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Sample records for serum cholinesterase inhibition

  1. Occupational determinants of serum cholinesterase inhibition among organophosphate-exposed agricultural pesticide handlers in Washington State

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    Hofmann, Jonathan N; Keifer, Matthew C; De Roos, Anneclaire J; Fenske, Richard A; Furlong, Clement E; van Belle, Gerald; Checkoway, Harvey

    2010-01-01

    Objective To identify potential risk factors for serum cholinesterase (BuChE) inhibition among agricultural pesticide handlers exposed to organophosphate (OP) and N-methyl-carbamate (CB) insecticides. Methods We conducted a longitudinal study among 154 agricultural pesticide handlers who participated in the Washington State cholinesterase monitoring program in 2006 and 2007. BuChE inhibition was analyzed in relation to reported exposures before and after adjustment for potential confounders using linear regression. Odds ratios estimating the risk of ‘BuChE depression’ (>20% from baseline) were also calculated for selected exposures based on unconditional logistic regression analyses. Results An overall decrease in mean BuChE activity was observed among study participants at the time of follow-up testing during the OP/CB spray season relative to pre-season baseline levels (mean decrease of 5.6%, P < 0.001). Score for estimated cumulative exposure to OP/CB insecticides in the past 30 days was a significant predictor of BuChE inhibition (β = −1.74, P < 0.001). Several specific work practices and workplace conditions were associated with greater BuChE inhibition, including mixing/loading pesticides and cleaning spray equipment. Factors that were protective against BuChE inhibition included full-face respirator use, wearing chemical-resistant boots, and storing personal protective equipment in a locker at work. Conclusions Despite existing regulations, agricultural pesticide handlers continue to be exposed to OP/CB insecticides at levels resulting in BuChE inhibition. These findings suggest that modifying certain work practices could potentially reduce BuChE inhibition. Replication from other studies will be valuable. PMID:19819864

  2. Study of Serum Amylase and Serum Cholinesterase in Organophosphorus Poisoning

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    Sharan Badiger

    2016-04-01

    Full Text Available Background: Poisoning due to organophosphorus compounds is most commonly seen. Earlier plasma cholinesterase level was used to assess the severity of poisoning. Presently serum amylase is being recommended as a better indicator of severity. Aims and Objectives: To study plasma cholinesterase and serum amylase levels in acute organophosphorus and to correlate serum amylase levels with clinical severity and outcome. Material and Methods: A total of 80 patients in the study admitted to a tertiary care centre within 24 hours with a history of organophosphorus poisoning were included in study. Estimation of plasma cholinesterase and serum rd amylase was done at the time of admission, and on 3 th day and on 5 day. Results: Occurrence of organophosphorus poisoning was more common among age group 21-30 years and among males (57.5%. They were 25 (31.2% farmers, 23 (28.8% st u d e n ts, a n d 2 2 ( 2 7 . 5% h o u s ewi v e s. Monocrotophos (45.0% was commonly used compound. Mean value of plasma cholinesterase and serum amylase at admission are 3693 U/L, and 185.4 U/L. There was significant inhibition of plasma cholinesterase and elevation of serum amylase at th admission with return to normal values on 5 day. Conclusion: Plasma cholinesterase inhibition 200 U/L has been associated with poor prognosis and proneness to respiratory failure.

  3. [How aliphatic alcohols and ph affect reactional capability of the horse blood serum cholinesterase at its interaction with organophosphorus inhibitors].

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    Basova, N E; Kormilitsin, B N; Perchenok, A Iu; Rozengart, E V; Saakov, V S; Suvorov, A A

    2013-01-01

    There was studied action of aliphatic alcohols (ethanol, propanol, isopropanol, n-butanol, isobutanol, secbutanol, tretbetanol) and pH on various kinds of reactional capability the serum cholinesterase. At the alcohols-affected inhibition of the cholinesterase hydrolytic activity, the determining role was played not the total number carbon atoms in the alcohol molecule, but by the "effective length" of the carbohydrate chain. The fact that the presence of alcohols did not affect parameters of the reverse cholinesterase inhibition with onium ions tetramethylammonium and choline allows suggesting the absence of effect solvents on specific acetylcholine sorption in the enzyme active center. With aid of two rows of hydrophobic organophosphorus inhibitors (OPI), we have managed to estimate both the degree and the character itself of the modifying action of alcohols and pH on the process of irreversible inhibition of serum cholinesterase.

  4. Serum Acetyl Cholinesterase as a Biomarker of Arsenic Induced Neurotoxicity in Sprague-Dawley Rats

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    Paul B. Tchounwou

    2005-04-01

    Full Text Available Arsenic is an environmental toxicant, and one of the major mechanisms by which it exerts its toxic effect is through an impairment of cellular respiration by inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Recent studies have pointed out that arsenic toxicity is associated with the formation of reactive oxygen species, which may cause severe injury/damage to the nervous system. The main objective of this study was to conduct biochemical analysis to determine the effect of arsenic trioxide on the activity of acetyl cholinesterase; a critical important nervous system enzyme that hydrolyzes the neurotransmitter acetylcholine. Four groups of six male rats each weighing an average 60 + 2 g were used in this study. Arsenic trioxide was intraperitoneally administered to the rats at the doses of 5, 10, 15, 20mg/kg body weight (BW, one dose per 24 hour given for five days. A control group was also made of 6 animals injected with distilled water without chemical. Following anaesthesia, blood specimens were immediately collected using heparinized syringes, and acetyl cholinesterase detection and quantification were performed in serum samples by spectrophotometry. Arsenic trioxide exposure significantly decreased the activity of cholinesterase in the Sprague-Dawley rats. Acetyl cholinesterase activities of 6895 + 822, 5697 + 468, 5069 + 624, 4054 + 980, and 3158 + 648 U/L were recorded for 0, 5, 10, 15, and 20 mg/kg, respectively; indicating a gradual decrease in acetyl cholinesterase activity with increasing doses of arsenic. These findings indicate that acetyl

  5. Inhibition kinetics of human serum butyrylcholinesterase by Cd2+, Zn2+ and Al3+: comparison of the effects of metal ions on cholinesterases

    International Nuclear Information System (INIS)

    Sarkarati, B.; Cokugras, A.N.; Tezcan, E.F.

    1999-01-01

    Butyrylcholinesterase (BChE, EC 3.1.1.8) has been purified about 6600-fold from human serum with a procedure including ammonium sulfate fractionation (55-70%) with acid step at pH 4.5 and procainamide-Sepharose 4B affinity chromatography. The purified enzyme exhibited negative cooperativity with respect to butyrylthiocholine (BTCh) binding at pH 7.5. K S was found to be 0.128±0.012 mM. Inhibition kinetics of the enzyme by Cd 2+ , Zn 2+ and Al 3+ were studied in detail. The 1/v vs 1/[BTCh] plots in the absence (control plot) and in the presence of different concentrations of cations intersected above 1/[BTCh]-axis. The data were analyzed by means of a nonlinear curve fitting program. The results demonstrated that all of the three cations are the linear mixed-type inhibitors of BChE. Ca 2+ and Mg 2+ had no effect on the enzyme activity in the experimental conditions. But when the enzyme was inhibited by 0.5 mM Cd 2+ or Zn 2+ , Ca 2+ and Mg 2+ partially reactivated the inhibited allosteric form of BChE. Results were compared with data obtained from brain BChE purified from sheep. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

  6. Diethyl 2-(Phenylcarbamoylphenyl Phosphorothioates: Synthesis, Antimycobacterial Activity and Cholinesterase Inhibition

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    Jarmila Vinšová

    2014-05-01

    Full Text Available A new series of 27 diethyl 2-(phenylcarbamoylphenyl phosphorothioates (thiophosphates was synthesized, characterized by NMR, IR and CHN analyses and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and two strains of Mycobacterium kansasii. The best activity against M. tuberculosis was found for O-{4-bromo-2-[(3,4-dichlorophenylcarbamoyl]phenyl} O,O-diethyl phosphorothioate (minimum inhibitory concentration of 4 µM. The highest activity against nontuberculous mycobacteria was exhibited by O-(5-chloro-2-{[4-(trifluoromethylphenyl]carbamoyl}-phenyl O,O-diethyl phosphorothioate with MIC values from 16 µM. Prepared thiophosphates were also evaluated against acetylcholinesterase from electric eel and butyrylcholinesterase from equine serum. Their inhibitory activity was compared to that of the known cholinesterases inhibitors galanthamine and rivastigmine. All tested compounds showed a higher (for AChE inhibition and comparable (for BChE inhibition activity to that of rivastigmine, with IC50s within the 8.04 to 20.2 µM range.

  7. Native and tabun-inhibited cholinesterase interactions with oximes

    International Nuclear Information System (INIS)

    Kovarik, Z.; Katalinic, M.; Sinko, G.

    2009-01-01

    The phosphorylation of the serine hydroxyl group in the active site of acetylcholinesterase (AChE) inactivates this essential enzyme in neurotransmission. Its related enzyme butyrylcholinesterase (BChE) also interacts with organophosphorus compounds (OP) scavenging anti-cholinesterase agents and protects synaptic AChE from inhibition. Oximes are reactivators of AChE phosphorylated by OP including insecticides and nerve agents. The effectiveness of oxime-assisted reactivation is primarily attributed to the nucleophilic displacement rate of organophosphate, but efficiency varies with the structure of the bound organophosphate, the structure of the oxime as well as rates of several other cholinesterase's reactions. Besides reactivating cholinesterases, oximes also reversibly inhibit both cholinesterases and protect them from phosphorylation by OP. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE and plasma BChE. Herein we bring an overview of in vitro interactions of native and tabun-inhibited AChE and BChE with oximes together with conformational analysis of the oximes relating molecular properties to their reactivation potency.(author)

  8. Assessment of serum level cholinesterase as a biomarker of liver cirrhosis in Egyptian cirrhotic patients

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    Mona A. Amin

    2017-09-01

    Full Text Available Serum cholinesterase levels are closely correlated with the severity of liver disease. The aim of the paper was to assess the value of serum cholinesterase in evaluating liver reserve function in cirrhotic patients. 90 patients with liver cirrhosis and thirty healthy control group were included. Liver cirrhosis patients were classified according to child score into three equal groups: Child A liver cirrhosis, Child B liver cirrhosis and Child C liver cirrhosis. Patients were subjected to clinical evaluation, laboratory analysis, abdominal U/S. Measuring serum cholinesterase, and Calculation of both Child and model of end stage liver disease (MELD scores. The level of serum cholinesterase was higher in control group than the three groups of liver cirrhosis with median (IQR 17,410 (12,111-21,774, 7528 (5200-9856, 6021 (4500-7542, 3828.5 (1541-6060, respectively P<0.001. And the level of serum cholinesterase was higher in Child A more than Child B and Child C and the level of serum cholinesterase was higher in Child B more than Child C with very strong negative correlation between serum Cholinesterase level and Child score (r=-0.9, P<0.001. Also strong negative correlation between serum Cholinesterase level and MELD score (r=- 0.85, P=0.001, and positive correlation with prothrombin concentration (r=0.554, P=0.009, and serum albumin levels (r=0.582, P=0.0002. Serum cholinesterase is a good biomarker of cirrhosis. Since it distinguishes decompensated from compensated cirrhosis well, low levels in cirrhosis may serve as a useful prognostic marker of advanced liver disease.

  9. Inhibition of cholinesterase by essential oil from food plant.

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    Chaiyana, Wantida; Okonogi, Siriporn

    2012-06-15

    Inhibition of cholinesterase has attracted much attention recently because of its potential for the treatment of Alzheimer's disease. In this work, the anticholinesterase activities of plant oils were investigated using Ellman's colorimetric method. The results indicate that essential oils obtained from Melissa officinalis leaf and Citrus aurantifolia leaf showed high acetylcholinesterase and butyrylcholinesterase co-inhibitory activities. C. aurantifolia leaf oil revealed in this study has an IC(50) value on acetylcholinesterase and butyrylcholinesterase of 139 ± 35 and 42 ± 5 μg/ml, respectively. GC/MS analysis revealed that the major constituents of C. aurantifolia leaf oil are monoterpenoids including limonene, l-camphor, citronellol, o-cymene and 1,8-cineole. Copyright © 2012 Elsevier GmbH. All rights reserved.

  10. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

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    Magdalena Markowicz-Piasecka

    2017-01-01

    Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  11. Exposure of nonbreeding migratory shorebirds to cholinesterase-inhibiting contaminants in the western hemisphere

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    Strum, K.M.; Hooper, M.J.; Johnson, K.A.; Lanctot, Richard B.; Zaccagnini, M.E.; Sandercock, B.K.

    2010-01-01

    Migratory shorebirds frequently forage and roost in agricultural habitats, where they may be exposed to cholinesterase-inhibiting pesticides. Exposure to organophosphorus and carbamate compounds, common anti-cholinesterases, can cause sublethal effects, even death. To evaluate exposure of migratory shorebirds to organophosphorus and carbamates, we sampled birds stopping over during migration in North America and wintering in South America. We compared plasma cholinesterase activities and body masses of individuals captured at sites with no known sources of organophosphorus or carbamates to those captured in agricultural areas where agrochemicals were recommended for control of crop pests. In South America, plasma acetylcholinesterase and butyrylcholinesterase activity in Buff-breasted Sandpipers was lower at agricultural sites than at reference sites, indicating exposure to organophosphorus and carbamates. Results of plasma cholinesterase reactivation assays and foot-wash analyses were inconclusive. A meta-analysis of six species revealed no widespread effect of agricultural chemicals on cholinesterase activity. however, four of six species were negative for acetylcholinesterase and one of six for butyrylcholinesterase, indicating negative effects of pesticides on cholinesterase activity in a subset of shorebirds. Exposure to cholinesterase inhibitors can decrease body mass, but comparisons between treatments and hemispheres suggest that agrochemicals did not affect migratory shorebirds' body mass. Our study, one of the first to estimate of shorebirds' exposure to cholinesterase-inhibiting pesticides, suggests that shorebirds are being exposed to cholinesterase- inhibiting pesticides at specific sites in the winter range but not at migratory stopover sites. future research should examine potential behavioral effects of exposure and identify other potential sitesand levels of exposure. ?? The Cooper Ornithological Society 2010.

  12. Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

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    Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

    2014-11-01

    Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice

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    Andrea R. Durrant

    2012-06-01

    Full Text Available The cholinesterases, acetylcholinesterase and butyrylcholinesterase (pseudocholinesterase, are abundant in the nervous system and in other tissues. The role of acetylcholinesterase in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates acetylcholinesterase and butyrylcholinesterase in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While acetylcholinesterase in mdx-sera is elevated, butyrylcholinesterase is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T is a negative modulator of butyrylcholinesterase, but not of acetylcholinesterase, in male mouse sera. T-removal elevated both butyrylcholinesterase activity and the butyrylcholinesterase/acetylcholinesterase ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.

  14. Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

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    Wright, C I; Guela, C; Mesulam, M M

    1993-01-01

    Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease. Images PMID:8421706

  15. Arylesterase Phenotype-Specific Positive Association Between Arylesterase Activity and Cholinesterase Specific Activity in Human Serum

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    Yutaka Aoki

    2014-01-01

    Full Text Available Context: Cholinesterase (ChE specific activity is the ratio of ChE activity to ChE mass and, as a biomarker of exposure to cholinesterase inhibitors, has a potential advantage over simple ChE activity. Objective: To examine the association of several potential correlates (serum arylesterase/paraoxonase activity, serum albumin, sex, age, month of blood collection, and smoking with plasma ChE specific activity. Methods: We analyzed data from 195 cancer-free controls from a nested case-control study, accounting for potential confounding. Results: Arylesterase activity had an independent, statistically significant positive association with ChE specific activity, and its magnitude was the greatest for the arylesterase phenotype corresponding to the QQ PON1192 genotype followed by phenotypes corresponding to QR and RR genotypes. Serum albumin was positively associated with ChE specific activity. Conclusions: Plasma arylesterase activity was positively associated with plasma ChE specific activity. This observation is consistent with protection conferred by a metabolic phenotype resulting in reduced internal dose.

  16. Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy.

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    Niebroj-Dobosz, I; Hausmanowa-Petrusewicz, I

    1989-09-01

    Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in infantile and juvenile spinal muscular atrophy (SMA) was determined. The total AChE activity was either normal or decreased in the childhood SMA (Type 1), the other SMA groups and disease controls (ALS, X-linked SMA). In the majority of SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found. This was accompanied by changes in the other asymmetric and globular forms. The latter was, however, not specific for SMA Type 1 cases. The ChE activity was increased in the majority of SMA cases as well as disease controls. The asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes is obscure.

  17. A new method to characterize the kinetics of cholinesterases inhibited by carbamates.

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    Xiao, Qiaoling; Zhou, Huimin; Wei, Hong; Du, Huaqiao; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

    2017-09-10

    The inhibition of cholinesterases (ChEs) by carbamates includes a carbamylation (inhibition) step, in which the drug transfers its carbamate moiety to the active site of the enzyme and a decarbamylation (activity recovery) step, in which the carbamyl group is hydrolyzed from the enzyme. The carbamylation and decarbamylation kinetics decide the extent and the duration of the inhibition, thus the full characterization of candidate carbamate inhibitors requires the measurement of the kinetic constants describing both steps. Carbamylation and decarbamylation rate constants are traditionally measured by two separate set of experiments, thus making the full characterization of candidate inhibitors time-consuming. In this communication we show that by the analysis of the area under the inhibition-time curve of cholinesterases inhibited by carbamates it is possible to calculate the decarbamylation rate constant from the same data traditionally used to characterize only the carbamylation kinetics, therefore it is possible to obtain a full characterization of the inhibition with a single set of experiments. The characterization of the inhibition kinetics of human and dog plasma butyrylcholinesterase and of human acetylcholinesterase by bambuterol and bambuterol monocarbamate enantiomers was used to demonstrate the validity of the approach. The results showed that the proposed method provides reliable estimations of carbamylation and decarbamylation rate constants thus representing a simple and useful approach to reduce the time required for the characterization of carbamate inhibitors. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Estimation of plasma tacrine concentrations using an in vitro cholinesterase inhibition assay

    International Nuclear Information System (INIS)

    Moriearty, P.L.; Kenny, W.; Kumar, V.

