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At least 937 records · Page 52Linked to original sources
PubMed1993

Uptake and transport of macromolecules by the intestine: possible role in clinical disorders (an update).

The intestine is exposed to a wide variety of macromolecules. Because macromolecules are antigenic, mechanisms have evolved in the gastrointestinal tract to regulate their absorption. Macromolecular uptake can be beneficial in delivering essential factors for growth and in sampling the antigenic milieu of the gastrointestinal tract. Specific transport mechanisms exist to execute this physiological absorption. However, inappropriate and uncontrolled antigen transport may occur in disease states or as a prelude to disease states in the gastrointestinal tract. Such transport may result in immune responses that are harmful. This review examines physiological transport of macromolecules through epithelia and through M cells. It also considers uncontrolled transport and its relation to disease states. The review concludes with an examination of the interrelationship between antigen transport and an altered immune system in the establishment of gastrointestinal disease.

Animals↗
PubMed2005

Towards building the silicon cell: a modular approach.

Systems Biology aims to understand quantitatively how properties of biological systems can be understood as functions of the characteristics of, and interactions between their macromolecular components. Whereas, traditional biochemistry focused on isolation and characterization of cellular components, the challenge for Systems Biology lies in integration of this knowledge and the knowledge about molecular interactions. Computer models play an important role in this integration. We here discuss an approach with which we aim to link kinetic models on small parts of metabolism together, so as to form detailed kinetic models of larger chunks of metabolism, and ultimately of the entire living cell. Specifically, we will discuss techniques that can be used to model a sub-network in isolation of a larger network of which it is a part, while still maintaining the dynamics of the larger complete network. We will start by outlining the JWS online system, the silicon cell project, and the type of models we propose. JWS online is a model repository, which can be used for the storage, simulation and analysis of kinetic models. We advocate to integrate a top-down approach, where measurements on the complete system are used to derive fluxes in a detailed structural model, with a bottom-up approach, consisting of the integration of molecular mechanism-based detailed kinetic models into the structural model.

Animals↗
PubMed1992

Thermodynamic model of cooperativity in a dimeric protein: unique and independent parameters formulation.

A model of the cooperative interaction of ligand binding to a dimeric protein is presented based upon the unique and independent parameters (UIP) thermodynamic formulation (Gutheil and McKenna, Biophys. Chem. 45 (1992) 171-179). The analysis is developed from an initial model which includes coupled conformational and ligand binding equilibria. This completely general model is then restricted to focus on conformationally mediated cooperative interactions between the ligands and the expressions for the apparent ligand binding constant and the apparent ligand-ligand interaction constant are derived. The conditions under which there is no cooperative interaction between the ligands are found as roots to a polynomial equation. Consideration of the distribution of species among the various conformational states in this general model leads to a set of inequalities which can be represented as a two dimensional plot of boundaries. By superimposing a contour plot of the value of the apparent ligand-ligand interaction constant over the plot of boundaries a complete graphical representation of this system is achieved similar to a phase diagram. It is found that the parameter space homologous to Koshland-Nemethy-Filmer type of model is most consistent with both positive and negative cooperativity in this model. The maximal amount of positive and negative cooperativity are found to be simple functions of Kc, the equilibrium constant associated with the change of a subunit and ligand from the unligated to ligated conformation. It is shown that under certain limiting conditions the apparent allosteric interaction between ligands is equal to the conformational interaction between subunits. The methods presented are generally applicable to the theoretical analysis of thermodynamic interactions in complex systems.

Kinetics↗
PubMedDate not supplied

[Nonequilibrium distribution as a feature of biological systems].

It is suggested that the amount of energy extracted by a dissipative biological system from macroergic compounds depends on the energetic state of the system. The non-linear character of this relationship with the maximum in intermediate phases and presence of the upper limit of energetic states in the system with an energy increase cause a decrease of population of intermediate levels and an increase of the upper and lower levels. The antientropic distribution is presented as a principal thermodynamic peculiarity of biological systems.

Macromolecular Substances↗
PubMed1993

Molecular analysis of Drosophila glutamate receptors.

Insects and other invertebrates use L-glutamate as a neurotransmitter in the central nervous system and at the neuromuscular junction. In contrast to the well-studied effects of L-glutamate on invertebrate muscle cells, relatively little is known about the physiological role of glutamate receptors (GluRs) in the invertebrate central nervous system. We have applied a molecular cloning approach to elucidate the molecular structure of neuronal and muscle-specific Drosophila glutamate receptor subunits (DGluRs). Several domains conserved between rat GluR subunits and DGluRs indicate regions of high functional significance. Drosophila genetics may now be used as a valuable experimental tool to gain further insight into the role of DGluRs in development, synaptic plasticity and control of gene expression.

