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PubMed1990

Indium labelled leucocyte scanning in pyrexia of unknown origin.

Pyrexia of unknown origin (PUO), the commonest cause of which is occult infection, represents a difficult diagnostic problem. Radiolabelled white cell scanning provides a non-invasive and potentially useful diagnostic tool in this condition, but its efficacy remains controversial. In a retrospective study, we analysed 30 111In white cell scans, performed between 1983 and 1988 in 25 patients with PUO, strictly defined as a fever of at least 3 weeks duration reaching 38.3 degrees C on more than three occasions and investigated in hospital for a minimum of 7 days. Eleven studies were on post-operative patients who, although developing fever within 1 week of surgery, satisfied the above criteria. Overall, the diagnostic sensitivity and specificity were 55% and 74% respectively, with an overall accuracy of 67%. This improved to 91% in the post-operative patients compared to an accuracy of 52% in spontaneous PUO. Accuracy did not correlate with duration of symptoms, leucocytosis or index of clinical suspicion. In conclusion, although 111In white cell scanning is not particularly useful for the investigation of spontaneous PUO, it does have a role in post-operative PUO.

Adult↗
PubMed1987

Indium-111-labelled granulocyte accumulation in respiratory tract of patients with bronchiectasis.

18 patients with severe bronchiectasis and persistent purulent sputum production were investigated, by the use of gamma scans, between acute exacerbations of their symptoms to determine localisation and traffic of 111In-labelled granulocytes in the lungs. Labelled granulocytes appeared in the respiratory tract of 16 patients within 24 h of their injection. Uptake occurred almost exclusively in areas demonstrated by computed tomography (CT) to be bronchiectatic. However, 111In uptake was not demonstrated in 21 of the 55 segments showing bronchiectasis on CT, and these were therefore thought to be not actively inflamed. The whole-body loss of radioactivity up to 4-7 days following injection of the labelled cells ranged from 0 to 53% and correlated with 24 h purulent sputum volume (r = 0.45, p less than 0.01) and with CT extent of moderate and severe bronchiectasis (r = 0.40, p less than 0.05), but not with overall CT extent of bronchiectasis, age, forced expiratory volume in one second, or duration of purulent sputum production in years.

Adult↗
PubMedDate not supplied

Activation of prophenoloxidase in the plasma and haemocytes of the marine mussel Perna viridis Linnaeus.

Phenoloxidase activity was detected in plasma and haemocytes of the marine mussel Perna viridis. This enzyme exists as a proenzyme, prophenoloxidase (proPO), in both these haemolymph fractions and could be activated in vitro by exogenous proteases (trypsin and alpha-chymotrypsin) and a detergent (sodium dodecyl sulphate). In addition, laminarin (a polymer of beta-1,3 glucan) and bacterial lipopolysaccharides (LPSa) effectively triggered proPO activation in these haemolymph fractions. The activation of proPO by non-self molecules was dependent upon calcium ions at a low concentration. This activation process appeared to involve a limited proteolysis, since serine protease inhibitors (soybean trypsin inhibitor, benzamidine or p-nitrophenyl-p'-guanidinobenzoate) suppressed conversion of proPO to the active enzyme. This study demonstrates the selective response of plasma and haemocytic proPO to activation by different types of bacterial LPS tested and suggests that proPO system in both plasma and haemocytes of P. viridis serves an important function in non-self recognition and host immune reactions.

Animals↗
PubMed1998

Thujaplicin-copper chelates inhibit replication of human influenza viruses.