    1989-01-01

    THA (9-amino, 1,2,3,4-tetrahydroacridine; tacrine) is currently under study as a cholinesterase (ChE) inhibitor in Alzheimer disease. In this study, a sensitive radiometric assay for THA inhibition of human plasma ChE, suitable for detection of effects of orally administered drug, is described. The assay is sensitive in a range of 4-50 ng/ml plasma. Reversibility of the inhibition permits distinguishing of drug effects on ChE from changes in amount of enzyme synthesized during treatment

  19. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats

    International Nuclear Information System (INIS)

    Ray, A.; Liu, J.; Karanth, S.; Gao, Y.; Brimijoin, S.; Pope, C.

    2009-01-01

    We evaluated the inhibition of striatal cholinesterase activity following intracerebral administration of paraoxon assaying activity either in tissue homogenates ex vivo or by substrate hydrolysis in situ. Artificial cerebrospinal fluid (aCSF) or paraoxon in aCSF was infused unilaterally (0.5 μl/min for 2 h) and ipsilateral and contralateral striata were harvested for ChE assay ex vivo. High paraoxon concentrations were needed to inhibit ipsilateral striatal cholinesterase activity (no inhibition at < 0.1 mM; 27% at 0.1 mM; 79% at 1 mM paraoxon). With 3 mM paraoxon infusion, substantial ChE inhibition was also noted in contralateral striatum. ChE histochemistry generally confirmed these concentration- and side-dependent effects. Microdialysates collected for up to 4 h after paraoxon infusion inhibited ChE activity when added to striatal homogenate, suggesting prolonged efflux of paraoxon. Since paraoxon efflux could complicate acetylcholine analysis, we evaluated the effects of paraoxon (0, 0.03, 0.1, 1, 10 or 100 μM, 1.5 μl/min for 45 min) administered by reverse dialysis through a microdialysis probe. ChE activity was then monitored in situ by perfusing the colorimetric substrate acetylthiocholine through the same probe and measuring product (thiocholine) in dialysates. Concentration-dependent inhibition was noted but reached a plateau of about 70% at 1 μM and higher concentrations. Striatal acetylcholine was below the detection limit at all times with 0.1 μM paraoxon but was transiently elevated (0.5-1.5 h) with 10 μM paraoxon. In vivo paraoxon (0.4 mg/kg, sc) in adult rats elicited about 90% striatal ChE inhibition measured ex vivo, but only about 10% inhibition measured in situ. Histochemical analyses revealed intense AChE and glial fibrillary acidic protein staining near the cannula track, suggesting proliferation of inflammatory cells/glia. The findings suggest that ex vivo and in situ cholinesterase assays can provide very different views into enzyme

  20. Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: a kinetics-molecular modeling approach.

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    Torres, Juliana M; Lira, Aline F; Silva, Daniel R; Guzzo, Lucas M; Sant'Anna, Carlos M R; Kümmerle, Arthur E; Rumjanek, Victor M

    2012-09-01

    The natural indole alkaloids, the β-carbolines, are often associated with cholinesterase inhibition, especially their quaternary salts, which frequently have higher activity than the free bases. Due to lack of information explaining this fact in the literature, the cholinesterase inhibition by the natural product harmane and its two β-carbolinium synthetic derivative salts (N-methyl and N-ethyl) was explored, together with a combination of kinetics and a molecular modeling approach. The results, mainly for the β-carbolinium salts, demonstrated a noncompetitive inhibition profile, ruling out previous findings which associated cholinesterase inhibition by β-carbolinium salts to a possible mimicking of the choline moiety of the natural substrate, acetylcholine. Molecular modeling studies corroborate this kind of inhibition through analyses of inhibitor/enzyme and inhibitor/substrate/enzyme complexes of both enzymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. The reactivation effect of pralidoxime in human blood on parathion and paraoxon–induced cholinesterase inhibition

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    Mahvash Jafari

    2006-03-01

    Full Text Available In this investigation the reactivation of cholinesterases by pralidoxime in parathion and paraoxon intoxication in plasma and erythrocytes were studied. For this purpose, human plasma and erythrocytes were incubated with various concentrations of parathion (0.1-10 µM and paraoxon (0.03-0.3 µM at 37 oC for 10 min. Then, pralidoxime (10-300 µM was added to the samples and incubated for 10 min before cholinesterases assay. The results showed that effects of parathion and paraoxon were dose dependent. These agents inhibited more than 85% of butyrylcholinesterase (BChE and acetylcholinesterase (AChE activity and the inhibitory effect of paraoxon was 10 times more than parathion. BChE activity was significantly higher than the control at 100 µM of pralidoxime and it reduced inhibitory effects of parathion to less than 50% and of paraoxon to 42% of control. When pralidoxime (10 µM was added to erythrocytes, the inhibitory effects of two organophosphates were reduced to less than 15%. At higher concentrations of pralidoxime (>100 µM, both BChE and AChE activities were inhibited.

  2. Modulation of fusiform cortex activity by cholinesterase inhibition predicts effects on subsequent memory.

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    Bentley, P; Driver, J; Dolan, R J

    2009-09-01

    Cholinergic influences on memory are likely to be expressed at several processing stages, including via well-recognized effects of acetylcholine on stimulus processing during encoding. Since previous studies have shown that cholinesterase inhibition enhances visual extrastriate cortex activity during stimulus encoding, especially under attention-demanding tasks, we tested whether this effect correlates with improved subsequent memory. In a within-subject physostigmine versus placebo design, we measured brain activity with functional magnetic resonance imaging while healthy and mild Alzheimer's disease subjects performed superficial and deep encoding tasks on face (and building) visual stimuli. We explored regions in which physostigmine modulation of face-selective neural responses correlated with physostigmine effects on subsequent recognition performance. In healthy subjects physostigmine led to enhanced later recognition for deep- versus superficially-encoded faces, which correlated across subjects with a physostigmine-induced enhancement of face-selective responses in right fusiform cortex during deep- versus superficial-encoding tasks. In contrast, the Alzheimer's disease group showed neither a depth of processing effect nor restoration of this with physostigmine. Instead, patients showed a task-independent improvement in confident memory with physostigmine, an effect that correlated with enhancements in face-selective (but task-independent) responses in bilateral fusiform cortices. Our results indicate that one mechanism by which cholinesterase inhibitors can improve memory is by enhancing extrastriate cortex stimulus selectivity at encoding, in a manner that for healthy people but not in Alzheimer's disease is dependent upon depth of processing.

  3. Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.

    Science.gov (United States)

    Tsurkan, Lyudmila G; Hatfield, M Jason; Edwards, Carol C; Hyatt, Janice L; Potter, Philip M

    2013-03-25

    Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms. We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer's disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  4. Quantitative estimation of cholinesterase-specific drug metabolism of carbamate inhibitors provided by the analysis of the area under the inhibition-time curve.

    Science.gov (United States)

    Zhou, Huimin; Xiao, Qiaoling; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

    2017-09-10

    Several molecules containing carbamate groups are metabolized by cholinesterases. This metabolism includes a time-dependent catalytic step which temporary inhibits the enzymes. In this paper we demonstrate that the analysis of the area under the inhibition versus time curve (AUIC) can be used to obtain a quantitative estimation of the amount of carbamate metabolized by the enzyme. (R)-bambuterol monocarbamate and plasma butyrylcholinesterase were used as model carbamate-cholinesterase system. The inhibition of different concentrations of the enzyme was monitored for 5h upon incubation with different concentrations of carbamate and the resulting AUICs were analyzed. The amount of carbamate metabolized could be estimated with cholinesterases in a selected compartment in which the cholinesterase is confined (e.g. in vitro solutions, tissues or body fluids), either in vitro or in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Cholinesterase-based biosensors.

    Science.gov (United States)

    Štěpánková, Šárka; Vorčáková, Katarína

    2016-01-01

    Recently, cholinesterase-based biosensors are widely used for assaying anticholinergic compounds. Primarily biosensors based on enzyme inhibition are useful analytical tools for fast screening of inhibitors, such as organophosphates and carbamates. The present review is aimed at compilation of the most important facts about cholinesterase based biosensors, types of physico-chemical transduction, immobilization strategies and practical applications.

  6. Inhibition on cholinesterase and tyrosinase by alkaloids and phenolics from Aristotelia chilensis leaves.

    Science.gov (United States)

    Cespedes, Carlos L; Balbontin, Cristian; Avila, Jose G; Dominguez, Mariana; Alarcon, Julio; Paz, Cristian; Burgos, Viviana; Ortiz, Leandro; Peñaloza-Castro, Ignacio; Seigler, David S; Kubo, Isao

    2017-11-01

    It is reported in this study the effect of isolates from leaves of Aristotelia chilensis as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes. The aim of the paper was to evaluate the activity of A. chilensis towards different enzymes. In addition to pure compounds, extracts rich in alkaloids and phenolics were tested. The most active F5 inhibited AChE (79.5% and 89.8% at 10.0 and 20.0 μg/mL) and against BChE (89.5% and 97.8% at 10.0 and 20.0 μg/mL), showing a strong mixed-type inhibition against AChE and BChE. F3 (a mixture of flavonoids and phenolics acids), showed IC 50 of 90.7 and 59.6 μg/mL of inhibitory activity against AChE and BChE, inhibiting the acetylcholinesterase competitively. Additionally, F3 showed and high potency as tyrosinase inhibitor with IC 50 at 8.4 μg/mL. Sample F4 (anthocyanidins and phenolic composition) presented a complex, mixed-type inhibition of tyrosinase with a IC 50 of 39.8 μg/mL. The findings in this investigation show that this natural resource has a strong potential for future research in the search of new phytotherapeutic treatments for cholinergic deterioration ailments avoiding the side effects of synthetic drugs. This is the first report as cholinesterases and tyrosinase inhibitors of alkaloids and phenolics from A. chilensis leaves. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment

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    Radosław Świercz

    2013-08-01

    Full Text Available Background: Organophosphates are cholinesterase (ChE inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP poisoning symptomatology. In rodents, corticosterone (CORT is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT response and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET [2-methyl-1,2-di(pyridin-3-ylpropan-1-one] blocks CORT synthesis by inhibiting steoid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP [2-chloro-1-(2,4-dichlorophenyl ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. Material and Methods: The purose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. Conclusion: The following was observed in the MET-treated rats: i no rise in plasma CORT concentration after the CVP administration, ii a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  8. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet

    Directory of Open Access Journals (Sweden)

    Dimitrov Mitko

    2009-08-01

    Full Text Available Abstract Background N,N-Diethyl-3-methylbenzamide (deet remains the gold standard for insect repellents. About 200 million people use it every year and over 8 billion doses have been applied over the past 50 years. Despite the widespread and increased interest in the use of deet in public health programmes, controversies remain concerning both the identification of its target sites at the olfactory system and its mechanism of toxicity in insects, mammals and humans. Here, we investigated the molecular target site for deet and the consequences of its interactions with carbamate insecticides on the cholinergic system. Results By using toxicological, biochemical and electrophysiological techniques, we show that deet is not simply a behaviour-modifying chemical but that it also inhibits cholinesterase activity, in both insect and mammalian neuronal preparations. Deet is commonly used in combination with insecticides and we show that deet has the capacity to strengthen the toxicity of carbamates, a class of insecticides known to block acetylcholinesterase. Conclusion These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health.

  9. Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity.

    Science.gov (United States)

    Karasova, Jana Zdarova; Hroch, Milos; Musilek, Kamil; Kuca, Kamil

    2016-02-01

    Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 54.96 ng/ml) after i.m. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent π-π or π-cationic interaction aside at the AChE catalytic site.

  10. Divergent effects of postmortem ambient temperature on organophosphorus- and carbamate-inhibited brain cholinesterase activity in birds

    Science.gov (United States)

    Hill, E.F.

    1989-01-01

    Time- and temperature-dependent postmortem changes in inhibited brain cholinesterase (ChE) activity may confound diagnosis of field poisoning of wildlife by anticholinesterase pesticide. Carbamate-inhibited ChE activity may return to normal within 1 to 2 days of exposure of intact carcass to moderate ambient temperature (18-32C). Organophosphorus-inhibited ChE activity becomes more depressed over the same time. Uninhibited ChE activity was resilient to above freezing temperature to 32C for 1 day and 25C for 3 days. Carbamate- and organophosphorus-inhibited ChE can be separated by incubation of homogenate for 1 hour at physiological temperatures; carbamylated ChE can be readily reactivated while phosphorylated ChE cannot.

  11. Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health

    OpenAIRE

    Bentley, P.; Driver, J.; Dolan, R. J.

    2008-01-01

    Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject plac...

  12. DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS BY PHYSOSTIGMINE, CARBARYL AND PROPOXUR AND THE RELATIONSHIP TO INHIBITION OF BRAIN CHOLINESTERASE

    Science.gov (United States)

    The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physo...

  13. Cholinesterase Inhibition and Depression of the Photic After Discharge of Flash Evoked Potentials Following Acute or Repeated Exposures to a Mixture of Carbaryl and Propoxur

    Science.gov (United States)

    While information exists regarding inhibition of cholinesterase (ChE) activity, little is known about neurophysiological changes produced by a mixture of N-methyl carbamate pesticides. Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration o...

  14. Inhibition of Cholinesterases and Some Pro-Oxidant induced Oxidative Stress in Rats Brain by Two Tomato (Lycopersicon Esculentum) Varieties

    Science.gov (United States)

    Oboh, G.; Bakare, O.O.; Ademosun, A.O.; Akinyemi, A.J.; Olasehinde, T.A.

    2015-01-01

    This study sought to investigate the effects of two tomato varieties [Lycopersicon esculentum Mill. var. esculentum (ESC) and Lycopersicon esculentum Mill. var. cerasiforme (CER)] on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities in vitro. Phenolics content, carotenoids characterisation, inhibition of Fe2+ and quinolinic acid-induced malondialdehyde (MDA) production in rats brain homogenate and NO* scavenging abilities were also assesed in addition to the AChE and BChE inhibition assays. There was no significant difference in the AChE inhibitory ability of the samples, while CER had significantly higher BChE inhibitory activity. Furthermore, the tomatoes inhibited Fe2+ and quinolinic acid-induced MDA production and further exhibited antioxidant activities through their NO* scavenging abilities. There was no significant difference in the phenolic content of the samples, while significantly high amounts of lycopene were detected in the tomatoes. The cholinesterase-inhibition and antioxidant properties of the “tomatoes” could make them good dietary means for the management of neurodegenerative disorders.

  15. Serum Total Cholinesterase Activity on Admission Is Associated with Disease Severity and Outcome in Patients with Traumatic Brain Injury.

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    Qing-Hong Zhang

    Full Text Available Traumatic brain injury (TBI is one of the leading causes of neurological disability. In this retrospective study, serum total cholinesterase (ChE activities were analyzed in 188 patients for diagnostic as well as predictive values for mortality.Within 72 hours after injury, serum ChE activities including both acetylcholinesterase and butyrylcholinesterase were measured. Disease severity was evaluated with Acute Physiology and Chronic Health Evaluation (APACHE II score, Glasgow Coma Score, length of coma, post-traumatic amnesia and injury feature. Neurocognitive and functional scores were assessed using clinical records. Of 188 patients, 146 (77.7% survived and 42 (22.3% died within 90 days. Lower ChE activities were noted in the non-survivors vs. survivors (5.94±2.19 vs. 7.04±2.16 kU/L, p=0.023, in septic vs. non-infected patients (5.93±1.89 vs. 7.31±2.45 kU/L, p=0.0005 and in patients with extremely severe injury vs. mild injury (6.3±1.98 vs. 7.57±2.48 kU/L, p=0.049. The trajectories of serum ChE levels were also different between non-survivors and survivors, septic and non-infected patients, mild and severely injured patients, respectively. Admission ChE activities were closely correlated with blood cell counts, neurocognitive and functional scores both on admission and at discharge. Receiver operating characteristic analysis showed that the area under the curve for ChE was inferior to that for either APACHE II or white blood cell (WBC count. However, at the optimal cutoff value of 5 kU/L, the sensitivity of ChE for correct prediction of 90-day mortality was 65.5% and the specificity was 86.4%. Kaplan-Meier analysis showed that lower ChE activity (5 kU/L (p=0.04. After adjusting for other variables, ChE was identified as a borderline independent predictor for mortality as analyzed by Binary logistic regression (P=0.078.Lowered ChE activity measured on admission appears to be associated with disease severity and outcome for TBI patients.