Animals↗
PubMed2000

A thermodynamic molecular switch in biological systems: ribonuclease S' fragment complementation reactions.

It is well known that essentially all biological systems function over a very narrow temperature range. Most typical macromolecular interactions show DeltaH degrees (T) positive (unfavorable) and a positive DeltaS degrees (T) (favorable) at low temperature, because of a positive (DeltaCp degrees /T). Because DeltaG degrees (T) for biological systems shows a complicated behavior, wherein DeltaG degrees (T) changes from positive to negative, then reaches a negative value of maximum magnitude (favorable), and finally becomes positive as temperature increases, it is clear that a deeper-lying thermodynamic explanation is required. This communication demonstrates that the critical factor is a temperature-dependent DeltaCp degrees (T) (heat capacity change) of reaction that is positive at low temperature but switches to a negative value at a temperature well below the ambient range. Thus the thermodynamic molecular switch determines the behavior patterns of the Gibbs free energy change and hence a change in the equilibrium constant, K(eq), and/or spontaneity. The subsequent, mathematically predictable changes in DeltaH degrees (T), DeltaS degrees (T), DeltaW degrees (T), and DeltaG degrees (T) give rise to the classically observed behavior patterns in biological reactivity, as may be seen in ribonuclease S' fragment complementation reactions.

Amino Acid Substitution↗
PubMed1995

Anaphylactic reaction to local administration of rifamycin SV.

BACKGROUND AND OBJECTIVE: Systemic reactions during anesthesia are commonly attributed to muscle relaxants, hypnotics, macromolecular solutions, latex, or parenteral antibiotics. After exclusion of these different components as causes, we were interested in the potential implication of rifamycin in the systemic reaction, which occurred during anesthesia, and in the immunologic mechanism by which it can trigger this reaction. METHODS: We report four cases of systemic reactions occurring after local administration of rifamycin. Three patients needed orthopedic surgery, and the fourth needed a urethrotomy. Severe systemic reactions occurred in all four patients when the surgeon washed the incision area with a rifamycin solution. All patients correctly responded to appropriate treatment and recovered. Skin tests were performed 2 months after the incident with the drugs used during anesthesia, latex, and rifamycin. To assess the relationship with a possible IgE-mediated mechanism, two in vitro tests were concomitantly performed to evaluate the cell reactivity to rifamycin: (1) determination of histamine release from peripheral basophils and (2) platelet cytotoxicity test, which explored the presence on platelets of specific IgE antibodies bound to the low-affinity receptor for IgE. RESULTS: Skin tests were performed with different drugs used during surgery, and results were only positive for rifamycin in the four cases, accompanied in two cases by a systemic reaction. Histamine release from basophils was positive in three of four patients. The platelet cytotoxicity test results were positive in all four cases. CONCLUSION: It appears that rifamycin, used locally during surgery, is apt to trigger severe systemic anaphylactic reactions, which are linked to an IgE-related process. This situation is worth pointing out, especially in patients who undergo repeated orthopedic operations during which, at least in Europe, rifamycin is commonly used for the prevention of local sepsis.

Administration, Topical↗
PubMed2002

Drug delivery system of anti-fungal and parasitic agents.

The antifungal agents for systemic mycoses are only a few in number. Among them amphotericin-B is still the most widely used drug, but substantial side effects including nephrotoxicity limits its clinical usefulness. Efforts to lower the toxicity are synthesis of AMPH-B analogues such as AMPH-B esters and encapsulation in lipid vesicles in the forms of liposomal AMPH-B (AmBisome), amphotericin-B lipid complex (Abelcet), amphotericin-B colloidal dispersion (Amphocil) and intralipid AMPH-B. The newer formulations are effective against wide range of fungi, may be given in higher doses and nephrotoxicity is lowered. Although all of them showed comparable efficacies, a standard formulation is yet to be determined. In Japan, studies on efficacies of lipid nanosphere-encapsulated AMPH-B are in progress. Special drug career systems and dosage forms, such as nanoparticles and liposomes hold the promise of overcoming the pharmacokinetic limitations. Nanoparticles are stable, solid colloidal particles consisting of macromolecular material and vary in size. Nanoparticles represent an interesting carrier system for the specific enrichment in macrophage containing organs like liver and spleen. Injectable nanoparticle carriers have important potential applications as in site-specific drug delivery. Modifications of liposomes in order to avoid uptake by RES, thus increase targetability has been attempted. A novel targetable liposome 34A-PEG-L modified with polyethylene glycol conjugated with MoAb, 34A specific to murine pulmonary epithelia has been evaluated in murine pulmonary aspergillosis. 34A-PEG-L-AmB showed higher tissue concentration and comparable efficacy than other AMPH-B formulations.

Amphotericin B↗
PubMed1986

[Physiopathologic bases of the treatment of systemic scleroderma].