The effects of alpha-, beta- and gamma-thujaplicins and six of their metal chelates on human influenza virus-induced apoptosis in Madin-Darby canine kidney (MDCK) cells were examined by DNA fragmentation and flow cytometry. Among the compounds tested, thujaplicin copper chelates inhibited apoptosis induced in the infected MDCK cells with influenza A/PR/8/34(H1N1), A/Shingapol/1/57(H2N2), A/Aichi/2/68(H3N2) and B/Lee/40 viruses, at concentrations of more than 5 microM. These results indicate that the copper chelates inhibit influenza virus-induced apoptosis and that the inhibitory effects may be independent of influenza virus subtype or types. Furthermore, the copper chelates also inhibited the release of the viruses from the infected MDCK cells during apoptosis. The anti-apoptotic effects of the copper chelates may occur 2 4 h postinfection, suggesting that the copper chelates affect MDCK cells directly in the early stage of influenza virus-induced apoptosis. In this study, we demonstrated that thujaplicin-copper chelates inhibit influenza virus-induced apoptosis of MDCK cells and also inhibit virus replication and release from the infected cells.

Animals↗
PubMed1999

Teratogenicity of thujaplicin in ICR mice.

Beta-thujaplicin (TP) was studied by in vitro and in vivo tests for teratogenicity using ICR mice. In the in vitro study, TP (0, 3.125, 6.25, 12.5 microg/ml medium) dissolved in dimethyl sulfoxide (DMSO) was administered to cultured embryos on 9 day of gestation. After 24 hr of exposure to TP, the embryos were examined for developmental parameters and external anomalies. Growth retardation and embryos with facial dysplasia or hydrocyst of the tail tip were observed among the embryos given 12.5 microg/ml. In the in vivo study, TP (0, 420, 560, 750 or 1000 mg/kg) dissolved in olive oil was administered orally to pregnant mice on day 9 of gestation. All foetuses were removed from the uterus on day 18 of gestation, and were examined for external and skeletal anomalies. Various types of malformations were observed in the mice given 560 mg/kg or more. The number of litters having foetuses with external or skeletal anomalies increased in proportion to the dose of TP. The regression lines of Y (probit response) on X (log dose) for external anomalies was Y = 4.87X-8.43 . The 1% effective dose (ED1) for the malformation was 190 mg/kg. The present study shows that TP has teratogenic effects on mice.

Abnormalities, Drug-Induced↗
PubMed2000

Biophysical and pharmacological characterization of voltage-sensitive calcium currents in neonatal rat inferior colliculus neurons.

Calcium conductances have been found in neonatal inferior colliculus neurons, however the biophysical and pharmacological profiles of the underlying calcium currents have not yet been characterized. In this study, we examined which types of voltage-activated calcium currents comprise the whole-cell inward current of neonatal inferior colliculus neurons (10-22microm in diameter). On the basis of their voltage-dependence and pharmacological sensitivities, three major components of barium currents were identified. A low threshold voltage-activated current that activated around -70mV, a mid threshold voltage-activated current that activated near -50mV, and a high threshold voltage-activated current that activated around -40mV. Low and mid threshold voltage-activated currents were present in 33% and 41% of the recordings, respectively, whereas high threshold voltage-activated currents were recorded in all inferior colliculus neurons tested. Nickel chloride (50microM) and U-92032 (1microM), which both block low threshold voltage-activated currents, reduced the amplitude of low threshold voltage-activated peak currents at a test potential of -60mV by 72% and 10%, respectively. In addition, 50microM nickel chloride and 1microM U-92032 reduced the amplitude of mid threshold voltage-activated peak currents measured at -20mV by 55% and 21%, respectively. Further pharmacological analysis indicated the presence of multiple types of high threshold voltage-activated currents in neonatal inferior colliculus neurons. The dihydropyridine nimodipine (1microM), a selective L-type current antagonist, reduced the amplitude of high threshold voltage-activated peak currents by 25%. In addition, FPL 64176 (1microM), a non-dihydropyridine L-type current agonist caused a dramatic 534% increase in the amplitude of the slow sustained component of the tail current measured at -40mV. These data indicate that inferior colliculus neurons express L-type channels. omega-Conotoxin GVIA (1microM), a selective blocker of N-type current, inhibited high threshold voltage-activated peak currents by 28% indicating the presence of N-type channels. omega-Agatoxin IVA (300nM), a potent P/Q-type antagonist, reduced high threshold voltage-activated peak currents by 27%, suggesting that inferior colliculus neurons express P/Q-type channels. Concomitant application of nimodipine (1microM), omega-conotoxin GVIA (1microM) and omega-agatoxin IVA (300nM) onto inferior colliculus neurons decreased the control high threshold voltage-activated peak currents only by 62%.Thus, inferior colliculus neurons may express at least one more type of calcium current in addition to low and mid threshold voltage-activated currents and L-type, N-type and P/Q-type high threshold currents.