  16. Antioxidant activity and cholinesterase inhibition studies of four flavouring herbs from Alentejo.

    Science.gov (United States)

    Arantes, Sílvia; Piçarra, Andreia; Candeias, Fátima; Caldeira, A Teresa; Martins, M Rosário; Teixeira, Dora

    2017-09-01

    Essential oils (EOs) and aqueous extracts of aerial parts of four aromatic species, Calamintha nepeta, Foeniculum vulgare, Mentha spicata and Thymus mastichina, from southwest of Portugal were characterised chemically and analysed in order to evaluate their antioxidant potential and cholinesterase inhibitory activities. The main components of EOs were oxygenated monoterpenes, and aqueous extracts were rich in phenol and flavonoid compounds. EOs and aqueous extracts presented a high antioxidant potential, with ability to protect the lipid substrate, free radical scavenging and iron reducing power. Furthermore, EOs and extracts showed AChE and BChE inhibitory activities higher than rivastigmine, the standard drug. Results suggested the potential use of EOs and aqueous extracts of these flavouring herbs as nutraceutical or pharmaceutical preparations to minimise the oxidative stress and the progression of degenerative diseases.

  17. Effects of Agricultural Management Policies on the Exposure of Black-Winged Stilts (Himantopus himantopus Chicks to Cholinesterase-Inhibiting Pesticides in Rice Fields.

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    Gregorio M Toral

    Full Text Available Levels of exposure to pesticides in rice fields can be significant depending on the environmental policies practiced. The aim of European Union integrated management policy is to reduce pesticide use and impact on environment. Rice fields provide an alternative breeding habitat for many waterbirds that are exposed to the pesticides used and therefore can be valuable indicators of their risk for wildlife. To evaluate integrated management success we examined exposure of Black-winged Stilts (Himantopus himantopus to cholinesterase-inhibiting pesticides in rice fields under different types of management by measuring plasma cholinesterase activity. Cholinesterase activity was lower in birds sampled in (a 2008 after a period of intense pesticide application, than in (b 2005-2007 and 2011 in rice fields subject to integrated management in Doñana (SW Spain and (c in control natural wetlands in Spain and Morocco. During 2009 and 2010, cholinesterase activity was lower in rice fields in Doñana than in rice fields in Larache and Sidi Allal Tazi (NW Morocco. Our results suggest that integrated management successfully reduced the exposure of Black-winged Stilts to pesticides in most of the years. Care should be taken to implement mosquito and pest crop controls on time and with environmentally friendly products in order to reduce its impact on wildlife.

  18. Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry

    International Nuclear Information System (INIS)

    Carletti, Eugenie; Santoni, Gianluca; Colletier, Jacques-Philippe; Schopfer, Lawrence M.; Lockridge, Oksana; Masson, Patrick; Nachon, Florian; Weik, Martin

    2013-01-01

    Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aero-toxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bio-scavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 Angstroms snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H 2 16 O or H 2 18 O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP. (authors)

  19. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae

    Directory of Open Access Journals (Sweden)

    Freylan Mena Torres

    2012-03-01

    Full Text Available Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE, glutathione S-transferase (GST and lipid peroxidation (LPO are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus were exposed to the organophosphorus nematicide, ethoprophos. Acute (96hr exposure was conducted with pesticide concentrations ranging from 0.1μg/L to 1 500μg/L. The 96hr LC50 calculated was 859.7μg/L. After exposure, three biomarkers (ChE, GST and LPO were analyzed in fish that survived the acute test. The lowest observed effect concentration (LOEC regarding ChE activity inhibition was 50μg/L. This concentration produced a significant inhibition (p0.05 in GST activity and LPO were observed in A. tropicus larvae after exposure to ethoprophos.

  20. Differential swimming performance of two natricine snakes exposed to a cholinesterase-inhibiting pesticide

    International Nuclear Information System (INIS)

    Hopkins, W.A.; Winne, C.T.; DuRant, S.E.

    2005-01-01

    Environmental contaminants have direct effects on organisms at the molecular, cellular, and tissue levels, but the net results of these sub-organismal effects are only consequential to exposed populations if they alter organism-level traits that ultimately influence fitness (e.g., growth, locomotor performance, reproduction, and survival). Here, we explore the possibility that the swimming performance of neonate black swamp snakes (Seminatrix pygaea) and diamondback water snakes (Nerodia rhombifer) may be affected by exposure to carbaryl (2.5 and 5.0 mg/L). The highest concentration of carbaryl caused greater reductions in swim velocity in S. pygaea than in N. rhombifer. Most individuals recovered from the effects of carbaryl on swimming performance within 96 h, but recovery was significantly slower in S. pygaea than in N. rhombifer. We hypothesize that the sensitivity of S. pygaea may arise from its highly permeable integument compared to other natricines. Our findings suggest that performance can serve as an ecologically relevant response to contaminant exposure in reptiles and warrants further study. - Exposure to a cholinesterase inhibitor reduces swimming velocity in snakes

  1. Differential swimming performance of two natricine snakes exposed to a cholinesterase-inhibiting pesticide

    Energy Technology Data Exchange (ETDEWEB)

    Hopkins, W.A. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States)]. E-mail: hopkins@srel.edu; Winne, C.T. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States); DuRant, S.E. [University of Georgia, Savannah River Ecology Laboratory, Wildlife Ecotoxicology and Physiological Ecology Program, PO Drawer E, Aiken, SC 29802 (United States)

    2005-02-01

    Environmental contaminants have direct effects on organisms at the molecular, cellular, and tissue levels, but the net results of these sub-organismal effects are only consequential to exposed populations if they alter organism-level traits that ultimately influence fitness (e.g., growth, locomotor performance, reproduction, and survival). Here, we explore the possibility that the swimming performance of neonate black swamp snakes (Seminatrix pygaea) and diamondback water snakes (Nerodia rhombifer) may be affected by exposure to carbaryl (2.5 and 5.0 mg/L). The highest concentration of carbaryl caused greater reductions in swim velocity in S. pygaea than in N. rhombifer. Most individuals recovered from the effects of carbaryl on swimming performance within 96 h, but recovery was significantly slower in S. pygaea than in N. rhombifer. We hypothesize that the sensitivity of S. pygaea may arise from its highly permeable integument compared to other natricines. Our findings suggest that performance can serve as an ecologically relevant response to contaminant exposure in reptiles and warrants further study. - Exposure to a cholinesterase inhibitor reduces swimming velocity in snakes.

  2. Plasma cholinesterase inhibition in the clay-colored robin (Turdus grayi) exposed to diazinon in maradol papaya crops in Yucatan, Mexico

    Science.gov (United States)

    Cobos, V.M.; Mora, M.A.; Escalona, G.

    2006-01-01

    The use of organophosphorous pesticides in agriculture can result in intoxication of birds foraging in sprayed crops. Effects on birds resulting from pesticide intoxication are varied and include behavioral and reproductive effects, including death. One widely used insecticide in Maradol papaya crops is diazinon which has been associated with various incidents of intoxication and death of wild birds. The objective of this study was to evaluate the impact of diazinon application to papaya crops on plasma cholinesterase activity of the clay-colored robin (Turdus grayi). We captured clay-colored robins foraging in a papaya crop the following day after the field had been sprayed with diazinon at a dose of 1.5 kg/ha during March and May, respectively. We took a blood sample from the brachialis vein of the birds captured and measured plasma enzymatic activity. The plasma samples from birds used as controls were taken during the same time period and were analyzed in a similar way. Enzymatic activity of males was greater than that of females (53,52%) and mean cholinesterase inhibition was 49.43%. Cholinesterase inhibition was greater during May than in March probably due to more continuous exposure and ingestion of the insecticide through food and possible absorption through the skin. This degree of enzymatic inhibition is possibly affecting the behavior of the clay-colored robin and could result in death in severe cases.

  3. Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health.

    Science.gov (United States)

    Bentley, Paul; Driver, Jon; Dolan, Ray J

    2008-02-01

    Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visuo-attentional processing would be impaired relative to controls, yet partially susceptible to improvement with the cholinesterase inhibitor physostigmine. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of effects of physostigmine on stimulus- and attention- related brain activations, plus between-group comparisons for these. Subjects viewed face or building stimuli while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed slower than controls in both tasks, while physostigmine benefited the patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in patients relative to controls, but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed physostigmine-induced enhancement of stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased stimulus and task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. The differences in brain activations between groups and treatments were not attributable merely to performance (reaction time) differences. Our results demonstrate

  4. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur

    International Nuclear Information System (INIS)

    Padilla, S.; Marshall, R.S.; Hunter, D.L.; Lowit, A.

    2007-01-01

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n = 4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r 2 = 0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r 2 = 0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides

  5. Inhibition of cholinesterase activity by extracts, fractions and compounds from Calceolaria talcana and C. integrifolia (Calceolariaceae: Scrophulariaceae).

    Science.gov (United States)

    Cespedes, Carlos L; Muñoz, Evelyn; Salazar, Juan R; Yamaguchi, Lydia; Werner, Enrique; Alarcon, Julio; Kubo, Isao

    2013-12-01

    Extracts, fractions and compounds from Calceolaria talcana and C. integrifolia exhibited strong inhibitory effects of the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes using the in vitro Ellman's method. The most active samples were from the ethyl acetate extract, which caused a mixed-type inhibition against AChE (69.8% and 79.5% at 100 and 200 μg/ml, respectively) and against BChE (98.5% and 99.8% at 100 and 200 μg/ml, respectively) and its major components verbascoside 8 (50.9% and 70.0% at 200 μg/ml, against AChE and BChE, respectively), martynoside 9, and fraction F-7 (which corresponds to a mixture of 8, 9, and other phenylethanoids and phenolics that remain unidentified) (80.2% and 85.3% at 100 and 200 μg/ml, against AChE, respectively and 99.1% and 99.7% at 100 and 200 μg/ml, against BChE, respectively) inhibited the acetylcholinesterase enzyme competitively. The most polar fraction F-5 from n-hexane extract (a mixture of naphthoquinones: 2-hydroxy-3-(1,1-dimethylallyl-1,4-naphthoquinone) 6, α-dunnione 7 and other polar compounds that remain unidentified) showed a mixed-type inhibition (71.5% and 72.1% against AChE and BChE at 200 μg/ml, respectively). Finally, the methanol-soluble residue presented a complex, mixed-type inhibition (39.9% and 67.9% against AChE and BChE at 200 μg/ml, respectively). The mixture F-3 with diterpenes was obtained from the n-hexane extract: (1,10-cyclopropyl-9-epi-ent-isopimarol) 1, 19-α-hydroxy-abietatriene 2, and F-4 a mixture of triterpenes α-lupeol 3, β-sitosterol 4, ursolic acid 5 together with a complex mixture of terpenes that did not show activity. In summary, extracts and natural compounds from C. talcana and C. integrifolia were isolated, identified and characterized as cholinesterase inhibitors.

  6. QSAR for cholinesterase inhibition by organophosphorus esters and CNDO/2 calculations for organophosphorus ester hydrolysis

    Science.gov (United States)

    Johnson, H.; Kenley, R. A.; Rynard, C.; Golub, M. A.

    1985-01-01

    Quantitative structure-activity relationships were derived for acetyl- and butyrylcholinesterase inhibition by various organophosphorus esters. Bimolecular inhibition rate constants correlate well with hydrophobic substituent constants, and with the presence or absence of catonic groups on the inhibitor, but not with steric substituent constants. CNDO/2 calculations were performed on a separate set of organophosphorus esters, RR'P(O)X, where R and R' are alkyl and/or alkoxy groups and X is fluorine, chlorine or a phenoxy group. For each subset with the same X, the CNDO-derived net atomic charge at the central phosphorus atom in the ester correlates well with the alkaline hydrolysis rate constant. For the whole set of esters with different X, two equations were derived that relate either charge and leaving group steric bulk, or orbital energy and bond order to the hydrogen hydrolysis rate constant.

  7. Correlation between Cholinesterase and Paraoxonase 1 Activities: Case Series of Pesticide Poisoning Subjects

    Directory of Open Access Journals (Sweden)

    S Austin Richard

    2013-08-01

    Full Text Available Introduction: Acute exposure to pesticide due to suicidal poisoning is the most extensive cause of pesticide exposure, compared with all other causes including agricultural or industrial exposure. Organophosphate (OP and carbamate group of pesticides can inhibit acetylcholinesterase; on the other hand, paraoxonase1 can detoxify organophosphate poisoning by hydrolyzing organophosphate metabolites. Methods: We have compared the serum paraoxonase1 status and cholinesterase activity of subjects who attempted to commit suicide by consuming OP pesticide. Cholinesterase and paraoxonase1 activity were measured spectrophotometrically using butyrylthiocholine and phenyl acetate as substrates, respectively. Results: A positive correlation was found between serum paraoxonase1 activity and cholinesterase activity among pesticide consumed subjects. Conclusion: Our results suggest that subjects with higher paraoxonase1 activity may have a better chance of detoxifying the lethal effect of acute organophosphate poisoning.

  8. Acute toxicity and cholinesterase inhibition of the nematicide ethoprophos in larvae of gar Atractosteus tropicus (Semionotiformes: Lepisosteidae

    Directory of Open Access Journals (Sweden)

    Freylan Mena Torres

    2012-03-01

    Full Text Available Biomarkers are a widely applied approach in environmental studies. Analyses of cholinesterase (ChE, glutathione S-transferase (GST and lipid peroxidation (LPO are biomarkers that can provide information regarding early effects of pollutants at different biochemical levels on an organism. The aim of this study was to evaluate the biomarker approach on a Costa Rican native and relevant species. For this, larvae of gar (Atractosteus tropicus were exposed to the organophosphorus nematicide, ethoprophos. Acute (96hr exposure was conducted with pesticide concentrations ranging from 0.1μg/L to 1 500μg/L. The 96hr LC50 calculated was 859.7μg/L. After exposure, three biomarkers (ChE, GST and LPO were analyzed in fish that survived the acute test. The lowest observed effect concentration (LOEC regarding ChE activity inhibition was 50μg/L. This concentration produced a significant inhibition (p0.05 in GST activity and LPO were observed in A. tropicus larvae after exposure to ethoprophos.El proceso de reproducción inducida de Atractosteus tropicus es útil para la acuicultura y la reintroducción en zonas donde las poblaciones silvestres se han reducido considerablemente. En larvas de esta especie se evaluó la toxicidad aguda, así como la respuesta de tres biomarcadores: actividad colinesterasa (ChE, actividad de Glutation S-transferasa (GST y peroxidación de lípidos (LPO. Asimismo, se realizaron exposiciones agudas (96hr a etoprofos (nematicida organofosforado, en donde se utilizaron concentraciones entre 0.1μg/L y 1 500μg/L del nematicida. La concentración letal 50 (LC50 calculada fue de 859.7μg/L; la máxima concentración sin efecto en los organismos (NOEC 10μg/L y la concentración más baja en la cual se observó algún efecto (LOEC 50μg/L. A esa concentración, el efecto observado fue una reducción significativa (p0.05 luego de la exposición de los organismos a etoprofos.

  9. Changes of serum pancreatic stone protein and cholinesterase contents in children with sepsis and their correlation with systemic inflammatory response and target organ damage

    Directory of Open Access Journals (Sweden)

    Zhi-Hong Ren

    2017-10-01

    Full Text Available Objective: To study the changes of serum pancreatic stone protein (PSP and cholinesterase (ChE contents in children with sepsis and their correlation with systemic inflammatory response and target organ damage. Methods: A total of 64 children with sepsis who were treated in the hospital between January 2015 and January 2017 were selected as observation group, and 50 healthy children who received vaccination in the hospital during the same period were selected as normal control group. The contents of PSP, ChE, inflammatory factors as well as liver and kidney function indexes in the two groups were detected. Pearson test was used to assess the correlation of serum PSP and ChE contents with systemic inflammatory response and target organ damage in children with sepsis. Results: Serum PSP content of observation group was higher than that of control group while ChE content was lower than that of control group; serum inflammatory factors PCT, CRP, IL-1, IL-6 and IL-10 contents of observation group were higher than those of normal control group; liver function indexes TBIL, ALT and AST contents were higher than those of normal control group; kidney function indexes Scr and BUN contents were higher than those of normal control group. Pearson test showed that the serum PSP and ChE contents in children with sepsis were directly correlated with the systemic inflammatory response as well as liver and renal function injury. Conclusion: Serum PSP content significantly increases while ChE content significantly decreases in children with sepsis and the specific change is directly correlated with the overall disease severity.

  10. Japanese Encephalitis Virus Infection Results in Transient Dysfunction of Memory Learning and Cholinesterase Inhibition.

    Science.gov (United States)

    Chauhan, Prashant Singh; Khanna, Vinay Kumar; Kalita, Jayantee; Misra, Usha Kant

    2017-08-01

    Cholinergic system has an important role in memory and learning. Abnormal cognitive and behavioral changes have been reported in Japanese encephalitis (JE), but their basis has not been comprehensively evaluated. In this study, we report memory and learning and its association with acetylcholinesterase (AChE) activity, JE virus titer, and with histopathological observations in a rat model of JE. Wistar rats were intracerebrally inoculated on 12th day with 3 × 10 6  pfu/ml of JE virus. Memory and learning were assessed by the active and passive avoidance tests on 10, 33, and 48 days post inoculation (dpi). After 10, 33, and 48 dpi AChE activity, Japanese encephalitis virus (JEV) titer and histopathological changes were studied in the frontal cortex, thalamus, midbrain, cerebellum, and hippocampus. There was significant impairment in memory and learning on 10 dpi which started improving from 33 dpi to 48 dpi by active avoidance test. Passive avoidance test showed decrease in transfer latency time of retention trial compared to acquisition on first, second, and third retention day trial compared to controls. AChE inhibition was more marked in the hippocampus, frontal cortex, and cerebellum on 10 dpi. However, AChE activity started improving from 33 dpi to 48 dpi. AChE activity in the thalamus and midbrain correlated with active avoidance test on 10 dpi and 33 dpi. Histopathological studies also revealed improvement on 33 and 48 compared to 10 dpi. The present study demonstrates transient memory and learning impairment which was associated with reduction in AChE, JEV titer, and damage in different brain regions of JEV infected rats.