Numerous drugs have been suggested for the treatment of systemic scleroderma. They may be studied and classified according to their site of action on the chain of events that leads from vascular abnormalities to sclerosis of the skin. Thus, proline analogues, colchicine, lathyrogenic agents, D-penicillamine, coagulation factor XIII and oestrogens are thought to act on collagens and their metabolism. Ketanserin has been suggested by the discovery of tryptophan abnormalities. Corticosteroids exert an inhibitory effect on fibroblasts. The use of calcium antagonists, angiotensin-converting enzyme inhibitors, prostacyclin and anti-platelets rests on the presence of vascular abnormalities. The purpose of treatments with immunosuppressive drugs or plasma exchanges is to act on possible lymphocytic and/or macropageal factors.

Blood Platelets↗
PubMed2003

Intratumour heterogeneity in the uptake of macromolecular therapeutic agents in human melanoma xenografts.

Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human serum albumin ((99m)Tc-HSA) was studied in human melanoma xenografts in an attempt to identify transport barriers leading to inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumours. The Bioscope imaging system, which can detect the distribution of (99m)Tc in 10-microm-thick tissue sections with a spatial resolution of just above 50 microm, was used to image the (99m)Tc-HSA uptake. Xenografted tumours of four human melanoma cell lines were included in the study. Significant intratumour heterogeneity in the uptake of (99m)Tc-HSA was detected. The heterogeneity had two distinctly different components, one random and one radial component. The uptake was lowest in the centre of the tumours and increased towards the tumour periphery. This radial heterogeneity was superimposed by a random heterogeneity, that is, spots with high uptake colocalised with spots with high vascular density and regions without significant uptake colocalised with necrotic regions. The magnitude of the heterogeneity did not change significantly with time after the administration of (99m)Tc-HSA. The tumours showed a random and a radial heterogeneity in blood perfusion similar to that in the uptake of (99m)Tc-HSA. The observations reported here suggest that the intratumour heterogeneity in the distribution of (99m)Tc-HSA was initiated primarily because of heterogeneity in the supply of (99m)Tc-HSA through the microvasculature, and that the presence of severe transport barriers in the tumour interstitium prevented significant equalisation of the initial heterogeneity with time. Consequently, strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on increasing the tumour blood perfusion to increase the total uptake and improving the diffusion conditions in the tumour interstitium to diminish the heterogeneity in the uptake.

Animals↗
PubMed2003

ADP-ribosylation factor 6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth.

The mechanisms coordinating adhesion, actin organization, and membrane traffic during growth cone migration are poorly understood. Neuritogenesis and branching from retinal neurons are regulated by the Rac1B/Rac3 GTPase. We have identified a functional connection between ADP-ribosylation factor (Arf) 6 and p95-APP1 during the regulation of Rac1B-mediated neuritogenesis. P95-APP1 is an ADP-ribosylation factor GTPase-activating protein (ArfGAP) of the GIT family expressed in the developing nervous system. We show that Arf6 has a predominant role in neurite extension compared with Arf1 and Arf5. Cotransfection experiments indicate a specific and cooperative potentiation of neurite extension by Arf6 and the carboxy-terminal portion of p95-APP1. Localization studies in neurons expressing different p95-derived constructs show a codistribution of p95-APP1 with Arf6, but not Arf1. Moreover, p95-APP1-derived proteins with a mutated or deleted ArfGAP domain prevent Rac1B-induced neuritogenesis, leading to PIX-mediated accumulation at large Rab11-positive endocytic vesicles. Our data support a role of p95-APP1 as a specific regulator of Arf6 in the control of membrane trafficking during neuritogenesis.

ADP-Ribosylation Factor 6↗
PubMed1976

[Regulation processes in biological systems. I. General principles and enzymatic control mechanisms].

A property, characteristic of all living organisms, is the ability to adapt their metabolism to changes of environment. Such an adaptation, i.e. a regulation of metabolism, is made possible not only by nervous and hormonal mechanisms, but it is also caused by the cooperation of enzymes and enzyme systems localized in different cell areas and may called "enzymic regulations". Enzymes are functional units of complex chemical systems. Although present knowledge in this area is primitive, it is already apparent that the properties of regulatory enzymes are very precisely tailored to the needs of the cells in which they occur. The kinetic behaviour of an enzyme can be rationally interpreted only in terms of metabolic function and the structural features of an enzyme molecule are only the means by which this behaviour is attained. Each enzyme has evolved in the context of a metabolizing cell and the progress in understanding the kinetic and structural properties of enzymes will be aided by progress toward understanding the interactions in which that enzyme participates in the living cell. It is certain that we have only just begun to comprehend the ways in which the enzymes interact to produce a stable, yet flexible and responsive metabolic unit.

Adaptation, Physiological↗
PubMed2002

Physical properties of compounds promoting oral delivery of macromolecular drugs.

