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At least 847 records · Page 47Linked to original sources
PubMed2000

The influence of nicotinic receptor subunit composition upon agonist, alpha-bungarotoxin and insecticide (imidacloprid) binding affinity.

A series of cell lines stably expressing recombinant nicotinic acetylcholine receptors (nAChRs) has been established by transfection of mammalian (rat) and insect (Drosophila) nicotinic subunit cDNAs. By equilibrium radioligand binding, we have examined the influence of individual subunits upon the affinity of two nicotinic agonists (epibatidine and methylcarbamylcholine), an antagonist (the snake neurotoxin, alpha-bungarotoxin) and a recently developed chloronicotinyl insecticide (imidacloprid). Imidacloprid bound with very low affinity to the rat alpha4/beta2 nAChR but did so with high affinity to hybrid nAChRs containing Drosophila alpha subunits co-assembled with rat beta2. Of the subunit combinations examined, imidacloprid showed highest affinity binding to nAChRs containing the recently identified Drosophila alpha subunit, D alpha3, co-assembled with beta2. In contrast, no specific binding of imidacloprid was detected when D alpha3 was co-expressed with the mammalian neuronal beta4 subunit, or with the muscle-type (gamma or delta) subunits. However, despite the absence of imidacloprid binding to D alpha3/beta4, D alpha3/gamma or D alpha3/delta, these subunit combinations all exhibited high affinity binding of other nicotinic radioligands. Epibatidine showed substantially higher affinity binding to subunit combinations containing neuronal (beta2 or beta4) subunits than it did to combinations containing muscle-type (gamma or delta) subunits. In contrast, alpha-bungarotoxin bound with higher affinity to combinations containing muscle-type subunits. Our results demonstrate that both alpha and non-alpha subunits exert a profound influence upon the affinity of nicotinic ligands for recombinant nAChRs.

Animals↗
PubMed1998

Identification of the binding site for a low-molecular-weight inhibitor of plasminogen activator inhibitor type 1 by site-directed mutagenesis.

A novel low-molecular-weight inhibitor, AR-H029953XX, was developed from a known fibrinolytic compound, flufenamic acid, which prevented complex formation of human plasminogen activator inhibitor type 1 (PAI-1) with tissue plasminogen activator (tPA) by inhibition of PAI-1. To explore the binding site for AR-H029953XX, mutants of human PAI-1 were constructed by site-directed mutagenesis and were then expressed in CHO cells, purified, activated, and characterized. (1) PAI-1 with mutations in the reactive center loop: L1-PAI-1 (P10, Ser337Glu) had stability and activity similar to those of wild-type PAI-1 (wt-PAI-1), and L2-PAI-1 (P12, Ala335Glu) was highly stable but was a substrate for tPA. (2) PAI-1 with mutations near the binding epitope for the strongly inhibiting monoclonal antibody CLB-2C8: C1-PAI-1 (Phe114Glu), C2-PAI-1 (Val121Phe), C3-PAI-1 (Arg76Glu/Arg115Glu/Arg118Glu), and C4-PAI-1 (Arg115Glu) were all comparable in activity and stability to wt-PAI-1. AR-H029953XX (Ki = 25 microM) prevented complex formation between tPA and active wt-PAI-1 as well as that with mutants L1-, L2-, C1-, C2-, and C4-PAI-1. AR-H029953XX also inhibited binding of these PAI-1 variants to the antibody CLB-2C8, as measured by surface plasmon resonance. In contrast, AR-H029953XX had almost no inhibitory effect on the complex formation of tPA with C3-PAI-1. Moreover, AR-H029953XX had no effect on the binding rate of CLB-2C8 to C3-PAI-1, or on the binding to latent PAI-1 or to cleaved L2-PAI-1. The binding site of AR-H029953XX thus appears to be located in the neighborhood of the postulated epitope for CLB-2C8, near residues Arg76 and/or Arg118. This specific domain of the PAI-1 molecule might thus also be important for the mechanism of inhibitory activity toward tPA. Moreover, the structure of this region in active PAI-1 has to be different from the corresponding regions in latent and cleaved PAI-1.

Animals↗
PubMed1972

Characterization and partial purification of the acetylcholine receptor from Torpedo electroplax.