  11. Synthesis, characterization, X-ray crystallography, acetyl cholinesterase inhibition and antioxidant activities of some novel ketone derivatives of gallic hydrazide-derived Schiff bases.

    Science.gov (United States)

    Gwaram, Nura Suleiman; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; Buckle, Michael J C; Sukumaran, Sri Devi; Chung, Lip Yong; Othman, Rozana; Alhadi, Abeer A; Yehye, Wageeh A; Hadi, A Hamid A; Hassandarvish, Pouya; Khaledi, Hamid; Abdelwahab, Siddig Ibrahim

    2012-02-28

    Alzheimer's disease (AD) is the most common form of dementia among older people and the pathogenesis of this disease is associated with oxidative stress. Acetylcholinesterase inhibitors with antioxidant activities are considered potential treatments for AD. Some novel ketone derivatives of gallic hydrazide-derived Schiff bases were synthesized and examined for their antioxidant activities and in vitro and in silico acetyl cholinesterase inhibition. The compounds were characterized using spectroscopy and X-ray crystallography. The ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays revealed that all the compounds have strong antioxidant activities. N-(1-(5-bromo-2-hydroxyphenyl)-ethylidene)-3,4,5-trihydroxybenzohydrazide (2) was the most potent inhibitor of human acetyl cholinesterase, giving an inhibition rate of 77% at 100 μM. Molecular docking simulation of the ligand-enzyme complex suggested that the ligand may be positioned in the enzyme's active-site gorge, interacting with residues in the peripheral anionic subsite (PAS) and acyl binding pocket (ABP). The current work warrants further preclinical studies to assess the potential for these novel compounds for the treatment of AD.

  12. 21 CFR 862.3240 - Cholinesterase test system.

    Science.gov (United States)

    2010-04-01

    ... obtained by this device are used in the diagnosis and treatment of cholinesterase inhibition disorders (e.g., insecticide poisoning and succinylcholine poisoning). (b) Classification. Class I. ...

  13. BRAIN CHOLINESTERASE INHIBITION AND DEPRESSION OF THE PHOTIC AFTER DISCHARGE (PHAD) OF FLASH EVOKED POTENTIALS (FEPS) IN LONG EVANS RATS FOLLOWING ACUTE OR REPEATED EXPOSURES TO A MIXTURE OF CARBARYL AND PROPOXUR.

    Science.gov (United States)

    Carbaryl and propoxur are N-methyl carbamate pesticides (NMCs) which are part of the EPA’s cumulative risk assessments for NMCs. These NMCs inhibit cholinesterase (ChE) activity and may lead to cholinergic disruption of CNS function. We used decreases in the PhAD of FEPs to indic...

  14. The Effect of Diazinon on Cholinesterase Activity in Plasma and Erythrocytes of Male and Female Rats and the Protective Role of Vitamin E

    Directory of Open Access Journals (Sweden)

    F. Rahimi Anbarkeh

    2015-01-01

    Full Text Available Introduction & Objective: Diazinon (DZN is an organophosphate insecticide that one of the mechanisms of toxicity is the inhibition of cholinesterase. The aim of the present study was to evaluate the effects of diazinon on cholinesterase activity in blood serum and erythrocytes of male and female rats and to assess the protective role of vitamin E. Materials & Methods: In this experimental study, 60 adult wistar rats including 30 male and 30 female rats were selected and divided into 5 groups (n = 6: control group (without any intervention, sham group (received only pure olive oil daily, experimental group 1 (DZN daily, 60 mg/kg, experimental group 2 (received DZN+ vitamin E daily, with the same dose and experimental group 3(received vitamin E daily 200 mg/kg. Diazinon and solvent were injected intraperitoneally and vitamin E was given by gavage. After 2 weeks 3 ml blood was taken from the heart tissue, and titrimetric and Ellman’s method respectively were used for serum and erythrocyte cholinesterases activity assay. Results: In both genders, due to administration of diazinon, we observed significant reduction in serum and erythrocytes cholinesterase activity. The use of vitamin E increased serum and erythrocytes cholinesterase activity in experimental group 2 of female rats but inhibition in erythrocyte and serum cholinesterase activity was not recovered in experimental group 2 of male rats. Conclusion: According to a further reduction of these enzymes activity in female rats with the use of diazinon, it can be concluded that female rats are more sensitive than male rats and it seems that vitamin E as an antioxidants has a protective effect on cholinesterase activity and reduces the toxicity of DZN. (Sci J Hamadan Univ Med Sci 2015; 21 (4:294-303

  15. Serum cholinesterase polymorphism (CHE1 and CHE2 loci) among several Indian groups from Amazon region of Brazil, and segregation of the C5 variant in families.

    Science.gov (United States)

    Guerreiro, J F; Santos, S E; Aguiar, G F

    1989-04-01

    Eight Indian tribes from the Amazon region of Brazil (Araweté, Arara, Yamamadi, Kararaô, Karitiana, Waiampi, Surui and Cinta Larga) were studied for the distribution of the atypical and C5 variants of serum cholinesterase. None of them presented the CHE1*A allele, but the C5 variant was found in the Araweté (20.4%), Kararaô (15.6%), Karitiana (50.5%), Surui (12.3%) and Cinta Larga (19.6%) tribes. The frequency of the C5+ phenotype in the Karitiana is the highest reported thus far in human populations. Segregation studies considering the C5 variant were made among the Karitiana, and also among the Urubu-Kaapor and Munduruku tribes previously studied by Guerreiro et al [1987a, 1987b]. Most of the data were in agreement with the genetic hypothesis, but they also revealed a significant lack of the C5+ phenotype in offspring from C5+ X C5+ matings, as well as the occurrence of two C5+ children from C5- X C5- unions, in the Urubu-Kaapor tribe.

  16. Serum protein inhibition of thyrotropin binding to human thyroid tissue

    International Nuclear Information System (INIS)

    Beall, G.N.; Chopra, I.J.; Solomon, D.H.; Kruger, S.R.

    1978-01-01

    We used a modificaton of the TSH radioreceptor assay to detect TSH-binding inhibition (TBI) activity in serum and serum fractions from normal subjects and patients with Graves' disease. TBI activity is present in normal IgG prepared by DEAE-Sephadex chromatography and in normal globulins prepared by precipitation at 1.6 M ammonium sulfate. Other normal serum proteins also had TBI activity when large concentrations were tested. Gel filtration chromatography and powder block electrophoresis were used to prepare fractions of normal and Graves' disease sera. In these fractions from normal serum, TBI activity was found in both γ-globulin and α-globulin-albumin fractions electrophoretically and in both 7S and 4S peaks from gel filtration. TBI activity from Graves' disease patients' sera was similarly distributed, but relatively more TBI accompanied the electrophoretic γ-globulins. Sepharose Protein-A and anti-IgG were used as immunoabsorbents to isolate and purify IgG from normal and Graves' disease sera. TBI activity in IgG was proportional to the IgG concentration, indicating that the TBI which migrates as a γ-globulin electrophoretically is an IgG and thus may possibly be an antibody. Inhibitory activity found in normal serum globulins and in the non-IgG fractions of both normal and abnormal sera seriously interferes with attempts to use the TSH radioreceptor assay to study the hypothesized anti-TSH receptor antibody in the serum of patients with Graves' disease

  17. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.

    2008-05-01

    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  18. Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

    Science.gov (United States)

    Khan, Nehal A; Khan, Imtiaz; Abid, Syed M A; Zaib, Sumera; Ibrar, Aliya; Andleeb, Hina; Hameed, Shahid; Iqbal, Jamshed

    2018-01-01

    Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Comparative chemical profiling, cholinesterase inhibitions and anti-radicals properties of essential oils from Polygonum hydropiper L: a preliminary anti- Alzheimer's study.

    Science.gov (United States)

    Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Khan, Mir Azam; Ahmad, Waqar; Shah, Muhammad Raza; Imran, Muhammad; Ahmad, Sajjad

    2015-11-04

    Cholinesterase inhibition is a vital target for the development of novel and mechanism based inhibitors, owing to their role in the breakdown of acetylcholine (ACh) neurotransmitter to treat various neurological disorders including Alzheimer's disease (AD). Similarly, free radicals are implicated in the progression of various diseases like neurodegenerative disorders. Due to lipid solubility and potential to easily cross blood brain barrier, this study was designed to investigate the anticholinesterase and antioxidant potentials of the standardized essential oils from the leaves and flowers of Polygonum hydropiper. Essential oils from the leaves (Ph.LO) and flowers (Ph.FO) of P. hdropiper were isolated using Clevenger apparatus. Oil samples were analyzed by GC-MS to identify major components and to attribute the antioxidant and anticholinesterase activity to specific components. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials of the samples were determined following Ellman's assay. Antioxidant assays were performed using 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) and hydrogen peroxide (H2O2) free radical scavenging assays. In the GC-MS analysis 141 and 122 compounds were indentified in Ph.LO and Ph.FO respectively. Caryophylene oxide (41.42 %) was the major component in Ph.FO while decahydronaphthalene (38.29 %) was prominent in Ph.LO. In AChE inhibition, Ph.LO and Ph.FO exhibited 87.00** and 79.66***% inhibitions at 1000 μg/ml with IC50 of 120 and 220 μg/ml respectively. The IC50 value for galanthamine was 15 μg/ml. In BChE inhibitory assay, Ph.LO and Ph.FO caused 82.66*** (IC50 130 μg/ml) and 77.50***% (IC50 225 μg/ml) inhibitions respectively at 1000 μg/ml concentration. In DPPH free radical scavenging assay, Ph.LO and Ph.FO exhibited IC50 of 20 and 200 μg/ml respectively. The calculated IC50s were 180 & 60 μg/ml for Ph.LO, and 45 & 50 μg/ml for Ph.FO in scavenging

  20. Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs.

    Science.gov (United States)

    Ramsay, Rona R; Tipton, Keith F

    2017-07-15

    The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC 50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

  1. Brain cDNA clone for human cholinesterase

    International Nuclear Information System (INIS)

    McTiernan, C.; Adkins, S.; Chatonnet, A.; Vaughan, T.A.; Bartels, C.F.; Kott, M.; Rosenberry, T.L.; La Du, B.N.; Lockridge, O.

    1987-01-01

    A cDNA library from human basal ganglia was screened with oligonucleotide probes corresponding to portions of the amino acid sequence of human serum cholinesterase. Five overlapping clones, representing 2.4 kilobases, were isolated. The sequenced cDNA contained 207 base pairs of coding sequence 5' to the amino terminus of the mature protein in which there were four ATG translation start sites in the same reading frame as the protein. Only the ATG coding for Met-(-28) lay within a favorable consensus sequence for functional initiators. There were 1722 base pairs of coding sequence corresponding to the protein found circulating in human serum. The amino acid sequence deduced from the cDNA exactly matched the 574 amino acid sequence of human serum cholinesterase, as previously determined by Edman degradation. Therefore, our clones represented cholinesterase rather than acetylcholinesterase. It was concluded that the amino acid sequences of cholinesterase from two different tissues, human brain and human serum, were identical. Hybridization of genomic DNA blots suggested that a single gene, or very few genes coded for cholinesterase

  2. Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.

    Science.gov (United States)

    Saeed, Aamer; Mahesar, Parvez Ali; Zaib, Sumera; Khan, Muhammad Siraj; Matin, Abdul; Shahid, Mohammad; Iqbal, Jamshed

    2014-05-06

    The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimer's diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 μM whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 μM. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimer's disease (AD). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. Pesticide Exposure and Cholinesterase Levels in Migrant Farm Workers in Thailand.

    Science.gov (United States)

    Thetkathuek, Anamai; Yenjai, Pornthip; Jaidee, Wanlop; Jaidee, Patchana; Sriprapat, Poonsak

    2017-01-01

    In this study, we examined the effects of pesticides in migrant farm workers from Cambodia after workplace exposure on fruit plantations in eastern Thailand. We studied 891 migrant farm workers employed on pineapple, durian, and rambutan plantations in Thailand. Data were collected via a detailed questionnaire survey and measurements of serum cholinesterase level (SChE). The majority of subjects was male (57.7%), with an average age of 30.3 years. Most subjects (76.8%) were moderately aware of good industrial hygiene practices. SChE level was divided into four groups based on the results. Only 4.4% had normal levels of cholinesterase activity, 20.5% had slightly reduced levels, 58.5% had markedly reduced levels and were "at risk," and 16.6% who had highest levels of cholinesterase inhibition were deemed to be in an "unsafe" range. SChE was classified into two groups, SChE value of 87.5 was "normal" and 39 acres, use a backpack sprayer, or have a low level of compliance with accepted industrial hygiene practices. These three classes of workers are at increased risk of chemical exposures and developing acute or chronic illness from pesticide exposures.

  4. [Cholinesterases in total blood measured with a semiquantitative technique, and plasma or erythrocyte cholinesterases measured with quantitative techniques].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2007-06-01

    An equivalence model which allows comparison of blood cholinesterase values, measured by Lovibond (semiquantitative technique), and Michel, EQM, Monotest (erythrocyte and plasma cholinesterases) values measured by quantitative techniques is required. The performance of Lovibond (Edson tintometric and Limperos & Ranta techniques) were compared with quantitative techniques. The experimental design was descriptive, cross-sectional, and prospective. From a working population (18-59 years) in Valle de Aburrá and Near East of Antioquia. 827 representative samples were chosen for their lack of exposure to cholinesterase-inhibiting plaguicides and affiliated to the Social Security System. (1) 827 workers were classified by Lovibond in four categories: 821 values with 75% of cholinesterase activity or greater (categories 75, 87.5 and 100%) and 6 with cholinesterase activity smaller than 75%. (2) With each quantitative method, the mean values of erythrocyte and plasmatic cholinesterase corresponding to the four values obtained with Lovibond were statistically different to each other. (3) The mean values of each quantitative technique increased when increased the tintometric method value. (4) Lovibond classified the low enzymatic erythrocyte activity very poorly (61-73%), but the classification of the low enzymatic plasma activity was almost completely in error (94-96%). The values of erythrocyte or plasma cholinesterase were adequately estimated by both the quantitative techniques of Michel and EQM and by Lovibond, but only when the enzymatic activity is normal. Lovibond, however, had a poor capacity to designate as "low" the values that were low according to the quantitative tests.

  5. Proline-Based Carbamates as Cholinesterase Inhibitors

    Czech Academy of Sciences Publication Activity Database

    Pizova, H.; Havelková, M.; Štěpánková, Š.; Bak, A.; Kauerová, T.; Kozik, V.; Oravec, Michal; Imramovský, A.; Kollár, P.; Bobáľ, P.; Jampílek, J.

    2017-01-01

    Roč. 22, č. 11 (2017), č. článku 1969. ISSN 1420-3049 R&D Projects: GA MŠk(CZ) LO1415; GA MŠk(CZ) EF16_013/0001609 Institutional support: RVO:86652079 Keywords : proline * carbamates * in vitro cholinesterase inhibition * in vitro cytotoxicity assay * CoMSA * IVE-PLS * molecular docking study Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 2.861, year: 2016

  6. Evaluation of a clinic-based cholinesterase test kit for the Washington State Cholinesterase Monitoring Program.

    Science.gov (United States)

    Hofmann, Jonathan N; Carden, Angela; Fenske, Richard A; Ruark, Harold E; Keifer, Matthew C

    2008-07-01

    The Washington State Cholinesterase Monitoring Program for pesticide handlers requires blood draws at local clinics, with samples tested at a central laboratory. At present, workers with inhibited cholinesterase activity may be re-exposed before they can be removed from work. In this study we explored the option of on-site testing at local clinics using the EQM Test-mate Kittrade mark, a portable cholinesterase test kit. Test kit cholinesterase activity measurements were performed on 50 blood samples by our research staff, and compared to measurements on the same samples by the Washington State Public Health Laboratory. Another set of samples was also analyzed with the test kit by medical staff at an eastern Washington clinic. Triplicate measurements with the test kit had a 3.3% average coefficient of variation (CV) for plasma cholinesterase (PChE), and a 3.5% average CV for erythrocyte cholinesterase (AChE) measurements. The kit's PChE measurements were similar to PHL measurements (average ratio of 0.98) when performed in the laboratory, but had a tendency to underestimate activity when used in the clinic setting (average ratio of 0.87). The kit systematically overestimated AChE activity by 42-48% relative to the PHL measurements, regardless of where the samples were analyzed. This easy-to-use test kit appeared to be a viable method for clinic-based PChE measurements, but was less consistent for AChE measurements performed in the clinic. Absolute measurements with the kit need to be evaluated carefully relative to standardized methods. (c) 2008 Wiley-Liss, Inc.

  7. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  8. Coumarins as cholinesterase inhibitors: A review.

    Science.gov (United States)

    de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

    2016-07-25

    The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Tubule urate and PAH transport: sensitivity and specificity of serum protein inhibition

    International Nuclear Information System (INIS)

    Grantham, J.J.; Kennedy, J.; Cowley, B.

    1987-01-01

    Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [ 14 C]urate and p-[ 3 H]aminohippurate ([ 3 H]PAH) in rabbit S 2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, the authors examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and γ-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation or urate and PAH by isolated nonperfused segments. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit γ-globulin, but not by Cohn-fractionated bovine serum albumin. α-Lactalbumin and β-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and γ-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and γ-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S 2 proximal tubules. They suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH

  10. Human erythrocytes inhibit complement-mediated solubilization of immune complexes by human serum

    International Nuclear Information System (INIS)

    Dorval, B.L.