Animals↗
PubMed1998

Effects of zinc oxide on the attachment of Staphylococcus aureus strains.

We examined the attachment of Staphylococcus aureus to plastic tissue-culture coverslips after incubation for 24 h. The attachment to coverslips was weaker in rabbit plasma with 5% zinc oxide (ZnO) than in the control rabbit plasma without ZnO (P < 0.01). Plasma coagulation by S. aureus strains was not detected in plasma with 5% ZnO after incubation for 24 h. The membranous structure (an immature biofilm) was formed on the coverslips by S. aureus cells in plasma after incubation for 24 h. The colony counts of S. aureus cells on the membranous structures were lower in plasma with 5% ZnO, plasma with 0.2% hinokitiol, plasma with 5% ZnO + 0.2% hinokitiol, plasma with cefdinir at 4 minimum inhibitory concentration (MIC) and plasma with levofloxacin at 4 MIC, than in the control plasma after incubation for 24 h (P < 0.01). The colonies on the membranous structures completely disappeared in the case of plasma with 5% ZnO and 0.2% hinokitiol. The colony counts on membranous structures were lower in plasma with cefdinir at 4 MIC or levofloxacin at 4 MIC containing 5% ZnO than in plasma with cefdinir at 4 MIC or levofloxacin at 4 MIC only, (P < 0.05). The MICs of hinokitiol against S. aureus strains peaked at an MIC distribution of 16-32 micrograms/ml. The peak shifted to below 1 microgram/ml by adding 5% ZnO in agar plate method. The results suggest that the attachment of S. aureus cells to the coverslips is suppressed in the presence of 5% ZnO and that antistaphylococcal activities of cefdinir, levofloxacin and hinokitiol increase in the presence of 5% ZnO.

Animals↗
PubMed1994

Local unfolding and the stepwise loss of the functional properties of tubulin.

Tubulin exhibits a number of characteristic functions that can be used to identify it. They include the ability to polymerize to microtubules, GTPase activity, and the binding of numerous antimitotic drugs and fluorophores. These functions can be differentially modified by low (0.1-1.0M) urea concentrations, and such urea-induced modifications are stable over time periods of minutes to hours. These intermediate states suggest the existence of restricted regions in the protein each of which is associated with a function and its own urea sensitivity. In order of decreasing sensitivity to urea these effects are decreased rate of polymerization of tubulin to microtubules > decreased extent of polymerization approximately decreased GTPase activity > enhanced fluorescence of a rapidly binding analogue of colchicine-MTPT [2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone] approximately decreased proteolysis by trypsin (after alpha Arg339) and by chymotrypsin (after beta Tyr281) > enhanced fluorescence of 1-anilino-8-naphthalenesulfonic acid (ANS). Additional evidence for the independent behavior of the restricted regions stems from the markedly different time dependence of the response to urea. These low urea concentrations do not induce significant changes in tryptophan fluorescence, suggesting that the observed effects are due to local unfolding. At higher urea concentrations (2-4 M), the enhanced fluorescence of the ligands is abolished; MTPT fluorescence decreases at lower urea concentrations than ANS fluorescence. Moreover, tubulin becomes highly susceptible to proteolysis at multiple sites, and tryptophan emission shows a red-shift, as expected. Multistep unfolding in response to denaturants has been reported for some other proteins. Tubulin appears to be an extreme example of such local responses that proceed under milder conditions than the global transition to the unfolded state.

