Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0276640 (TEM)
 20,729 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A single intratracheal instillation of porcine pancreatic elastase (PPE, 100 U/Kg) induces in rabbits bronchial secretory cell metaplasia as well as emphysematous changes. The mucus hypersecretion and the marked reduction of ciliated cells matched by a high percentage of atypical cilia are responsible for the delayed mucociliary clearance in this model. S-Carboxymethylcysteine lysine salt (SCMC-LYS, 0.35 g/Kg b.w.), given per os daily for 10 days starting 2 days before elastase administration, significantly ameliorated the mucociliary clearance. The pharmacological treatment did not modify the degree of secretory cell metaplasia and the percentage of atypical cilia, or prevent the alveolar wall destruction. At TEM examination, the morphological aspects of secretion occurring in bronchial tree of PPE-treated animals were rarely visible in the PPE + SCMC-LYS treated group. The beneficial effect of SCMC-LYS on mucociliary clearance may be ascribed to an antisecretagogue effect of this drug through elastase inhibition and to a reduction of mucus viscosity.
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PMID:Effect of S-carboxymethylcysteine lysine salt on mucociliary clearance in rabbits with secretory cell metaplasia. 785 Feb 57

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyimino) acetyl] amino]-2-carboxy-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-(2-hydroxyethyl)-1H-pyrazoli um hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylocci at < or = 4 micrograms/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 micrograms of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active beta-lactam tested against staphylococci. The MIC of FK-037 for 90% of the strains tested (MIC90) was 0.06 micrograms/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 microgram/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC90 for Klebsiella pneumoniae and Enterobacter cloacae was 8 micrograms/ml, similar to that for cefepime, but all isolates were inhibited by 2 micrograms of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of > 32 micrograms/ml with Bush type 2b' beta-lactamases were inhibited by 4 micrograms of FK-037 per ml. E. cloacae, Citrobacter freundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 microgram/ml, compared to 32 microgram/ml for cefepime and ceftazidime and 8 microgram/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, more than or equal 32 microgram/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e beta-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV -5 at less than or equal 8 microgram/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.
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PMID:In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin. 846 Sep 25

Results on surfactant gels containing densely packed multilamellar vesicles are reported. The gels form spontaneously when the bilayers of L alpha or L3 phases of alkyldimethylaminoxide and cosurfactant are charged up by the addition of ionic surfactant or HCl. The rheological behaviour on addition of excess salt was studied by dynamic rheological measurements for systems with surfactants of different chainlengths. Both the storage modulus, G', and the yield stress, sigma y, decay with rising salinity. This effect is caused by the reduction of both the electrical contribution of the bending constants of the bilayers and the compression modulus of the vesicles. The influence of the charge density on the rheological properties was determined. G' and sigma y increase with charge density and reach a plateau that depends on the chainlength of the surfactant. Measurements on samples prepared with waterglycerol mixtures show that the moduli and the yield stress value are independent of the solvent viscosity. Photographs of the surfactant gels that were taken with the interference contrast microscopy technique are presented. They reveal that some of the vesicles are much bigger than expected on the basis of TEM micrographs. The mean size of the vesicles can be estimated on basis of conductivity data. This method yields an average number of 5-6 shells per vesicle and corresponds with the value taken from the electron micrograph. The rheological data are explained with a model that was recently introduced by van der Linden. In connection with a model due to Lekkerkerker for the electric contribution of the bending constant of the bilayers and our own calculations of the osmotic pressure the van der Linden formula yields good results for describing the experimental data.
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PMID:Gels from surfactant solutions with densely packed multilamellar vesicles. 880 25

Fluid absorption by Necturus small intestine has been studied using radiolabeled dextrans as molecular probes of the paracellular pathway under voltage-clamped conditions. Fluxes of H3-dextrans of MW up to 20K were followed in both directions between mucosal (M) and serosal (S) baths by fractionating those that passed the epithelium as a function of molecular radius. Consideration of the unstirred layers in the baths and the surface geometry rules out any contribution made by solute polarization. The geometry of the paracellular system was measured by light microscopy, TEM and SEM, and values were used in conjunction with a program that calculates convective-diffusive coupling in the tight junctions, intercellular spaces and subepithelium in series. The results indicate that the net fluxes are due to the convection of fluid through two opposing paracellular fluid circuits with different size selectivity, resulting in net absorption at small radii. Alanine at 20 mM stimulates fluid and salt uptake by a factor of 2. Its effect on the two convective components is to increase the M to S flux and decrease the S to M. The selectivities are not significantly different from those before alanine treatment. The volume absorption predicted from the net probe fluxes is very close to that measured gravimetrically across the epithelium.
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PMID:Fluid recirculation in Necturus intestine and the effect of alanine. 923 89