    1987-01-01

    The aim of this study was to develop an autologus human system to evaluate the effects of human erythrocytes on solubilization of immune complex precipitates (IC) by human serum. Incubation of IC with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed erythrocytes were added to human serum or guinea pig serum binding of IC to the erythrocyte occurred and IC solubilization was inhibited significantly (p <.025). Sheep erythrocytes did not bind IC or inhibit IC solubilization. To evaluate the role of human erythrocyte complement receptor (CR1) on these findings, human erythrocytes were treated with trypsin or anti-CR1 antibodies. Both treatments abrogated IC binding to human erythrocytes but did not affect the ability of the human erythrocyte to inhibit IC solubilization. Radioimmunoassay was used to measure C3, C4 and C5 activation in human serum after incubation with IC, human erythrocytes, human erythrocytes plus IC, whole blood or in whole blood plus IC

  11. Ramalina capitata (Ach.) Nyl. acetone extract: HPLC analysis, genotoxicity, cholinesterase, antioxidant and antibacterial activity.

    Science.gov (United States)

    Zrnzevic, Ivana; Stankovic, Miroslava; Stankov Jovanovic, Vesna; Mitic, Violeta; Dordevic, Aleksandra; Zlatanovic, Ivana; Stojanovic, Gordana

    2017-01-01

    In the present investigation, effects of Ramalina capitata acetone extract on micronucleus distribution on human lymphocytes, on cholinesterase activity and antioxidant activity (by the CUPRAC method) were examined, for the first time as well as its HPLC profile. Additionally, total phenolic compounds (TPC), antioxidant properties (estimated via DPPH, ABTS and TRP assays) and antibacterial activity were determined. The predominant phenolic compounds in this extract were evernic, everninic and obtusatic acids. Acetone extract of R. capitata at concentration of 2 μg mL -1 decreased a frequency of micronuclei (MN) for 14.8 %. The extract reduces the concentration of DPPH and ABTS radicals for 21.2 and 36.1 % (respectively). Values for total reducing power (TRP) and cupric reducing capacity (CUPRAC) were 0.4624 ± 0.1064 μg ascorbic acid equivalents (AAE) per mg of dry extract, and 6.1176 ± 0.2964 μg Trolox equivalents (TE) per mg of dry extract, respectively. The total phenol content was 670.6376 ± 66.554 μg galic acid equivalents (GAE) per mg of dry extract. Tested extract at concentration of 2 mg mL -1 exhibited inhibition effect (5.2 %) on pooled human serum cholinesterase. The antimicrobial assay showed that acetone extract had inhibition effect towards Gram-positive strains. The results of manifested antioxidant activity, reducing the number of micronuclei in human lymphocytes, and antibacterial activity recommends R. capitata extract for further in vivo studies.

  12. Molecular modeling and biological evaluation of 2-N,N-dimethylaminecyclohexyl 1-N‧,N‧-dimethylcarbamate isomers and their methylsulfate salts as cholinesterases inhibitors

    Science.gov (United States)

    Bocca, Cleverson C.; Rittner, Roberto; Höehr, Nelci F.; Pinheiro, Glaucia M. S.; Abiko, Layara A.; Basso, Ernani A.

    2010-11-01

    This work presents a detailed theoretical and experimental study on the inhibitory properties of 2- N,N-dimethylaminecyclohexyl 1- N',N'-dimethylcarbamate isomers and their methylsulfate salts against the cholinesterases enzymes. The in vitro inhibition test performed by the Ellman's method showed that the salt form compounds were more active than the neutral ones in cholinesterases inhibition. The trans salt showed good selectivity towards the inhibition of erythrocyte cholinesterase with a maximum limit around 90% and 55% for the plasma cholinesterase inhibition. Molecular modeling, docking and experimental results performed in this study showed to be important initial steps toward the development of a novel pharmaceuticals in the fight against Alzheimer's disease.

  13. Effects of two oxadiazolidinones on cholinesterases and acetylcholine receptors

    International Nuclear Information System (INIS)

    Bakry, N.; Lockyer, S.; Sherby, S.; Eldefrawi, A.; Eldefrawi, M.

    1986-01-01

    Inhibition of acetylcholinesterase (AChE) and butyryl cholinesterase (BuChE) by 3-(2,3-dihydro-2,2-dimethyl-benzofuran-'7-yl)-5-methoxy-1,3,4-oxadiazol-2( 3 H)-one (DBOX) and 3-(2-methoxyphenyl)-5-methoxy-1,3,4-oxadiazol-2( 3 H)-one (MPOX) was measured by the Ellmann spectrophotometric method. Inhibition was quasi first order and irreversible. DBOX was 2-3 orders of magnitude more potent than MPOX. Housefly brain AChE and horse serum BuChE were more sensitive than AChEs of red blood cells or eel and Torpedo electric organs. It is suggested that the nonesteratic oxadiazolidinones are activated to carbanillates on the surface of the enzyme and produce a carbanillated enzyme which ages rapidly. Carbamate anticholinesterases protected AChE against carbanillation as they did against phosphorylation. At higher concentrations, the two oxadiazolidinones also affected binding of [ 125 I] α bungarotoxin and [ 3 H]perhydrohistrionicotoxin to Torpedo nicotinic acetylcholine receptors, but did not affect binding of [ 3 H]quinuclidinyl benzilate to rat brain muscarinic receptors

  14. Phosphorylated Derivatives of Alkaloids and Nitrogen-containing Heterocycles — Cholinesterase Inhibitors

    Science.gov (United States)

    Sadykov, Abid S.; Dalimov, D. N.; Godovikov, Nikolai N.

    1983-10-01

    The review deals with the synthesis and anticholinesterase activities of phosphorylated derivatives of certain alkaloids and nitrogen-containing heterocycles. It is shown that the conformational properties of the alkaloid and nitrogen-containing heterocycle residues in the composition of the organophosphorus inhibitor (OPI) molecule play an important role in the inhibition of the catalytic activity of cholinesterases. The type of inhibition of cholinesterases also varies as a function of chemical structure. The bibliography includes 45 references.

  15. Exposureassessmentof greenhouseworkerswithanti-cholinesterase pesticides by biological monitoring

    Directory of Open Access Journals (Sweden)

    Sh Bakand

    2012-12-01

    Full Text Available   Background and Aims: Organophosphate compounds are the most popular insecticides with the widespread application in pest control. These toxic compounds interfere with the blood cholinesterase and inhibit the cholinestarse activity.Measurement of Cholinesterase activity is widely used for diagnosis of poisoning and adverse effects caused by pesticides. Green-house workers are one of the important occupational groups with the high risk of poisoning with organophosphate and karbamat pesticides .The purpose of this study was to assess the exposure of green-house workers with anti-cholinesterase toxic compounds by measuring the blood cholinesterase activity using electrometric method.   Methods: This research is a descriptive cross sectional study that carried out on farmers of the cucumber green-houses . In this study, 40 workers were selected and their blood cholinesterase enzyme activity were measured using electrometric method . In electrometric method the reduction of cholinesterase activity can be measured through recording the changes of blood pH induced by anticholinestrase agents . The results were analyzed by version16 of spss software.   Results: Based on the obtained results the amount of erythrocyte cholinesterase enzyme inhibition was between 1 / 77% to 35 / 4% and the mean and standard deviation was 23 / 2% ±9 / 68.   Similarly, the amount of plasma cholinesterase enzyme inhibition was between 1% to 28% and the mean and standard deviation was equal to 16/57 ±7 / 92.   Following the analysis of results 25% (n=10 of the workers were identified with no poisoning, 17.5% (n = 7 with minor poisoning , 55% (n=22 with moderate poisoning and 2.5% (n=1 with severe poisoning.     Conclusion : Organophosphate poisoning has been reported as the third cause of poisoning and also the leading cause of poisoning deaths in our country.Therefore, considering the results of this research and the importance of the evaluation of workers exposure

  16. Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies.

    Science.gov (United States)

    Ferlemi, Anastasia-Varvara; Katsikoudi, Antigoni; Kontogianni, Vassiliki G; Kellici, Tahsin F; Iatrou, Grigoris; Lamari, Fotini N; Tzakos, Andreas G; Margarity, Marigoula

    2015-07-25

    Our aim was to investigate the possible effects of regular drinking of Rosmarinus officinalis L. leaf infusion on behavior and on AChE activity of mice. Rosemary tea (2% w/w) phytochemical profile was investigated through LC/DAD/ESI-MS(n). Adult male mice were randomly divided into two groups: "Rosemary-treated" that received orally the rosemary tea for 4weeks and "control" that received drinking water. The effects of regular drinking of rosemary tea on behavioral parameters were assessed by passive avoidance, elevated plus maze and forced swimming tests. Moreover, its effects on cerebral and liver cholinesterase (ChE) isoforms activity were examined colorimetricaly. Phytochemical analysis revealed the presence of diterpenes, flavonoids and hydroxycinnamic derivatives in rosemary tea; the major compounds were quantitatively determined. Its consumption rigorously affected anxiety/fear and depression-like behavior of mice, though memory/learning was unaffected. ChE isoforms activity was significantly decreased in brain and liver of "rosemary treated" mice. In order to explain the tissue ChE inhibition, principal component analysis, pharmacophore alignment and molecular docking were used to explore a possible relationship between main identified compounds of rosemary tea, i.e. rosmarinic acid, luteolin-7-O-glucuronide, caffeic acid and known AChE inhibitors. Results revealed potential common pharmacophores of the phenolic components with the inhibitors. Our findings suggest that rosemary tea administration exerts anxiolytic and antidepressant effects on mice and inhibits ChE activity; its main phytochemicals may function in a similar way as inhibitors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Different Cholinesterase Inhibitor Effects on CSF Cholinesterases in Alzheimer Patients

    Science.gov (United States)

    Nordberg, Agneta; Darreh-Shori, Taher; Peskind, Elaine; Soininen, Hilkka; Mousavi, Malahat; Eagle, Gina; Lane, Roger

    2014-01-01

    Background The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. Methods and Findings AD patients aged 50–85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman’s colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2%increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. Conclusion The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation. PMID:19199870

  18. Migration inhibition of immune mouse spleen cells by serum from x-irradiated tumor-bearing mice

    International Nuclear Information System (INIS)

    Moroson, H.

    1978-01-01

    Tumor-specific antigens of the chemically induced MC 429 mouse fibrosarcoma were detected in a 3 M KCl extract of tumor by the inhibition of migration of specifically immune spleen cells. Using this assay with serum from tumor-bearing mice no tumor antigen was detected in serum of mice bearing small tumors, unless the tumor was exposed to local x irradiation (3000 R) 1 day prior to collection of serum. It was concluded that local x irradiation of tumor caused increased concentration of tumor antigen in the serum. When the tumor was allowed to grow extremely large, with necrosis, then host serum did cause migration inhibition of both nonimmune and immune spleen cells. This migration-inhibition effect was not associated with tumor antigen, but with a nonspecific serum factor

  19. Inhibiting Endogenous Cortisol Blunts the Meal-Entrained Rise in Serum Leptin

    Science.gov (United States)

    Laferrère, Blandine; Abraham, Cynthia; Awad, Marianne; Jean-Baptiste, Stephanie; Hart, Allison B.; Garcia-Lorda, Pilar; Kokkoris, Peter; Russell, Colleen D.

    2010-01-01

    Context Administration of glucocorticoids increases serum leptin levels in lean and obese individuals. A morning meal produces an increase in insulin, a cortisol peak, and an increase in leptin; these changes do not occur during fasting. Objective The objective of this study was to investigate whether inhibiting endogenous cortisol secretion with metyrapone decreases 24-h serum leptin levels and to determine whether a meal-related midmorning surge in cortisol is a prerequisite for the meal-entrained nocturnal rise in leptin. Design This was a randomized, cross-over study. Setting The study was performed at the General Clinical Research Center. Participants Lean males were studied. Intervention In study 1, seven lean men were studied for 24 h while their endogenous cortisol secretions were manipulated as follows: 1) CONTROL; 2) cortisol suppression by metyrapone (MET); and 3) MET and oral hydrocortisone (at 0900 h) (MET + CORT). Subjects were all fed a eucaloric diet (two meals at 1100 and 1700 h). In study 2, six men were studied without pharmacological intervention for 24 h on two occasions: once under a complete fast (FAST) and once in a feeding condition (one meal at 1100 h; FED). Main Outcome Measure The main outcome measure was serum leptin. Results MET significantly suppressed serum cortisol at 0800 h, midmorning, and over the 24-h period. As a result of cortisol suppression, 24-h serum leptin levels were decreased vs. control values despite similar insulin responses to meals. Administering a single dose of hydrocortisone to MET subjects potently stimulated serum leptin compared with the effect of MET alone. Conclusions Our data demonstrate that endogenous cortisol secretion is necessary for the maintenance of serum leptin levels over 24 h in lean, normally fed males. PMID:16537679

  20. In Vivo Reactivation by Oximes of Inhibited Blood, Brain and Peripheral Tissue Cholinesterase Activity Following Exposure to Nerve Agents in Guinea Pigs

    Science.gov (United States)

    2010-01-01

    nerve agent intoxication ( salivation , rhinorrhea, tremors,muscle asciculations, convulsions) at 60min following the 1.0× LD50 dose f GB, GF, VR or VX...reactivation of GF-, soman-, or VR-inhibited enzyme byHI-6 andHLö7. However, these in vitro experiments [24,25] were conducted with a pH of 8.0 at 25 ◦C...data. Even the study of Worek et al. [23] that was performed at a pH of 7.4 at 37 ◦C, whose in vitro kinetic data obtained from guinea pig RBC ghosts

  1. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

    Science.gov (United States)

    Zhu, Jie; Yang, Hongyu; Chen, Yao; Lin, Hongzhi; Li, Qi; Mo, Jun; Bian, Yaoyao; Pei, Yuqiong; Sun, Haopeng

    2018-12-01

    The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC 50 ) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC 50  = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

  2. Serum amyloid P component inhibits influenza A virus infections: in vitro and in vivo studies

    DEFF Research Database (Denmark)

    Horvath, A; Andersen, I; Junker, K

    2001-01-01

    . These studies were extended to comprise five mouse-adapted influenza A strains, two swine influenza A strains, a mink influenza A virus, a ferret influenza A reassortant virus, a influenza B virus and a parainfluenza 3 virus. The HA activity of all these viruses was inhibited by SAP. Western blotting showed......Serum amyloid P component (SAP) binds in vitro Ca(2+)-dependently to several ligands including oligosaccharides with terminal mannose and galactose. We have earlier reported that SAP binds to human influenza A virus strains, inhibiting hemagglutinin (HA) activity and virus infectivity in vitro...... that SAP bound to HA trimers, monomers and HA1 and HA2 subunits of influenza A virus. Binding studies indicated that galactose, mannose and fucose moieties contributed to the SAP reacting site(s). Intranasal administration of human SAP to mice induced no demonstrable toxic reactions, and circulating...

  3. Delivery of small interfering RNA for inhibition of endothelial cell apoptosis by hypoxia and serum deprivation

    International Nuclear Information System (INIS)

    Cho, Seung-Woo; Hartle, Lauren; Son, Sun Mi; Yang, Fan; Goldberg, Michael; Xu, Qiaobing; Langer, Robert; Anderson, Daniel G.

    2008-01-01

    RNA interference (RNAi) for anti-angiogenic or pro-apoptotic factors in endothelial cells (ECs) has great potential for the treatment of ischemic diseases by promoting angiogenesis or inhibiting apoptosis. Here, we report the utility of small interfering RNA (siRNA) in inhibiting EC apoptosis induced by tumor necrosis factor-α (TNF-α). siRNA was designed and synthesized targeting tumor necrosis factor-α receptor-1 (TNFR-1) and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1). Human umbilical vein endothelial cells (HUVECs) were cultured under in vitro hypoxic and serum-deprived conditions to simulate in vivo ischemic conditions. Two days after liposomal delivery of siRNA targeting TNFR-1 and SHP-1, significant silencing of each target (TNFR-1; 76.5% and SHP-1; 97.2%) was detected. Under serum-deprived hypoxic (1% oxygen) conditions, TNF-α expression in HUVECs increased relative to normoxic (20% oxygen) and serum-containing conditions. Despite enhanced TNF-α expression, suppression of TNFR-1 or SHP-1 by siRNA delivery not only enhanced expression of angiogenic factors (KDR/Flk-1 and eNOS) and anti-apoptotic factor (Bcl-xL) but also reduced expression of a pro-apoptotic factor (Bax). Transfection of TNFR-1 or SHP-1 siRNA significantly decreased the HUVEC apoptosis while significantly enhancing HUVEC proliferation and capillary formation. The present study demonstrates that TNFR-1 and SHP-1 may be useful targets for the treatment of myocardial or hindlimb ischemia

  4. Cholinesterase catalyzed hydrolysis of O-acyl derivatives of serotonin

    International Nuclear Information System (INIS)

    Makhaeva, G.F.; Suvorov, N.N.; Ginodman, L.N.; Antonov, V.K.; AN SSSR, Moscow. Inst. Bioorganicheskoj Khimii)

    1977-01-01

    Hydrolysis of O acyl serotonin derivatives containing the residues of monocarbon dicarbon and amino acids under the effect of horse serum butyryl cholinesterase and bull erythrocytic acetylcholinesterase has been studied. It has been established, that acetylcholinesterase hydrolizes O acetylserotonin only; butyrylcholinesterase hydrolizes all the compounds investigated, except for 5,5'-terephthaloildioxytriptamine. The kinetic parameters of hydrolysis were determined. O acyl serotonin derivatives turned out good substrates of butylrylcholinesterase; serotonin and 5.5'-terephtaloildioxytriptamine are effective competitine inhibitors of the enzyme. Estimating of resistance of O acyl serotonin derivatines to blood cholinesterase effect under physiological conditions shows that the compounds investigated with the exception of 5,5'-terephthaloildioxytriptamine must be quickly hydrolyzed under butyrylcholinesterase action. 5,5'-terephthaloildioxytriptamine is suggested as a radioprotective preparation with the prolonged effect, which agrees with the biological test results

  5. Origins on Inhibition of Cholinesterases by Organophosphates

    National Research Council Canada - National Science Library

    Kovach, Ildiko

    1999-01-01

    ... basis set at the MP2 level of theory. Molecular dynamics calculations using CHARMM of the solvated acetylcholinesterase and its Glul99Gln and Trp84Ala mutants covalently modified with soman support the proposition that the dealkylation...

