and/or the release of signal sequences.

Animals↗
PubMed2002

Exploitation of intracellular pH gradients in the cellular delivery of macromolecules.

Most cellular components such as the cytoplasm, endosomes, lysosomes, endoplasmic reticulum, Golgi bodies, mitochondria, and nuclei are known to maintain their own characteristic pH values. These pH values range from as low as 4.5 in the lysosome to about 8.0 in the mitochondria. Given these proton gradients around a neutral pH, weak acids, and bases with a pKa between 5.0 and 8.0 can exhibit dramatic changes in physicochemical properties. These compounds can be conjugated as such to macromolecules or incorporated into polymeric or liposomal formulations to promote the efficient cellular delivery of macromolecules. Mechanistically, the carrier molecules can facilitate favorable membrane partition, membrane fusion, transient pore formation, or membrane disruption. Drug carriers equipped with such pH-sensitive triggers and switches are able to significantly enhance the cellular delivery of macromolecules in vitro. However, the successful application of these molecules for efficient delivery in vivo requires the design of noncytotoxic, nonimmunogenic, serum compatible and biochemically labile carriers, systematic analysis of their mechanisms of action, and extensive animal studies.

Animals↗
PubMed2003

GAPDOCK: a Genetic Algorithm Approach to Protein Docking in CAPRI round 1.

As part of the first Critical Assessment of PRotein Interactions, round 1, we predict the structure of two protein-protein complexes, by using a genetic algorithm, GAPDOCK, in combination with surface complementarity, buried surface area, biochemical information, and human intervention. Among the five models submitted for target 1, HPr phosphocarrier protein (B. subtilis) and the hexameric HPr kinase (L. lactis), the best correctly predicts 17 of 52 interprotein contacts, whereas for target 2, bovine rotavirus VP6 protein-monoclonal antibody, the best model predicts 27 of 52 correct contacts. Given the difficult nature of the targets, these predictions are very encouraging and compare well with those obtained by other methods. Nevertheless, it is clear that there is a need for improved methods for distinguishing between "correct" and "plausible but incorrect" complexes.

Algorithms↗
PubMed2003

ZDOCK predictions for the CAPRI challenge.

The CAPRI Challenge is a blind test of protein-protein-docking algorithms that predict the complex structure from the crystal structures of the interacting proteins. We participated in both rounds of this blind test and submitted predictions for all seven targets, relying mainly on our Fast Fourier Transform based algorithm ZDOCK that combines shape complementarity, desolvation, and electrostatics. Our group made good predictions for three targets and had at least some success with three others. Implications of the treatment of prior biological information as well as contributions of manual inspection to docking predictions are also discussed.

Algorithms↗

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