At this time an amino acid substitution at position 276 in the TEM-1 enzyme is associated with an additional substitution at position 69 in natural beta-lactamase-inhibitor-resistant (IRT) beta-lactamases. The effect of the Asn276-->Asp substitution on resistance was assessed with the Asn276Asp variant, generated by site-directed mutagenesis. The mutant was resistant to beta-lactamase inhibitors, but the MICs of amoxicillin combined with clavulanic acid or tazobactam were strikingly different for E. coli strains producing the Asn276Asp variant and those producing naturally occurring IRTs with single or double substitutions. The inhibitory effects of clavulanic acid and tazobactam were the same in IRTs with substitutions at position 69 (IRT-5 and IRT-6). The effect of clavulanic acid on the MICs of amoxicillin for the Asn276Asp variant was greater than that of tazobactam. In IRTs with double substitutions, at positions 69 plus 276 (IRT-4, IRT-7, and IRT-8) or 69 plus 275 (IRT-14), tazobactam was a more potent inhibitor than clavulanic acid. The effect of the Asn276-->Asp substitution on the values of the kinetic constants and the concentration required to inhibit by 50% the hydrolysis of benzylpenicillin confirms that this single mutation is responsible for resistance to beta-lactamase inhibitors. Molecular modeling of the Asn276Asp mutant shows that Asp276 can form two salt bonds with Arg244 close to the penicillin-binding cavity. The addition of the Asp276 mutation to that preexisting at position 69 confers a higher selective advantage to bacteria, as shown by the reduction in beta-lactamase inhibitor efficiencies of the double variants. Therefore, the emergence of multiple mutations in TEM beta-lactamases by virtue of the use of beta-lactamase inhibitors increases selection pressure resulting in the convergent evolution of resistant strains.
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PMID:Phenotypic study of resistance of beta-lactamase-inhibitor-resistant TEM enzymes which differ by naturally occurring variations and by site-directed substitution at Asp276. 962 68

Chitosan is a polysaccharide that demonstrates much potential as a gene delivery system. The ability of a commercially available chitosan and depolymerized chitosan oligomers to condense plasmid was determined using TEM and microtitration calorimetry, while the diameter and stability of the resultant complexes were measured using laser light scattering. Selected complexes were physically stable to challenge with both serum and salt solutions. Parameters such as chitosan molecular weight, plasmid concentration and charge ratio influenced such stability. The effect of including a pH-sensitive endosomolytic peptide on the physicochemical properties of the complex was determined. The presence of a pH-sensitive endosomolytic peptide enhanced the levels of reporter gene expression in Cos-1 cells 4-fold. A selected complex containing a lytic peptide was administered in the upper small intestine and colon of rabbits, and reporter gene expression was measured in defined intestinal tissues. Reporter gene expression was enhanced in defined intestinal tissues, although levels of expression remained low. The combination of strong complex stability and low in vivo expression levels suggest that uptake and/or decomplexation, but not endosomal release, may be the critical rate-limiting steps in the uptake process.
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PMID:Chitosan and depolymerized chitosan oligomers as condensing carriers for in vivo plasmid delivery. 980 49

BLIP is a secreted protein from Streptomyces clavuligerus that inhibits a wide range of beta-lactamases. Here we investigate the tight interaction of BLIP, expressed heterologousely in E. coli, with TEM-1. Kinetic and thermodynamic constants were determined using methods with the proteins either in a homogeneous or in a heterogeneous phase. While values of Delta DeltaG(mut-wt) are similar whether measured by fluorescence quench, enzyme inhibition, or surface plasmon resonance, absolute values of DeltaG and kinetic constants vary. Association and dissociation rate constants of 10(5) M-1 s-1 and 10(-)4 s-1, respectively, and a nanomolar affinity were determined for the wild-type proteins. The highest affinity is measured at pH 7.5, with a decreasing association rate constant at higher pH values, and an increasing dissociation rate constant at lower pH values. The marginal effect of salt on the kinetics of binding, as well as the calculated surface potentials, suggests a limited role for electrostatic forces in guiding this reaction. Still, mutations of interfacial residues affect the rate of association significantly, so that an increase in the net negative charge on either protein reduces the association rate constant. We show that simple electrostatic rules can explain this behavior. BLIP inhibits the catalytic activity of TEM-1 by binding its active site. Yet, mutations of active site residues on TEM-1 only have a moderate though cooperative effect on the binding energy. This can be explained in light of the peripheral location of the active site in the interface between the two proteins.
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PMID:Biophysical characterization of the interaction of the beta-lactamase TEM-1 with its protein inhibitor BLIP. 989 Aug 78