  6. Study of deutero-isotopomer-induced inhibition of caffeine and phenobarbitone binding to human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Cherrah, Y.; Falconnet, J.B.; Desage, M.; Brazier, J.L.; Zini, R.; Tillement, J.P.

    1988-01-01

    The present study of inhibition provides confirmation to previously observed deuterium isotope effects on in vitro caffeine and phenobarbitone binding to human serum albumin (HSA). Addition of either 3,7(C(/sup 2/H)/sub 3/)/sub 2/ or 1,3,7(C(/sup 2/H)/sub 3/)/sub 3/ caffeine induces a 50% loss in both the extent of binding and binding parameters of the unlabelled analog. As concerns caffeine displacement from its HSA sites, it is shown that phenobarbitone and its 5-pentadeuterophenyl analog are equally potent inhibitors of caffeine binding, though individual HSA binding profiles differ. As for HSA binding interactions between phenobarbitone isotopomers, a 50% decrease in unlabelled phenobarbitone extent of binding is observed in the presence of its 5-pentadeuterophenyl analog. Results favor the hypothesis of differing binding sites for each isotopomer.

  7. Serum amyloid P component inhibits influenza A virus infections: in vitro and in vivo studies

    DEFF Research Database (Denmark)

    Horvath, A; Andersen, I; Junker, K

    2001-01-01

    Serum amyloid P component (SAP) binds in vitro Ca(2+)-dependently to several ligands including oligosaccharides with terminal mannose and galactose. We have earlier reported that SAP binds to human influenza A virus strains, inhibiting hemagglutinin (HA) activity and virus infectivity in vitro...... that SAP bound to HA trimers, monomers and HA1 and HA2 subunits of influenza A virus. Binding studies indicated that galactose, mannose and fucose moieties contributed to the SAP reacting site(s). Intranasal administration of human SAP to mice induced no demonstrable toxic reactions, and circulating...... on day 10 and these mice approached normal body weight, whereas control mice (one out of five surviving on day 10) died. The data provide evidence of the potential of intranasally administered SAP for prophylactic treatment of influenza A virus infections in humans....

  8. The history of cholinesterase reactivation: hydroxylamine and pyridinium aldoximes.

    Science.gov (United States)

    Petroianu, G A

    2012-10-01

    Hydroxylamine (NH2OH) the substance which will turn out to be of importance to those interested in the treatment of organophosporus cholinesterase inhibitor exposure, was synthesized by Wilhem Clemens Lossen in 1865 while working in Halle as an assistant in the laboratory of Wilhelm Heinrich Heintz. The Lossen synthesis generated hydroxylamine in aqueous solution. Anhydrous hydroxylamine was prepared almost simultaneously by Lobry de Bruyn and Crismer (1891). Using hydroxylamine as a starting point Meyer synthesized aldoximes and ketoximes (1897). Lange, a PhD student of Ladenburg, isolated 2-methyl-pyridine (alpha-picoline). Some fifty years later Wilson, working in the laboratory of Nachmansohn, demonstrated the ability of hydroxylamine to reactivate cholinesterase inhibited by organophosphates. Finally Wilson and Ginsburg using 2-methyl-pyridine as a starting point synthesized the first pyridinium aldoxime reactivator of clinical relevance, pralidoxime (1955).

  9. miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia.

    Science.gov (United States)

    Anton, Lauren; Olarerin-George, Anthony O; Schwartz, Nadav; Srinivas, Sindhu; Bastek, Jamie; Hogenesch, John B; Elovitz, Michal A

    2013-11-01

    Preeclampsia is characterized by hypertension and proteinuria in pregnant women. Its exact cause is unknown. Preeclampsia increases the risk of maternal and fetal morbidity and mortality. Although delivery, often premature, is the only known cure, early targeted interventions may improve maternal and fetal outcomes. Successful intervention requires a better understanding of the molecular etiology of preeclampsia and the development of accurate methods to predict women at risk. To this end, we tested the role of miR-210, a miRNA up-regulated in preeclamptic placentas, in first-trimester extravillous trophoblasts. miR-210 overexpression reduced trophoblast invasion, a process necessary for uteroplacental perfusion, in an extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent manner. Conversely, miR-210 inhibition promoted invasion. Furthermore, given that the placenta secretes miRNAs into the maternal circulation, we tested if serum expression of miR-210 was associated with the disease. We measured miR-210 expression in two clinical studies: a case-control study and a prospective cohort study. Serum miR-210 expression was significantly associated with a diagnosis of preeclampsia (P = 0.007, area under the receiver operator curves = 0.81) and was predictive of the disease, even months before clinical diagnosis (P preeclampsia that can help in identifying at-risk women for monitoring and treatment. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  10. Serum Müllerian inhibiting substance levels are lower in premenopausal women with breast precancer and cancer

    Directory of Open Access Journals (Sweden)

    Sticca Robert

    2011-05-01

    Full Text Available Abstract Background In preclinical studies, müllerian inhibiting substance (MIS has a protective affect against breast cancer. Our objective was to determine whether serum MIS concentrations were associated with cancerous or precancerous lesions. Blood from 30 premenopausal women was collected and serum extracted prior to their undergoing breast biopsy to assess a suspicious lesion found on imaging or physical examination. Based on biopsy results, the serum specimens were grouped as cancer (invasive or ductal carcinoma in situ, precancer (atypical hyperplasia or lobular carcinoma in situ, or benign. Findings Serum from women with cancer and precancer (p = .0009 had lower MIS levels than serum from women with benign disease. Conclusion Our findings provide preliminary evidence for MIS being associated with current breast cancer risk, which should be validated in a larger population.

  11. Evidence that L-Arginine inhibits glycation of human serum albumin (HSA) in vitro

    International Nuclear Information System (INIS)

    Servetnick, D.A.; Wiesenfeld, P.L.; Szepesi, B.

    1990-01-01

    Previous work by Brownlee has shown that glycation of bovine serum albumin can be reduced in the presence of aminoguanidine (AG). Presumably, the guanidinium group on AG interferes with further rearrangement of amadori products to advanced glycosylated end products (AGE). Since L-arginine (ARG) also contains a guanidinium group, its ability to inhibit the formation of AGE products was investigated. HSA was incubated at 37 degrees C in the presence or absence of glucose; with glucose and fructose; or with sugars in the presence or absence of ARG or AG. A tracer amount of U- 14 C-glucose was added to each tube containing sugars. Protein bound glucose was separated from unreacted glucose by gel filtration. Radioactivity, total protein, fluorescence, and glucose concentration were measured. Preliminary data show enhanced binding of 14 C-glucose to HSA with fructose at all time points. A 30-40% decrease in 14 C-glucose incorporation was observed when ARG or AG as present. ARG and AG were equally effective in inhibiting incorporation of 14 C-glucose. FPLC analysis is in progress to determine the type and degree of HSA crosslinking during the 2 week incubation period

  12. Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: a review of recent clinical studies.

    Science.gov (United States)

    Darreh-Shori, T; Soininen, H

    2010-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline associated with a deficit in cholinergic function. Inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE), such as donepezil, galantamine or rivastigmine, are widely prescribed as symptomatic treatments for AD. These agents exhibit a wide variation in their pharmacological properties. Here we review clinical data from 1998 to 2009 investigating the effect of different cholinesterase inhibitor treatments on the levels and activities of cholinesterases in the cerebrospinal fluid (CSF) of AD patients. These studies suggest that treatment with rapidly-reversible cholinesterase inhibitors (e.g. donepezil, galantamine, tacrine) are associated with marked and significant upregulation of AChE activities and protein levels in the CSF of AD patients. In contrast, pseudo-irreversible cholinesterase inhibition (e.g. rivastigmine) is associated with a significant decrease in both CSF AChE and BuChE activities, with no upregulation of CSF protein levels. Additionally, donepezil is associated with a decrease in the level of the AChE-R isoform relative to the synaptic AChE-S isoform, whereas rivastigmine seems to increase this ratio. These findings suggest that these agents exert different effects on CSF cholinesterases. The clinical effects of these pharmacological differences are yet to be fully established.

  13. A monocyte chemotaxis inhibiting factor in serum of HIV infected men shares epitopes with the HIV transmembrane protein gp41

    NARCIS (Netherlands)

    Tas, M.; Drexhage, H. A.; Goudsmit, J.

    1988-01-01

    This report describes that gp41, the transmembranous envelope protein of HIV, is able to inhibit monocyte chemotaxis (measured as FMLP-induced polarization). To study the presence of such immunosuppressive HIV env proteins in the circulation of HIV-infected men, fractions were prepared from serum

  14. Inhibition of human lymphocyte proliferative response by serum from Plasmodium falciparum infected patients

    DEFF Research Database (Denmark)

    Theander, T G; Svenson, M; Bygbjerg, I C

    1987-01-01

    initiation of treatment suppressed the in vitro lymphocyte proliferative response to both Plasmodium-derived antigens and an unrelated antigen (PPD-tuberculin). The suppressive effect was lost if the serum was incubated at 56 degrees C for 30 min, and the effect was not HLA-restricted since the inhibition...

  15. Separation of hemagglutination-inhibiting immunoglobulin M antibody to rubella virus in human serum by high-performance liquid chromatography.

    OpenAIRE

    Kobayashi, N; Suzuki, M; Nakagawa, T; Matumoto, M

    1986-01-01

    High-performance liquid chromatography was successfully used to separate hemagglutination-inhibiting immunoglobulin M (IgM) rubella virus antibody from IgG rubella virus antibody in human serum. The fractionation by high-performance liquid chromatography was as effective as sucrose density gradient centrifugation in separating IgM antibody from IgG antibody.

  16. PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

    International Nuclear Information System (INIS)

    Ellison, Corie A.; Crane, Alice L.; Bonner, Matthew R.; Knaak, James B.; Browne, Richard W.; Lein, Pamela J.; Olson, James R.

    2012-01-01

    Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n = 120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase) and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P ≤ 0.05) and PON1 192 (P ≤ 0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal. -- Highlights: ► CPF exposure resulted in an increase in TCPy and decreases in BuChE and AChE. ► CPOase activity decreased in subjects with the PON1 55LM and PON1 55 MM genotypes. ► Neither PON1 genotype nor CPOase activity had an effect on BuChE or AChE inhibition.

  17. PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

    Energy Technology Data Exchange (ETDEWEB)

    Ellison, Corie A., E-mail: cellison@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Crane, Alice L., E-mail: alcrane@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Bonner, Matthew R., E-mail: mrbonner@buffalo.edu [Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Knaak, James B., E-mail: jbknaak@aol.com [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Browne, Richard W., E-mail: rwbrowne@buffalo.edu [Department of Biotechnical and Clinical Laboratory Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Lein, Pamela J., E-mail: pjlein@ucdavis.edu [Department of Molecular Biosciences, University of California School of Veterinary Medicine, Davis, CA 95618 (United States); Olson, James R., E-mail: jolson@buffalo.edu [Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 (United States); Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214 (United States)

    2012-12-15

    Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n = 120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase) and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P ≤ 0.05) and PON1 192 (P ≤ 0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal. -- Highlights: ► CPF exposure resulted in an increase in TCPy and decreases in BuChE and AChE. ► CPOase activity decreased in subjects with the PON1 55LM and PON1 55 MM genotypes. ► Neither PON1 genotype nor CPOase activity had an effect on BuChE or AChE inhibition.

  18. Changes of serum levels of prealbumin (PAB), cholinesterase (CHE), total bile acid (TBA) and ALT as related to the severity of inflammatory process and hepatic fibrosis in patients with chronic virus B hepatitis

    International Nuclear Information System (INIS)

    Chi Xiaoxia; Chen Jianxiong; Xiong Ying

    2005-01-01

    Objective: To study the correlationship between the serum levels of PAB, CHE, TBA, ALT and the severity of the disease process in patients with chronic virus B hepatitis. Methods: Serum levels of PAB, CHE, ALT (with biochemical methods) and TBA (with RIA) were examined in 93 patients with biopsy proven virus B hepatitis and 46 controls. Results: The 93 patients were of two groups: a less advanced group (n=51) and a more advanced group (n=42). Serum TBA, ALT levels were significnatly higher and serum PAB, CHE levels were significantly lower in the more advanced group than those in the less advanced group (P 0 to s 4 . Changes of levels of ALT were of no regular pattern, but serum levels of TBA regularly increased and levels of PAB, CHE regularly decreased as the fibrosis grading proceeded from s 0 to s 4 and the differences between the levels in s 4 and any other grading were significant (P<0.01). Conclusion: Combined determination of these serum markers might reflect the degree of inflammatory process and hepatic fibrosis in patients with virus B hepatitis, leading to earlier detection of cirrhosis. (authors)

  19. Selective inhibition of aggregation/fibrillation of bovine serum albumin by osmolytes: Mechanistic and energetics insights.

    Directory of Open Access Journals (Sweden)

    Moumita Dasgupta

    Full Text Available Bovine serum albumin (BSA is an important transport protein of the blood and its aggregation/fibrillation would adversely affect its transport ability leading to metabolic disorder. Therefore, understanding the mechanism of fibrillation/aggregation of BSA and design of suitable inhibitor molecules for stabilizing its native conformation, are of utmost importance. The qualitative and quantitative aspects of the effect of osmolytes (proline, hydroxyproline, glycine betaine, sarcosine and sorbitol on heat induced aggregation/fibrillation of BSA at physiological pH (pH 7.4 have been studied employing a combination of fluorescence spectroscopy, Rayleigh scattering, isothermal titration calorimetry (ITC, dynamic light scattering (DLS and transmission electron microscopy (TEM. Formation of fibrils by BSA under the given conditions was confirmed from increase in fluorescence emission intensities of Thioflavin T over a time period of 600 minutes and TEM images. Absence of change in fluorescence emission intensities of 8-Anilinonaphthalene-1-sulfonic acid (ANS in presence of native and aggregated BSA signify the absence of any amorphous aggregates. ITC results have provided important insights on the energetics of interaction of these osmolytes with different stages of the fibrillar aggregates of BSA, thereby suggesting the possible modes/mechanism of inhibition of BSA fibrillation by these osmolytes. The heats of interaction of the osmolytes with different stages of fibrillation of BSA do not follow a trend, suggesting that the interactions of stages of BSA aggregates are osmolyte specific. Among the osmolytes used here, we found glycine betaine to be supporting and promoting the aggregation process while hydroxyproline to be maximally efficient in suppressing the fibrillation process of BSA, followed by sorbitol, sarcosine and proline in the following order of their decreasing potency: Hydroxyproline> Sorbitol> Sarcosine> Proline> Glycine betaine.

  20. Lentiviral-mediated RNAi targeting caspase-3 inhibits apoptosis induced by serum deprivation in rat endplate chondrocytes in vitro

    International Nuclear Information System (INIS)

    Ding, L.; Wu, J.P.; Xu, G.; Zhu, B.; Zeng, Q.M.; Li, D.F.; Lu, W.