Binding of acetylcholine in the concentration range 1 nM-1 muM was measured by equilibrium dialysis to a particulate preparation of Torpedo electroplax, without or with prior treatment of the tissue with one of three chemical modifying reagents. Significant reduction in binding of acetylcholine resulted after treatment with 1,4-dithiothreitol, p-chloromercuribenzoate, or p-(trimethylammonium)-benzenediazonium fluoroborate. Partial reversal of the reduction in binding occurred when dialysis was performed in the presence of 5,5'-dithiobis-(2-nitrobenzoic acid) or potassium ferricyanide (in the case of treatment with dithiothreitol), and 2-mercaptoethanol (in the case of treatment with p-chloromercuribenzoate). It is concluded that the functional acetylcholine-receptor macromolecule of Torpedo electroplax has disulfide bond(s), sulfhydryl group(s), and one or more of the amino acids vulnerable to diazotization by p-(trimethylammonium)-benzenediazonium fluoroborate. This, plus the effect of phospholipase C (EC 3.1.4.3) in elimination of detectable binding of acetylcholine after electrofocusing, is additional evidence that the functional acetylcholine receptor is a phospholipoprotein or a phospholipid-protein complex, which has a low isoelectric point of 4.5 +/- 0.2, yet is denatured by exposure to low pH for 24 hr. Due to this adverse effect, recovery of binding of acetylcholine after electrofocusing, as detected by equilibrium dialysis or ultrafiltration, is only 23% and, so far, only 6.3-fold purification of functional acetylcholine receptors by this technique is possible. Three or two forms of acetylcholinesterase (EC 3.1.1.7), whose peaks have isoelectric points ranging from 4.3 to 7.2, appear after electrofocusing of Torpedo extracted with 1% Triton X-100 or Lubrol, respectively. The major peak in either preparation has an isoelectric point of 5. Although the peaks of the functional acetylcholine receptors and of acetylcholinesterase of Torpedo electroplax are separable by electrofocusing, it has not been possible to isolate fractions that contain functional receptors but that are free of acetylcholinesterase. The opposite is possible.

Acetylcholine↗
PubMed1977

Properties of the Ames Salmonella mutants lodged in the gastrointestinal tract of gnotobiotic rats.

An association of the histidine auxotroph of Salmonella typhimurium (strain TA1538) within the gastrointestinal tract of otherwise germ-free Sprague-Dawley rats is maintained during observations for up to 7 months. The bacteria exceed concentrations of 10(7)/g in the forestomach and exceed concentrations of 10(8)/g in the lower bowel and feces. When carcinogens are ingested, the number of revertants in the feces increases. The ingestion of structurally related compounds which are not mutagenic to the bacteria in vitro and for which no evidence of carcinogenicity exists does not increase the number of revertants in the feces. The numbers of salmonella are increased by the addition of Lactobacillus plantarum and Bacteroides fragilis but the salmonella disappear from the gastrointestinal tract when the rats are conventionalized. With the additional flora, there is a decrease in the number of revertants appearing in the feces in response to a given dose of carcinogen. This decrease may reflect an effect of the flora on the activity of the metabolic pathway responsible for the presence of the ultimate carcinogen or it may simply be an effect on the salmonella mutants themselves.

Animals↗
PubMed1975

Isolation of an inducible amidase from Pseudomonas acidovorans AE1.

A bacterial strain, AEI, which hydrolysed acetanilide, was isolated from soil and identified as Pseudomonas acidovorans. Numerous amides, esters and enzyme inhibitors were tested as amidase inducers. Phenacetin was chosen as inducer for the large scale cultivation of these organisms because it was less toxic to the bacteria than acetanilide. The induction increased the enzymic activity 250-fold. In comparison, the type culture strain of P. acidovorans, ATTCCI5668, had no amidase activity which could be induced by phenacetin. Optimal growth conditions were established with respect to the concentration of carbon source and inducer so that about 10% of the extractable bacterial protein consisted of the amidase. The organisms were lysed with lysozyme in the presence of EDTA and the enzyme was isolated mainly by column chromatography procedures. A preparation form 60 g (wet wt) bacteria yielded about 100 mg highly purified amidase with a specific activity of 137 mugmol substrate hydrolysed/min/mg protien. In addition to acetanilide, the purified enzyme hydrolysed several other amides and esters. As standard substrate, p-nitroacetanilide was chosen.

Acetamides↗
PubMed1992

A sensitive umu test system for the detection of mutagenic nitroarenes in Salmonella typhimurium NM1011 having a high nitroreductase activity.