Anilino Naphthalenesulfonates↗
PubMed1991

Roles of ring C oxygens in the binding of colchicine to tubulin.

The roles of the oxygens in ring C of colchicine in its binding to tubulin were probed by a study of the interactions of two allocolchicine biphenyl analogues, 2,3,4,4'-tetramethoxy-1,1'-biphenyl (TMB) and 2,3,4-trimethoxy-4'-acetyl-1,1'-biphenyl (TKB), the first one containing a methoxy group in position 4', the second a keto group. Both analogues were found to bind specifically to the colchicine-binding site on tubulin in a rapidly reversible equilibrium. The standard free energies of binding at 25 degrees C were delta G zero (TKB) = 7.19 +/- 0.11 kcal mol-1 and delta G zero (TMB) = -6.76 +/- 0.22 kcal mol-1. The binding of TKB induced the same perturbation in protein circular dichroism at 220 nm as colchicine and allocolchicine, as well as quenching of protein tryptophan fluorescence. Binding of TMB did not affect the protein CD spectrum within experimental error and induced only a marginal quenching of protein fluorescence. Comparison with the binding properties of allocolchicine and its des(ring B) analogue 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB) [Medrano et al. (1989) Biochemistry 28, 5589-5599] has shown that the binding properties of the 4'-keto analogue (TKB) were closer to those of allocolchicine, even though the substituent in the 4'-position of TCB is identical with that of allocolchicine. It has been proposed that binding in the ring C subsite on tubulin, which is stabilized thermodynamically by stacking interactions, can be modulated in a nonidentical fashion by the carbonyl and the ether oxygens in the para position of ring C.

Binding, Competitive↗
PubMed1991

Mechanism of colchicine binding to tubulin. Tolerance of substituents in ring C' of biphenyl analogues.

The limits of structural variation of the substituent in position 4' of ring C' of biphenyl colchicine analogues (ring C in colchicine) were probed by the synthesis of a number of analogues and the examination of their binding to tubulin and its consequences. Binding was found to require the location in three-dimensional space of the oxygen in the 4'-substituent at a locus not far distant from those of the colchicine ring C oxygens. All those analogues that bind to the colchicine site of tubulin induced the GTPase activity and inhibited microtubule assembly, those containing a carbonyl group substoichiometrically and the others stoichiometrically. A similar relation was found for the induction of the abnormal polymerization of the colchicine analogue-tubulin complex, with methoxy-containing compounds requiring a higher temperature to induce the polymerization. A concerted analysis of the binding thermodynamics of colchicine and its various analogues has shown full consistency with the previously proposed two-step binding pathway that involves two nonidentical binding moieties in the ligand [Andreu, J. M., & Timasheff, S. N. (1982) Biochemistry 21, 534-543]. Comparison of the binding parameters of colchicine, its des(ring B) analogue (MTC), and ring A and C compounds individually with the thermodynamic parameters deduced for the first steps of the bindings of colchicine and MTC [Engelborghs, Y., & Fitzgerald, T. J. (1987) J. Biol. Chem. 262, 5204-5209] have led to the conclusion that binding can occur by two pathways leading to the identical product. In the first pathway, ring A binds first; this is followed by a rate-determining thermodynamically indifferent reaction (protein conformation change), and finally a rapid binding of ring C. In the second pathway, the events are the same except that the order of binding of the rings is reversed. Colchicine, due to the steric hindrance of ring B, can follow only the second pathway. For MTC, both kinetic pathways are open and binding may be initiated by random first contact of either ring A or ring C.

Animals↗
PubMed1989

Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin.

Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, and combretastatin A-2 (CS-A2), 3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are structurally simple natural products isolated from the South African tree Combretum caffrum. They inhibit mitosis and microtubule assembly and are competitive inhibitors of the binding of colchicine to tubulin [Lin et al. (1988) Mol. Pharmacol. 34, 200-208]. In contrast to colchicine, drug effects on tubulin were not enhanced by preincubating CS-A4 or CS-A2 with the protein. The mechanism of their binding to tubulin was examined indirectly by evaluating their effects on the binding of radiolabeled colchicine to the protein. These studies demonstrated rapid binding of both compounds to tubulin even at 0 degrees C (binding was complete at the earliest times examined), in contrast to the relatively slow and temperature-dependent binding of colchicine. Although the binding of the C. caffrum compounds to tubulin was quite tight, permitting ready isolation of near-stoichiometric amounts of drug-tubulin complex even in the absence of free drug, both CS-A4 and CS-A2 dissociated rapidly from tubulin in the presence of high concentrations of radiolabeled colchicine. Apparent rate constants for drug dissociation from tubulin at 37 degrees C were 3.2 x 10(-3) s-1 for CS-A4, 4.8 x 10(-3) s-1 for CS-A2, and 2.9 x 10(-5) s-1 for colchicine (half-lives of 3.6, 2.4, and 405 min, respectively). Thus, the effectiveness of the C. caffrum compounds as antimitotic agents appears to derive primarily from the rapidity of their binding to tubulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Alterations of rings B and C of colchicine are cumulative in overall binding to tubulin but modify each kinetic step.

The role of the elimination of ring B and/or the modification of ring C of colchicine in tubulin binding kinetics and thermodynamics has been characterized, using four different molecules. These ligands are colchicine (COL); 2-methoxy-5-(2',3',4'-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-on e (MTC), in which the central ring B has been reduced to one bond; allocolchicine (ALLO), in which ring C has been replaced by a six-membered ring; and 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB), where the same two modifications are made simultaneously. This paper describes the kinetics of association of ALLO with tubulin. The binding is accompanied by a fluorescence increase with slow biphasic kinetics, indicating binding to fast and slow tubulin isotypes. Binding to each of these isotypes occurs in two steps: a fast initial binding followed by a slower isomerization step. The K1 and k2 values for ALLO at 25 degrees C are 14,000 +/- 2,000 and 25,000 +/- 6,000 M-1 (fast and slow isotypes) and 0.055 +/- 0.003 s-1 and 0.013 +/- 0.001 s-1 (fast and slow isotype), respectively. For ALLO the reaction standard enthalpy change of the initial binding is 68 +/- 5 kJ.mol-1 (fast isotype) and 45 +/- 33 kJ.mol-1 (slow isotype) and the activation energy for the second forward step is 58 +/- 14 kJ.mol-1 (fast isotype) and 81 +/- 17 kJ.mol-1 (slow isotype). Displacement kinetics of bound ALLO by podophyllotoxin was monoexponential. The activation energy for the isomerization in the off direction is 107 +/- 7 kJ.mol-1. Comparison of the thermodynamic parameters for all four compounds shows that the modifications of both rings are cumulative with respect to overall binding. For the intermediate state there is a mutual influence of both modifications, suggesting an alteration of the reaction pathway.

Biphenyl Compounds↗
PubMed1999

Phosphate release during microtubule assembly: what stabilizes growing microtubules?

The molecular mechanism underlying microtubule dynamic instability depends on the relationship between the addition of tubulin-GTP to a growing microtubule and its hydrolysis in the microtubule lattice to tubulin-GDP, with release of inorganic phosphate (Pi). Since this relationship remains controversial, we have re-examined the release of Pi upon microtubule assembly using a fluorometric assay for Pi, based on the phosphate-binding protein of Escherichia coli [Brune M., Hunter, J. L., Corrie, J. E. T., and Webb, M. R. (1994) Biochemistry 33, 8262-8271]. Microtubule assembly and Pi release were monitored simultaneously in a standard fluorimeter as an increase in the turbidity and fluorescence, respectively, in tubulin-GTP solutions assembled under conditions supporting dynamic instability. At the steady state of assembly, Pi release is nonlinear with respect to time, proceeding at a rate determined by the following: (a) the intrinsic GTPase activity of the nonpolymerized tubulin-GTP, and (b) the microtubule number concentration, which decreases progressively. Direct observation of the time course of nucleated microtubule assembly indicates that Pi release is closely coupled to microtubule elongation, even during the initial stages of assembly when uncoupling of tubulin-GTP addition and GTP hydrolysis would be most evident. Studies of the inhibition and reversal of the growth phase by cytostatic drugs show no evidence of a burst of Pi release. We conclude that nucleotide hydrolysis can keep pace with tubulin-GTP addition rates of 200 molecules per second per microtubule and that extended caps of tubulin-GTP or tubulin-GDP-Pi are not generated in normal assembly, nor are they required to stabilize growing microtubules or to support the phenomenon of dynamic instability of microtubules at the steady state.