    2014-01-01

    Current studies find that degenerated cartilage endplates (CEP) of vertebrae, with fewer diffusion areas, decrease nutrient supply and accelerate intervertebral disc degeneration. Many more apoptotic cells have been identified in degenerated than in normal endplates, and may be responsible for the degenerated grade. Previous findings suggest that inhibition of apoptosis is one possible approach to improve disc regeneration. It is postulated that inhibition of CEP cell apoptosis may be responsible for the regeneration of endplates. Caspase-3, involved in the execution phase of apoptosis, is a candidate for regulating the apoptotic process. In the present study, CEP cells were incubated in 1% fetal bovine serum. Activated caspases were detected to identify the apoptotic pathway, and apoptosis was quantified by flow cytometry. Lentiviral caspase-3 short hairpin RNA (shRNA) was employed to study its protective effects against serum deprivation. Silencing of caspase-3 expression was quantified by reverse transcription-polymerase chain reaction and Western blots, and inhibition of apoptosis was quantified by flow cytometry. Serum deprivation increased apoptosis of rat CEP cells through activation of a caspase cascade. Lentiviral caspase-3 shRNA was successfully transduced into CEP cells, and specifically silenced endogenous caspase-3 expression. Surviving cells were protected by the downregulation of caspase-3 expression and activation. Thus, lentiviral caspase-3 shRNA-mediated RNAi successfully silenced endogenous caspase-3 expression, preventing inappropriate or premature apoptosis

  1. Lentiviral-mediated RNAi targeting caspase-3 inhibits apoptosis induced by serum deprivation in rat endplate chondrocytes in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Ding, L.; Wu, J.P. [Fudan University, Jinshan Hospital, Department of Orthopaedics, Shanghai, China, Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai (China); Xu, G. [Fudan University, Jinshan Hospital, Center Laboratory, Shanghai, China, Center Laboratory, Jinshan Hospital, Fudan University, Shanghai (China); Zhu, B.; Zeng, Q.M.; Li, D.F.; Lu, W. [Fudan University, Jinshan Hospital, Department of Orthopaedics, Shanghai, China, Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai (China)

    2014-05-09

    Current studies find that degenerated cartilage endplates (CEP) of vertebrae, with fewer diffusion areas, decrease nutrient supply and accelerate intervertebral disc degeneration. Many more apoptotic cells have been identified in degenerated than in normal endplates, and may be responsible for the degenerated grade. Previous findings suggest that inhibition of apoptosis is one possible approach to improve disc regeneration. It is postulated that inhibition of CEP cell apoptosis may be responsible for the regeneration of endplates. Caspase-3, involved in the execution phase of apoptosis, is a candidate for regulating the apoptotic process. In the present study, CEP cells were incubated in 1% fetal bovine serum. Activated caspases were detected to identify the apoptotic pathway, and apoptosis was quantified by flow cytometry. Lentiviral caspase-3 short hairpin RNA (shRNA) was employed to study its protective effects against serum deprivation. Silencing of caspase-3 expression was quantified by reverse transcription-polymerase chain reaction and Western blots, and inhibition of apoptosis was quantified by flow cytometry. Serum deprivation increased apoptosis of rat CEP cells through activation of a caspase cascade. Lentiviral caspase-3 shRNA was successfully transduced into CEP cells, and specifically silenced endogenous caspase-3 expression. Surviving cells were protected by the downregulation of caspase-3 expression and activation. Thus, lentiviral caspase-3 shRNA-mediated RNAi successfully silenced endogenous caspase-3 expression, preventing inappropriate or premature apoptosis.

  2. Lentiviral-mediated RNAi targeting caspase-3 inhibits apoptosis induced by serum deprivation in rat endplate chondrocytes in vitro

    Directory of Open Access Journals (Sweden)

    L. Ding

    2014-06-01

    Full Text Available Current studies find that degenerated cartilage endplates (CEP of vertebrae, with fewer diffusion areas, decrease nutrient supply and accelerate intervertebral disc degeneration. Many more apoptotic cells have been identified in degenerated than in normal endplates, and may be responsible for the degenerated grade. Previous findings suggest that inhibition of apoptosis is one possible approach to improve disc regeneration. It is postulated that inhibition of CEP cell apoptosis may be responsible for the regeneration of endplates. Caspase-3, involved in the execution phase of apoptosis, is a candidate for regulating the apoptotic process. In the present study, CEP cells were incubated in 1% fetal bovine serum. Activated caspases were detected to identify the apoptotic pathway, and apoptosis was quantified by flow cytometry. Lentiviral caspase-3 short hairpin RNA (shRNA was employed to study its protective effects against serum deprivation. Silencing of caspase-3 expression was quantified by reverse transcription-polymerase chain reaction and Western blots, and inhibition of apoptosis was quantified by flow cytometry. Serum deprivation increased apoptosis of rat CEP cells through activation of a caspase cascade. Lentiviral caspase-3 shRNA was successfully transduced into CEP cells, and specifically silenced endogenous caspase-3 expression. Surviving cells were protected by the downregulation of caspase-3 expression and activation. Thus, lentiviral caspase-3 shRNA-mediated RNAi successfully silenced endogenous caspase-3 expression, preventing inappropriate or premature apoptosis.

  3. Proline-Based Carbamates as Cholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Hana Pizova

    2017-11-01

    Full Text Available Series of twenty-five benzyl (2S-2-(arylcarbamoylpyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE, and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S-2-[(2-chlorophenylcarbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM was the most potent agent. On the other hand, benzyl (2S-2-[(4-bromophenyl-] and benzyl (2S-2-[(2-bromophenylcarbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S-2-[(2-hydroxyphenylcarbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA and principal component analysis (PCA. Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

  4. A review on cholinesterase inhibitors for Alzheimer's disease.

    Science.gov (United States)

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  5. Inactivation of pulmonary surfactant due to serum-inhibited adsorption and reversal by hydrophilic polymers: experimental

    DEFF Research Database (Denmark)

    Taeusch, H William; de la Serna, Jorge Bernardino; Perez-Gil, Jesus

    2005-01-01

    adsorption of surface active serum proteins. Aqueous suspensions of native porcine surfactant, organic extracts of native surfactant, and the clinical surfactants Curosurf, Infasurf, and Survanta spread on buffered subphases increase the surface pressure, pi, to approximately 40 mN/m within 2 min....... The variation with concentration, temperature, and mode of spreading confirmed Brewster angle microscopy observations that subphase to surface adsorption of surfactant is the dominant form of surfactant transport to the interface. However (with the exception of native porcine surfactant), similar rapid...... increases in pi did not occur when surfactants were applied to subphases containing serum. Components of serum are surface active and adsorb reversibly to the interface increasing pi up to a concentration-dependent saturation value, pi(max). When surfactants were applied to subphases containing serum...

  6. Serum amyloid P down-regulates CCL-1 expression, and inhibits ...

    African Journals Online (AJOL)

    Differentially expressed proteins in SAP-Tg and C57BL/6 serum were analyzed, and further determined by enzymelinked immunosorbent assay (ELISA) and ... SAP recombinant protein, ELISA results showed that CCL-1 secretion significantly ...

  7. Cholinesterase modulations in patients with acute bacterial meningitis

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Ofek, Keren; Qvist, Tavs

    2011-01-01

    The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis.......The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis....

  8. Phosalone-Induced Changes in Regional Cholinesterase Activities ...

    African Journals Online (AJOL)

    ... in Regional Cholinesterase Activities in Rat Brain during Behavioral Tolerance. ... lead to the gradual disappearance of the initial signs of toxicity over time, termed ... regions, striatum recorded a greater decrease in cholinesterase activity.

  9. Resorcinol-, catechol- and saligenin-based bronchodilating β2-agonists as inhibitors of human cholinesterase activity.

    Science.gov (United States)

    Bosak, Anita; Knežević, Anamarija; Gazić Smilović, Ivana; Šinko, Goran; Kovarik, Zrinka

    2017-12-01

    We investigated the influence of bronchodilating β2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with K i constants ranging from 9.4 μM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional π-π interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases.

  10. Anti-cholinesterase activity of the standardized extract of Syzygium aromaticum L.

    Science.gov (United States)

    Dalai, Manoj K; Bhadra, Santanu; Chaudhary, Sushil K; Bandyopadhyay, Arun; Mukherjee, Pulok K

    2014-04-01

    Clove (Syzygium aromaticum) is a well-known culinary spice with strong aroma; contains a high amount of oil known as clove oil. The major phyto-constituent of the clove oil is eugenol. Clove and its oil possess various medicinal uses in indigenous medicine as an antiseptic, anti-oxidant, analgesic and neuroprotective properties. Thus, it draws much attention among researchers from pharmaceutical, food and cosmetic industries. The aim of the present study was to determine the anti-cholinesterase activity of the methanol extract of clove, its oil and eugenol. In vitro anti-cholinesterase activity of S. aromaticum was performed by a thin layer chromatography bio autography, 96 well micro titer plate and kinetic methods. Reverse phase high performance liquid chromatography (RP-HPLC) analysis was carried out to identify the biomarker compound eugenol in clove oil. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition study revealed that eugenol possess better inhibition of the enzymes than extract and oil. Clove extract, its oil and eugenol showed better inhibition of AChE than BChE. Polyphenolic compound eugenol was detected through RP-HPLC analysis. The content of eugenol in essential oil was found to be 0.5 μg/ml. Kinetic analysis of the cholinesterase inhibition study of the extract; clove oil and eugenol have shown that they possess mixed type of inhibition for AChE and non-competitive type of inhibition for BChE. These results might be useful in explaining the effect of clove as anti-cholinesterase agent for the management of cognitive ailments like Alzheimer's disease.

  11. Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia.

    Science.gov (United States)

    Vidal-Petiot, Emmanuelle; Rea, Delphine; Serrano, Fidéline; Stehlé, Thomas; Gardin, Claude; Rousselot, Philippe; Peraldi, Marie-Noëlle; Flamant, Martin

    2016-03-01

    Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated. We retrospectively analyzed data from imatinib-treated patients explored in our renal physiology unit with measurement of glomerular filtration rate (urinary clearance of (51)CrEDTA) and of urinary clearance and tubular secretion of creatinine. Results were compared with those of controls matched for measured glomerular filtration rate, age, gender, and ethnicity. We also analyzed variations of serum creatinine before and during imatinib cessation and after imatinib resumption in patients enrolled in imatinib discontinuation studies. In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, -1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%. Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Development of Cholinesterase Inhibitors Using (a)-Lipoic Acid-benzyl Piperazine Hybrid Molecules

    International Nuclear Information System (INIS)

    Kim, Beomcheol; Lee, Seunghwan; Jang, Mi; Shon, Min Young; Park, Jeong Ho

    2013-01-01

    A series of hybrid molecules between (α)-lipoic acid (ALA) and benzyl piperazines were synthesized and their in vitro cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory activities were evaluated. Even though the parent compounds did not show any inhibitory activity against cholinesterase (ChE), all hybrid molecules showed BuChE inhibitory activity. Some hybrid compounds also displayed AChE inhibitory activity. Specifically, ALA-1-(3-methylbenzyl)piperazine (15) was shown to be an effective inhibitor of both BuChE (IC 50 = 2.3 ± 0.7 μM) and AChE (IC 50 = 30.31 ± 0.64 μM). An inhibition kinetic study using compound 15 indicated a mixed inhibition type. Its binding affinity (K i ) value to BuChE is 2.91 ± 0.15 μM

  13. Development of Cholinesterase Inhibitors Using (a)-Lipoic Acid-benzyl Piperazine Hybrid Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Beomcheol; Lee, Seunghwan; Jang, Mi; Shon, Min Young; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of)

    2013-11-15

    A series of hybrid molecules between (α)-lipoic acid (ALA) and benzyl piperazines were synthesized and their in vitro cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory activities were evaluated. Even though the parent compounds did not show any inhibitory activity against cholinesterase (ChE), all hybrid molecules showed BuChE inhibitory activity. Some hybrid compounds also displayed AChE inhibitory activity. Specifically, ALA-1-(3-methylbenzyl)piperazine (15) was shown to be an effective inhibitor of both BuChE (IC{sub 50} = 2.3 ± 0.7 μM) and AChE (IC{sub 50} = 30.31 ± 0.64 μM). An inhibition kinetic study using compound 15 indicated a mixed inhibition type. Its binding affinity (K{sub i}) value to BuChE is 2.91 ± 0.15 μM.

  14. A step toward the reactivation of aged cholinesterases-crystal structure of ligands binding to aged human butyrylcholinesterase

    NARCIS (Netherlands)

    Wandhammer, M.; Koning, M. de; Grol, M. van; Loiodice, M.; Saurel, L.; Noort, D.; Goeldner, M.; Nachon, F.

    2013-01-01

    Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no

  15. Multitarget Therapeutic Leads for Alzheimer's Disease: Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β-Amyloid (Aβ) Aggregation.

    Science.gov (United States)

    Tonelli, Michele; Catto, Marco; Tasso, Bruno; Novelli, Federica; Canu, Caterina; Iusco, Giovanna; Pisani, Leonardo; Stradis, Angelo De; Denora, Nunzio; Sparatore, Anna; Boido, Vito; Carotti, Angelo; Sparatore, Fabio

    2015-06-01

    Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β-amyloid (Aβ) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Aβ(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β-amyloid. In most cases, IC50 values were in the low micromolar and sub-micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 μM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Evolution of cholinesterases in the animal kingdom.

    Science.gov (United States)

    Pezzementi, Leo; Chatonnet, Arnaud

    2010-09-06

    Cholinesterases emerged from a family of enzymes and proteins with adhesion properties. This family is absent in plants and expanded in multicellular animals. True cholinesterases appeared in triploblastic animals together with the cholinergic system. Lineage specific duplications resulted in two acetylcholinesterases in most hexapods and in up to four genes in nematodes. In vertebrates the duplication leading to acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is now considered to be an ancient event which occurred before the split of osteichthyes. The product of one or the other of the paralogues is responsible for the physiological hydrolysis of acetylcholine, depending on the species lineage and tissue considered. The BChE gene seems to have been lost in some fish lineages. The complete genome of amphioxus (Branchiostoma floridae: cephalochordate) contains a large number of duplicated genes or pseudogenes of cholinesterases. Sequence comparison and tree constructions raise the question of considering the atypical ChE studied in this organism as a representative of ancient BChE. Thus nematodes, arthropods, annelids, molluscs, and vertebrates typically possess two paralogous genes coding for cholinesterases. The origin of the duplication(s) is discussed. The mode of attachment through alternative C-terminal coding exons seems to have evolved independently from the catalytic part of the gene. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  17. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor removal during reclamation of sewage to drinking water. ... Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water ...

  18. Inhibition of pulmonary surfactant adsorption by serum and the mechanisms of reversal by hydrophilic polymers: theory

    DEFF Research Database (Denmark)

    Zasadzinski, Joseph A; Alig, T F; Alonso, Coralie

    2005-01-01

    . The depletion force increases with polymer concentration as well as with polymer molecular weight. Increasing the surfactant concentration has a much smaller effect than adding polymer, as is observed. Natural hydrophilic polymers, like the SP-A present in native surfactant, or hyaluronan, normally present...... with the observations reported in the companion article (pages 1769-1779). Adding nonadsorbing, hydrophilic polymers to the subphase provides a depletion attraction between the surfactant aggregates and the interface, which can overcome the steric and electrostatic resistance to adsorption induced by serum...

  19. Dietary Compound Kaempferol Inhibits Airway Thickening Induced by Allergic Reaction in a Bovine Serum Albumin-Induced Model of Asthma.

    Science.gov (United States)

    Shin, Daekeun; Park, Sin-Hye; Choi, Yean-Jung; Kim, Yun-Ho; Antika, Lucia Dwi; Habibah, Nurina Umy; Kang, Min-Kyung; Kang, Young-Hee

    2015-12-16

    Asthma is characterized by aberrant airways including epithelial thickening, goblet cell hyperplasia, and smooth muscle hypertrophy within the airway wall. The current study examined whether kaempferol inhibited mast cell degranulation and prostaglandin (PG) release leading to the development of aberrant airways, using an in vitro model of dinitrophenylated bovine serum albumin (DNP-BSA)-sensitized rat basophilic leukemia (RBL-2H3) mast cells and an in vivo model of BSA-challenged asthmatic mice. Nontoxic kaempferol at 10-20 μM suppressed β-hexosaminidase release and cyclooxygenase 2 (COX2)-mediated production of prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) in sensitized mast cells. Oral administration of ≤20 mg/kg kaempferol blocked bovine serum albumin (BSA) inhalation-induced epithelial cell excrescence and smooth muscle hypertrophy by attenuating the induction of COX2 and the formation of PGD2 and PGF2α, together with reducing the anti-α-smooth muscle actin (α-SMA) expression in mouse airways. Kaempferol deterred the antigen-induced mast cell activation of cytosolic phospholipase A2 (cPLA2) responsive to protein kinase Cμ (PKCμ) and extracellular signal-regulated kinase (ERK). Furthermore, the antigen-challenged activation of Syk-phospholipase Cγ (PLCγ) pathway was dampened in kaempferol-supplemented mast cells. These results demonstrated that kaempferol inhibited airway wall thickening through disturbing Syk-PLCγ signaling and PKCμ-ERK-cPLA2-COX2 signaling in antigen-exposed mast cells. Thus, kaempferol may be a potent anti-allergic compound targeting allergic asthma typical of airway hyperplasia and hypertrophy.

  20. [The activity of blood cholinesterase in rats exposed to dimehypo].

    Science.gov (United States)

    Wan, Weiguo; Xu, Mailing; Zou, Hejian; Lu, Ailing; Shen, Xinyu; Chen, Yuming

    2002-12-01

    To determine whether and to what degree the activity of cholinesterase(ChE) is inhibited by dimehypo at different doses of dimehypo [scientific name: 2-dimethylamine-1,3-bi(sodium hyposulfit)]. Rats were dosed with dimehypo or methamidophos orally, and were randomly divided into four subgroups according to the pesticide doses, which were 1/16, 1/8, 1/4 and 1/2 of LD50 respectively(the LD50 of dimethypo and methamidophos is 342 mg/kg and 20 mg/kg respectively). The activity of ChE in blood was determined before and 30 min, 1, 2, 4 and 24 h after exposure. The modified Ellman Method was employed to measure the activity of ChE. 1/16 LD50 dose of dimehypo did not affect the activity of ChE. When the dose increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of dimehypo inhibited the activity of ChE by 35.9% compared with that of control group(P dimehypo at various doses was significantly lower than that in the rats dosed with corresponding doses of methamidophos(P dimehypo may inhibit the activity of ChE. However, as compared with methamidophos, dimehypo is a weaker inhibitor of ChE.

  1. Correlation interrelation between level of catecholamines and indices of cholinesterase system at minor radiation dose influence on liquidators of the Chernobyl NPP

    International Nuclear Information System (INIS)

    Makashev, Zh.K.; Zhurnist, A.G.; Uteshev, A.G.; Abylaev, Zh.A.

    2004-01-01

    For assessment of functional condition of sympathoadrenal system adrenalin (A) and noradrenaline (NA) concentrations were investigated as well as NA/A ratio in day's urine of Chernobyl NPP liquidators. Concurrently, it was determined the contents of acetylcholine and activity of cholinesterase in the blood serum of persons exposed to minor radiation dose with calculation of correlation Pearson coefficient. (author)

  2. Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors.