The spectroscopic and solution properties of a series of amidated acids (delivery agents), which promote the gastrointestinal absorption of USP heparin and other drugs that show poor oral bioavailability, are investigated using Raman and NMR spectroscopy. The results show evidence for self-association at low concentrations of delivery agents that increases as the concentration of the delivery agent is increased. The self-associate is characterized by ring-ring stacking interactions, and the best geometrical arrangement for the stacking is the parallel-shifted arrangement of the rings. In addition, the amide group participates in the formation of intermolecular hydrogen bonds in the self-associate. Unlike the rigid ring, the tails of these delivery agents remain relatively flexible in the self-associate. It is suggested that the limited solubility of the delivery agents at physiological pH arises from a percentage of protonated carboxyls. Their presence promotes the formation of intermolecular hydrophobic and ring stacking interactions, which are otherwise weakened by an ionized carboxyl group.

Acids↗
PubMed1988

Molecular modeling of protein structure and function: a bioinformatic approach.

This paper reports on the data/information structure of macromolecules as it extends beyond the three-dimensional conformation to include functional descriptors of biochemical (in vitro) and biological (in vivo) characteristics and as it contrasts with the limitations imposed by the data reduction and data classification techniques of traditional molecular modeling. Methodologies for structure-function representation are presented which are being incorporated within a knowledge-acquisition expert system. Examples of the bioinformatic approach are presented concerning macromolecular recognition by serine proteases and the use of Fourier transform-infrared (FT-IR) spectroscopy for structural assignment and analysis by a novel structure-perturbation approach.

Computer Simulation↗
PubMed1984

Subunit association of enzyme I of the Salmonella typhimurium phosphoenolpyruvate: glycose phosphotransferase system. Temperature dependence and thermodynamic properties.

The bacterial phosphoenolpyruvate:glycose phosphotransferase system plays an essential role in diverse physiological phenomena. To perform these functions, the system is stringently regulated, although the underlying molecular regulatory mechanisms have not been established. A potential target for this type of regulation is the first protein in the phosphotransfer sequence, Enzyme I, which catalyzes the following reaction: P-enolpyruvate + Enzyme I Mg2+ in equilibrium phospho-I + pyruvate. We reported previously that Enzyme I from Salmonella typhimurium consists of identical subunits which associate in a temperature-dependent manner; the mode of association was found to be either monomer-dimer or isodesmic. The association reaction has now been investigated by analytical gel chromatography at 8, 11, and 23 degrees C. At each temperature, the mode of association was strictly monomer-dimer. The apparent association equilibrium constant, K'a, increased dramatically with temperature, with an enthalpy of 54.8 +/- 6.3 kcal/mol. At 23 degrees C, K'a decreased slightly when the enzyme solution contained either Mg2+ or phosphoenolpyruvate. However, when both ligands were present, i.e. under conditions where Enzyme I is phosphorylated, K'a decreased significantly (25-fold at 11 degrees C and 50-fold at 23 degrees C). These results are in accord with a model for the action of Enzyme I which involves a cycle of association and dissociation. This model has potentially important implications for regulating Enzyme I and the bacterial phosphoenolpyruvate:glycose phosphotransferase system.

Macromolecular Substances↗
PubMed1993

Effects of systemic indomethacin, meclizine, and BW755C on chronic ultraviolet B-induced effects in hairless mouse skin.

Chronic exposure of hairless mice to ultraviolet B (UVB) radiation is associated with inflammation as well as an altered macromolecular composition of the dermis. This study was designed to determine whether or not various systemic anti-inflammatory agents inhibit chronic UVB-induced changes in the macromolecular content of the dermis and, if so, whether each agent had the same or different effects. The agents and doses were chosen for their ability to inhibit the changes induced by a single exposure to UVB radiation (increased vasopermeability, neutrophil accumulation, and skin-fold thickness). Indomethacin, a cyclooxygenase inhibitor, and meclizine, an H1 histamine receptor antagonist, were administered from slow-release pellets. BW755C, a combined cyclooxygenase and lipoxygenase inhibitor, was administered intraperitoneally 30 min prior to UVB exposure. Animals were exposed to UVB three times per week for 20-26 weeks or were unirradiated. The elastin, glycosaminoglycan and collagen content of the skin were determined by measuring the desmosine, uronic acid, and hydroxyproline levels, respectively. The amount of each macromolecule per area of skin increased after chronic UVB exposure. The increase in desmosine was inhibited by indomethacin; the increase in hydroxyproline was inhibited by meclizine and BW755C. None of the agents inhibited the uronic acid increase. These results suggest that chronic inflammation contributes to the dermal changes seen in chronically UVB-exposed skin and that different inflammatory mediators are involved in the increases observed in elastin, glycosaminoglycans, and collagen.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