Animals↗
PubMed2001

Total synthesis of tropoloisoquinolines: imerubrine, isoimerubrine, and grandirubrine.

A unified, ready access to the tropoloisoquinoline alkaloids imerubrine (1), grandirubrine (2), and isoimerubrine (3) is delineated and features sequential application of the intramolecular Diels-Alder reaction of an acetylene-tethered oxazole and the [4 + 3] cycloaddition of an oxyallyl. A regioselective synthesis of 1 was achieved by stereo- and regioselective oxidation of an 8-oxabicyclo[3.2.1]oct-6-en-3-one cycloadduct by means of the Moriarty method. Such a post-cycloaddition functionalization complements the synthetic utility of an alpha-alkoxy-substituted oxyallyl so as to broaden the scope of the oxyallyl [4 + 3] cycloaddition reaction.

Alkaloids↗
PubMed2005

Acaricidal activity of active constituent isolated in Chamaecyparis obtusa leaves against Dermatophagoides spp.

Acaricidal activities of materials derived from Chamaecyparis obtusa leaves against Dermatophagoides farinae and Dermatophagoides pteronyssinus were examined using the dry film method and compared with that of commercial benzyl benzoate and N,N-diethyl-m-toluamide (DEET). The active constituent of the C. obtusa leaves was identified as beta-thujaplicin (C10H12(O2)) by spectroscopic analyses. Responses varied with dose. On the basis of a 24 h LC50 value, acaricidal activity against D. farinaewas more pronounced with beta-thujaplicin (72.2 mg/m2) than benzyl benzoate (89.9 mg/m2) and DEET (377 mg/m2). Acaricidal activity against D. pteronyssinus was more pronounced in beta-thujaplicin (62.1 mg/m2) than benzyl benzoate (72.4 mg/m2) and DEET (193 mg/m2). These results indicate that acaricidal activity of C. obtusa leaves likely results from by beta-thujaplicin. Beta-thujaplicin merits further study as potential house dust mite control agents or lead compounds.

Benzoates↗
PubMed1984

Troponoids. 6. Troponylpiperazines: a new class of dopamine agonists.

A series of alkyltroponylpiperazine derivatives was synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine pathway. The compounds were compared to bromocriptine. The results indicate that dopaminergic activity is very sensitive to small changes in the troponylpiperazine moiety.

Animals↗
PubMed2001

Application of Lewis acid catalyzed tropone [6+4] cycloadditions to the synthesis of the core of CP-225,917.

The carbocyclic core of CP-225,917 and CP-263,114 is accessible through the [6+4] cycloaddition of a tropone with a 2-substituted cyclopentadiene. Examination of this reaction has revealed for the first time that this cycloaddition process is catalyzed by Lewis acids, including lanthanide triflates. Cycloadditions of several mono-, di-, and trisubstituted tropones with 2-silyloxycyclopentadienes using ZnCl(2) catalysis are found to proceed in good yield and, in many cases, with excellent diastereoselectivity. Subsequent transformation to the core of the CP-molecules involves a site-selective Baeyer-Villiger oxidation of a tricyclic diketone, followed by a syn-elimination process. [reaction: see text]

Acids↗