A sensitive umu test system for the detection of mutagenic nitroarenes has been developed using a new tester strain Salmonella typhimurium NM1011 having a high nitroreductase activity. The new strain was constructed by subcloning the bacterial nitroreductase gene into a plasmid pACYC184 and introducing the plasmid into the original strain S. typhimurium TA1535/pSK1002 harboring a fusion gene umuC'-'lacZ (pSK1002). Thus, the tester strain enabled us to monitor the genotoxic activities of various nitroarene compounds by measuring the beta-galactosidase activity in the cells. The sensitivity of strain NM1011 was compared with that of the parent tester strain S. typhimurium TA1535/pSK1002 or a nitroreductase-deficient strain S. typhimurium NM1000 with respect to the induction of umuC gene expression by 17 mutagenic nitroarenes. The newly developed strain with high nitroreductase activity had about 3 times higher nitrofurazone-reductase activity than the parent strain and was highly sensitive to the compounds 2-nitrofluorene, 1-nitronaphthalene, 2-nitronaphthalene, 1-nitropyrene, m-dinitrobenzene, 4,4'-dinitrobiphenyl, 3-nitrofluoranthene, 3,7-dinitrofluoranthene, 3,9-dinitrofluoranthene, 5-nitroacenaphthene and 2,4-dinitrotoluene. By contrast, the enzyme-deficient strain did not show any considerable response to 2-nitrofluorene, m-dinitrobenzene, 1-nitronaphthalene, 2-nitronaphthalene, 1-nitropyrene, 4,4'-dinitrobiphenyl, 3-nitrofluoranthene, 3,7-dinitrofluoranthene, 2,4-dinitrotoluene and 5-nitroacenaphthene. These results suggest that the newly developed tester strain with high nitroreductase activity is very useful for the detection of potent mutagenic nitroarene compounds.

Cloning, Molecular↗
PubMed2001

A study of 2,4,6-trinitrotoluene inhibition of benzo[a]pyrene uptake and activation in a microbial mutagenicity assay.

A number of in vitro and in vivo studies have determined that binary and complex mixtures may interact to produce a toxicity that could not be predicted based on the individual chemicals. The present study was conducted with a binary mixture of model compounds to investigate possible interactions affecting their mutagenicity. The compounds included Benzo[a]pyrene (BAP), a polycyclic aromatic hydrocarbon that is an indirect-acting mutagen of great environmental concern, and 2,4,6-Trinitrotoluene (TNT), a nitro-aromatic compound that is a direct-acting mutagen frequently found as a soil contaminant at munitions sites. This study indicated that a binary mixture of BAP and TNT failed to induce the positive mutagenic response in Salmonella typhimurium strain TA98 characteristic of either compound alone. Spectrofluorometric analysis of BAP, and kinetic analyses of 3HBAP uptake in the presence or absence of TNT using TA98 cells that were treated or untreated with activated rat liver microsomes were performed. In cells preloaded with BAP, cellular BAP fluorescence was rapidly suppressed in the presence of TNT. Mass spectroscopy of BAP and TNT mixtures revealed a number of products, believed to be the result of complexation and nitration, that may account for the antagonistic action of TNT on BAP-induced mutagenicity in TA98 cells. Further, kinetic studies indicated that TNT inhibited the incorporation of BAP into cells.

Animals↗
PubMed1992

Electrochemical characteristics of nitroheterocyclic compounds of biological interest. VIII. Stability of nitro radical anions from cyclic voltammetric studies.

The stability of the one electron addition product of four biologically important nitroheterocyclic compounds has been examined electrochemically. Using cyclic voltammetry the tendency of the nitro radical anion to undergo disproportionation was studied by two methods of analysis. The first was based on determining the voltammetric time-constant required for half of the reduction product, RNO2-., to react further. The second concerned the minimum volume of dimethylformamide which had to be added to the aqueous electrolytic medium to give a specific cyclic voltammetric response. Both methods were found to compare well with the results obtained for RNO2-. stabilities using a theoretically derived procedure for a second order reaction following a charge-transfer step. The use of these alternative approaches for quantifying the reactivity of reduction products is discussed. The time-constant method in particular may be useful in studying complex reaction pathways.

Chloramphenicol↗
PubMed1991

5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation.

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2H)pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a, which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)-induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a-m and the other pyridazinones 5-9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a, tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E2 (PGE2) production and interleukin-1 activity. Structure-activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.

Amrinone↗