The clinical use of beta-lactam antibiotics combined with beta-lactamase inactivators, such as clavulanate, has resulted in selection of beta-lactamases that are insensitive to inactivation by these molecules. Therefore, therapeutic combinations of an enzyme inactivator and a penicillin are harmless for bacteria harboring such an enzyme. The TEM beta-lactamase variants are the most frequently encountered enzymes of this type, and presently, 20 variants are designated as inhibitor-resistant TEM ("IRT") enzymes. Three mutations appear to account for the phenotype of the majority of IRT enzymes, one of them being the Asn276Asp substitution. In this study, we have characterized the kinetic properties of the inhibition process of the wild-type TEM-1 beta-lactamase and of its Asn276Asp variant with the three clinically used inactivators, clavulanic acid (clavulanate), sulbactam, and tazobactam, and we report the X-ray structure for the mutant variant at 2.3 A resolution. The changes in kinetic parameters for the interactions of the inhibitors with the wild-type and the mutant enzymes were more pronounced for clavulanate, and relatively inconsequential for sulbactam and tazobactam. The structure of the Asn276Asp mutant enzyme revealed a significant movement of Asp276 and the formation of a salt bridge of its side chain with the guanidinium group of Arg244, the counterion of the inhibitor carboxylate. A water molecule critical for the inactivation chemistry by clavulanate, which is observed in the wild-type enzyme structure, is not present in the crystal structure of the mutant variant. Such structural changes favor the turnover process over the inactivation chemistry for clavulanate, with profound phenotypic consequences. The report herein represents the best studied example of inhibitor-resistant beta-lactamases.
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PMID:X-ray structure of the Asn276Asp variant of the Escherichia coli TEM-1 beta-lactamase: direct observation of electrostatic modulation in resistance to inactivation by clavulanic acid. 1042 34

Mixtures of locust bean gum (LBG) with kappa-carrageenan (KC) in 0.1 M aqueous solutions of the mixed salts NaI/CsI were investigated by cryo-transmission electron microscopy (cryo-TEM) and dynamic viscoelastic measurements. Previous studies have shown that as the cesium content is increased in such mixed salt solutions, a transition occurs from molecularly dispersed helices to 'superhelical rods' of KC. We now found that LBG stabilises the superhelical rods, shifting the transition to a lower content of Cs for the mixtures than for KC alone. The formation of superhelical rods was evidenced both by cryo-TEM images and by an onset of thermal hysteresis in the coil helix transition of KC. In the mixtures, the transition temperatures on cooling and heating were insensitive to the proportions of LBG and KC present at all cesium contents. Under conditions where no helix aggregation occurred (no hysteresis) the mixtures showed high tan delta values and low storage moduli. Under aggregated conditions, gels formed, and gels with added LBG had enhanced moduli compared to gels with KC alone. On the basis of these results we propose that LBG associates to the super-helical rods of KC.
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PMID:Conformation and association of kappa-carrageenan in the presence of locust bean gum in mixed NaI/CsI solutions from rheology and cryo-TEM. 1045 72

An alternative method for the calcium phosphate apatite formation onto the surface of flocculated pure silica particles is reported, in an attempt to understand the possible mechanism for the apatite formation. A stable silica sol was flocculated by adding calcium ions in aqueous solution. The wet flocks were resuspended in a basic aqueous solution containing a calcium salt, trying to allow the absorption of calcium ions onto the silica surface through a hydrogen ion exchange. The as-prepared materials were immersed in a modified simulated body fluid at different temperatures (37 and 90 degrees C) and silica concentrations. It was found that these factors have a strong influence on the apatite formation. The apatite formation was confirmed by (31)P MAS-NMR, FT-Raman, XRD, and TEM.
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PMID:Apatite growth on calcium adsorbed surface of wet flocculated silica particles immersed in a modified simulated body fluid. 1063 51


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