    Science.gov (United States)

    Botić, Tanja; Defant, Andrea; Zanini, Pietro; Žužek, Monika Cecilija; Frangež, Robert; Janussen, Dorte; Kersken, Daniel; Knez, Željko; Mancini, Ines; Sepčić, Kristina

    2017-08-18

    The brominated pyrroloiminoquinone alkaloids discorhabdins B, L and G and 3-dihydro-7,8- dehydrodiscorhabdin C, isolated from methanol extracts of two specimens of Latrunculia sp. sponges collected near the Antarctic Peninsula, are here demonstrated for the first time to be reversible competitive inhibitors of cholinesterases. They showed K i for electric eel acetylcholinesterase of 1.6-15.0 μM, for recombinant human acetylcholinesterase of 22.8-98.0 μM, and for horse serum butyrylcholinesterase of 5.0-76.0 μM. These values are promising when compared to the current cholinesterase inhibitors used for treatment of patients with Alzheimer's disease, to counteract the acetylcholine deficiency in the brain. Good correlation was obtained between IC 50 data and results by molecular docking calculation on the binding interactions within the acetylcholinesterase active site, which also indicated the moieties in discorhabdin structures involved. To avoid unwanted peripheral side effects that can appear in patients using some acetylcholinesterase inhibitors, electrophysiological experiments were carried out on one of the most active of these compounds, discorhabdin G, which confirmed that it had no detectable undesirable effects on neuromuscular transmission and skeletal muscle function. These findings are promising for development of cholinesterase inhibitors based on the scaffold of discorhabdins, as potential new agents for treatment of patients with Alzheimer's disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Maternal serum alpha-fetoprotein levels are normal in Fanconi anemia: Can it be a lack of postnatal inhibition of AFP gene resulting in the elevation?

    Science.gov (United States)

    Aslan, Deniz; Karabacak, Recep Onur; Aslan, Oner Deniz

    2017-04-01

    We investigated the feasibility of using serum alpha-fetoprotein (AFP) levels as a screening test for prenatal diagnosis of Fanconi anemia (FA). Serial measurements in maternal serum were recorded. Parents, both heterozygous for FA, had declined prenatal molecular testing. The infant was born with no somatic abnormalities, and FA was confirmed by postnatal molecular analysis. Maternal serum AFP levels during each trimester of pregnancy were normal indicating that these levels cannot be used as a screening test in prenatal diagnosis. Three-year follow-up after birth showed constantly elevated serum levels in the patient from the start, suggesting a lack of postnatal inhibition on AFP gene. © 2016 Wiley Periodicals, Inc.

  4. Isolation and characterization of full-length cDNA clones coding for cholinesterase from fetal human tissues

    International Nuclear Information System (INIS)

    Prody, C.A.; Zevin-Sonkin, D.; Gnatt, A.; Goldberg, O.; Soreq, H.

    1987-01-01

    To study the primary structure and regulation of human cholinesterases, oligodeoxynucleotide probes were prepared according to a consensus peptide sequence present in the active site of both human serum pseudocholinesterase and Torpedo electric organ true acetylcholinesterase. Using these probes, the authors isolated several cDNA clones from λgt10 libraries of fetal brain and liver origins. These include 2.4-kilobase cDNA clones that code for a polypeptide containing a putative signal peptide and the N-terminal, active site, and C-terminal peptides of human BtChoEase, suggesting that they code either for BtChoEase itself or for a very similar but distinct fetal form of cholinesterase. In RNA blots of poly(A) + RNA from the cholinesterase-producing fetal brain and liver, these cDNAs hybridized with a single 2.5-kilobase band. Blot hybridization to human genomic DNA revealed that these fetal BtChoEase cDNA clones hybridize with DNA fragments of the total length of 17.5 kilobases, and signal intensities indicated that these sequences are not present in many copies. Both the cDNA-encoded protein and its nucleotide sequence display striking homology to parallel sequences published for Torpedo AcChoEase. These finding demonstrate extensive homologies between the fetal BtChoEase encoded by these clones and other cholinesterases of various forms and species

  5. Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

    Science.gov (United States)

    Chen, Yao; Zhu, Jie; Mo, Jun; Yang, Hongyu; Jiang, Xueyang; Lin, Hongzhi; Gu, Kai; Pei, Yuqiong; Wu, Liang; Tan, Renxiang; Hou, Jing; Chen, Jingyi; Lv, Yang; Bian, Yaoyao; Sun, Haopeng

    2018-12-01

    Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC 50  = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.

  6. Cholinesterase Enzymes Inhibitors from the Leaves of Rauvolfia Reflexa and Their Molecular Docking Study

    Directory of Open Access Journals (Sweden)

    Vikneswaran Murugaiyah

    2013-03-01

    Full Text Available Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E-3-(3,4,5-trimethoxyphenylacrylic acid (1, (E-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl acrylate (2, 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3 and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4. The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM and BChE (IC50 = 61.72 µM, respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

  7. Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.

    Science.gov (United States)

    Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran

    2013-03-25

    Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

  8. THE BACTERICIDAL ACTIVITY OF NORMAL GUINEA PIG SERUM AGAINST LISTERIA MONOCYTOGENES AND ITS INHIBITION BY A LISTERIAL CELL EXTRACT,

    Science.gov (United States)

    Normal guinea pig serum contains bactericidins active against Listeria monocytogenes. The listeriocidal activity of the serum did not increase after...factor. Lysozyme was not implicated in the bactericidal system. It was suggested that the bactericidal activity of guinea pig serum might be due either to

  9. Characterization of cholinesterases in plasma of three Portuguese native bird species: application to biomonitoring.

    Directory of Open Access Journals (Sweden)

    Cátia S A Santos

    Full Text Available Over the last decades the inhibition of plasma cholinesterase (ChE activity has been widely used as a biomarker to diagnose organophosphate and carbamate exposure. Plasma ChE activity is a useful and non-invasive method to monitor bird exposure to anticholinesterase compounds; nonetheless several studies had shown that the ChE form(s present in avian plasma may vary greatly among species. In order to support further biomonitoring studies and provide reference data for wildlife risk-assessment, plasma cholinesterase of the northern gannet (Morus bassanus, the white stork (Ciconia ciconia and the grey heron (Ardea cinerea were characterized using three substrates (acetylthiocholine iodide, propionylthiocholine iodide, and S-butyrylthiocholine iodide and three ChE inhibitors (eserine sulphate, BW284C51, and iso-OMPA. Additionally, the range of ChE activity that may be considered as basal levels for non-exposed individuals was determined. The results suggest that in the plasma of the three species studied the main cholinesterase form present is butyrylcholinesterase (BChE. Plasma BChE activity in non-exposed individuals was 0.48±0.11 SD U/ml, 0.39±0.12 SD U/ml, 0.15±0.04 SD U/ml in the northern gannet, white stork and grey heron, respectively. These results are crucial for the further use of plasma BChE activity in these bird species as a contamination bioindicator of anti-cholinesterase agents in both wetland and marine environments. Our findings also underscore the importance of plasma ChE characterization before its use as a biomarker in biomonitoring studies with birds.

  10. [Cholinesterase inhibitors for treating dementia. Review].

    Science.gov (United States)

    Kremer, Janus

    2010-01-01

    Alzheimer's disease is the most common form of dementia seen in the clinical practice. The principal risk factor is aging. There is not currently any available curative medication. However, there a family of drugs call the cholinesterase inhibitors (donepezile, galantamine and rivastigmine) the enhances cholinergic activity in the CNS. Also, memantine is available is a NMDA receptor modulator. A new transdermal way of administration is available now for rivastigmine. The rivastigmines patches are now a rational alternative focusing in getting more tolerance, better blood levels of the drug and compliance to treatment in Alzheimer's disease patients.

  11. In Search of an Effective in vivo Reactivator for Organophosphorus Nerve Agent-Inhibited Acetylcholinesterase in the Central Nervous System

    Science.gov (United States)

    2012-01-01

    nerve agents, such as sarin (GB), cyclosarin (GF), and VX, are potent inhibitors of the enzyme cholinesterase (ChE). Their toxic effects are due to...three nerve agents. Keywords: acetylcholinesterase; brain; cholinesterase inhibition; cholinesterase reactivation; cyclosarin; diacetylmonoxime...attributed, at least in part, to nuclophilic impedance [Ekstrom et al., 2006a; b; Hoskovcova et al., 2007]. Other AChE- inhibitors , such as soman, become

  12. Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation.

    Science.gov (United States)

    Li, Yan-Ping; Ning, Fang-Xian; Yang, Meng-Bi; Li, Yong-Cheng; Nie, Min-Hua; Ou, Tian-Miao; Tan, Jia-Heng; Huang, Shi-Liang; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

    2011-05-01

    A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  13. Brain cholinesterase response in the snakehead fish (Channa striata) after field exposure to diazinon

    DEFF Research Database (Denmark)

    van Cong, Nguyen; Phuong, Nguyen Thanh; Bayley, Mark

    2008-01-01

    The snakehead Channa striata is an economically important air-breathing fish species in the Mekong delta of Vietnam. Rice paddies, which are disturbed by the frequent application of agro-chemicals, are among the preferred habitats for this species during the rainy season. Diazinon is one of most...... commonly used chemicals in rice paddies. In the present study, exposure of adult snakehead fish to a single diazinon application in cages within a rice field resulted in long-term brain cholinesterase inhibition, while the water concentration of this insecticide fell below the detection limit within 3 days...

  14. [Correlation and conversion of plasma cholinesterase activity values using three techniques].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2007-07-01

    To determine mathematical correlations of three quantitative techniques to measure plasma cholinesterase, using reference values already established for two populations in the department of Antioquia, Colombia. In this descriptive, cross-sectional, prospective study, two independent, representative samples of working adults (18 to 65 years old) were examined. In both samples the adults worked for businesses associated with Colombia's Social Security system. Adults in the two samples had not been exposed to cholinesterase-inhibiting pesticides. The samples were from two neighboring regions of the department of Antioquia: one sample (415 adults) was from the Aburrá Valley, and the other (412 adults) was from Oriente Antioqueño (Eastern Antioquia). Plasma cholinesterase (EC 3.1.1.8) was measured using three quantitative methods: Michel, EQM, and Monotest. Linear regression equations were developed to correlate results of these three techniques. Six simple linear regression equations were defined to show the relationship of three measurement techniques for plasma cholinesterase. There was a moderate correlation of the three techniques (r = 0.686 to 0.771), but it increased (r = 0.744 to 0.811) when 12 (1.5%) outliers were eliminated. Associations among the three techniques were highly significant (P EQM (U/mL) = 0.40773 + 1.8757 (Michel [delta pH/h]); Michel (delta pH/h) = 0.25799 + 0.33871 (EQM [U/mL]); Monotest (U/L) = 462.0 + 4 565.0 (Michel [delta pH/h]); Michel (delta pH/h) = 0.42956 + 0.00012125 (Monotest [U/L]); EQM (U/mL) = 0.75333 + 0.00031056 (Monotest [U/L]); and Monotest (U/L) = 262.0 + 2 118.0 (EQM [U/mL]). The proposed mathematical models allow conversion of cholinesterase activity values using the Michel, EQM, and Monotest techniques. These models can be of assistance in Colombia and other countries where a variety of measurement techniques are used, and where it becomes difficult to compare the results of different studies. Having mathematical models

  15. Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

    Science.gov (United States)

    Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

    2014-07-15

    The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. The role of enzyme and substrate concentration in the evaluation of serum angiotensin converting enzyme (ACE) inhibition by enalaprilat in vitro.

    Science.gov (United States)

    Weisser, K; Schloos, J

    1991-10-09

    The relationship between serum angiotensin converting enzyme (ACE) activity and concentration of the ACE inhibitor enalaprilat was determined in vitro in the presence of different concentrations (S = 4-200 mM) of the substrate Hip-Gly-Gly. From Henderson plots, a competitive tight-binding relationship between enalaprilat and serum ACE was found yielding a value of approximately 5 nM for serum ACE concentration (Et) and an inhibition constant (Ki) for enalaprilat of approximately 0.1 nM. A plot of reaction velocity (Vi) versus total inhibitor concentration (It) exhibited a non-parallel shift of the inhibition curve to the right with increasing S. This was reflected by apparent Hill coefficients greater than 1 when the commonly used inhibitory sigmoid concentration-effect model (Emax model) was applied to the data. Slopes greater than 1 were obviously due to discrepancies between the free inhibitor concentration (If) present in the assay and It plotted on the abscissa and could, therefore, be indicators of tight-binding conditions. Thus, the sigmoid Emax model leads to an overestimation of Ki. Therefore, a modification of the inhibitory sigmoid Emax model (called "Emax tight model") was applied, which accounts for the depletion of If by binding, refers to It and allows estimation of the parameters Et and IC50f (free concentration of inhibitor when 50% inhibition occurs) using non-linear regression analysis. This model could describe the non-symmetrical shape of the inhibition curves and the results for Ki and Et correlated very well with those derived from the Henderson plots. The latter findings confirm that the degree of ACE inhibition measured in vitro is, in fact, dependent on the concentration of substrate and enzyme present in the assay. This is of importance not only for the correct evaluation of Ki but also for the interpretation of the time course of serum ACE inhibition measured ex vivo. The non-linear model has some advantages over the linear Henderson

  17. Yi Qi Qing Re Gao-containing serum inhibits lipopolysaccharide-induced rat mesangial cell proliferation by suppressing the Wnt pathway and TGF-β1 expression.

    Science.gov (United States)

    Yang, Liping; Sun, Xueyan; Zhan, Yongli; Liu, Huijie; Wen, Yumin; Mao, Huimin; Dong, X I; Li, Ping

    2016-04-01

    The aim of the present study was to investigate the effect of Yi Qi Qing Re Gao-containing serum (YQ-S) on rat mesangial cell (MC) proliferation and to investigate the underlying mechanism. MCs were divided into the control, lipopolysaccharide (LPS)-stimulated, YQ-S and fosinopril-containing serum (For-S) groups, and cultured for 48 h. An MTT assay was used to evaluate the proliferation of MCs. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis were conducted to detect the expression levels of Wnt4, β-catenin and transforming growth factor (TGF)-β1 in MCs. The results indicated that YQ-S inhibited LPS-induced MC proliferation. The Wnt4 and TGF-β1 mRNA expression levels were reduced in the YQ-S group (P<0.01 or P<0.05). Furthermore, the Wnt4, β-catenin and TGF-β1 protein expression levels were suppressed in the YQ-S group (P<0.01 or P<0.05). Therefore, YQ-S appears to inhibit MC proliferation, and its mechanism may involve the inhibition of the Wnt signaling pathway and downregulation of TGF-β1 expression.

  18. Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

    Science.gov (United States)

    Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

    2015-06-01

    By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  20. Nutritional Supplementation Inhibits the Increase in Serum Malondialdehyde in Patients with Wet Age-Related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Toshiyuki Matsuura

    2017-01-01

    Full Text Available Purpose. To compare serum levels of malondialdehyde (MDA in patients with wet age-related macular degeneration (wAMD, patients with dry AMD (dAMD, and patients without AMD and to evaluate the efficacy of nutritional supplementation for treating elevated serum MDA in patients with wAMD. Methods. MDA levels were measured in sera from 20 patients with wAMD, 20 with dAMD, and 24 without AMD. Patients with wAMD were randomized to receive or not receive nutritional supplementation (10 patients in each group, and MDA levels were measured after 3 months of treatment. Results. MDA levels in patients with wAMD were significantly greater compared with patients without AMD. In eyes with wAMD, there was a significant correlation between MDA levels and choroidal neovascularization lesion area. Serum MDA levels decreased in most patients that received supplementation and significantly increased in those who did not. Conclusion. Baseline serum MDA levels were elevated in patients with wAMD, and MDA levels were directly correlated with choroidal neovascularization lesion area. In addition, nutritional supplementation appeared to exert a protective effect against oxidative stress in patients with wAMD.

  1. Human serum paraoxonase-1 (hPON1): in vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium.

    Science.gov (United States)

    Türkeş, Cüneyt; Söyüt, Hakan; Beydemir, Şükrü

    2015-01-01

    In this study, we investigated the effects of antibacterial drugs (moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium) on human serum paraoxonase-1 (hPON1) enzyme activity from human serum in vitro conditions. For this purpose, hPON1 enzyme was purified from human serum using simple chromatographic methods. The antibacterial drugs exhibited inhibitory effects on hPON1 at low concentrations. Ki constants were calculated to be 2.641 ± 0.040 mM, 5.525 ± 0.817 mM, 35.092 ± 1.093 mM, 252.762 ± 5.749 mM and 499.244 ± 10.149 mM, respectively. The inhibition mechanism of moxifloxacin hydrochloride was competitive, whereas levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium were noncompetitive inhibitors.

  2. The Tick Salivary Protein Salp15 Inhibits the Killing of Serum-Sensitive Borrelia burgdorferi Sensu Lato Isolates▿

    OpenAIRE

    Schuijt, Tim J.; Hovius, Joppe W. R.; van Burgel, Nathalie D.; Ramamoorthi, Nandhini; Fikrig, Erol; van Dam, Alje P.

    2008-01-01

    Borrelia burgdorferi, the agent of Lyme disease, is transmitted by ticks. During transmission from the tick to the host, spirochetes are delivered with tick saliva, which contains the salivary protein Salp15. Salp15 has been shown to protect spirochetes against B. burgdorferi-specific antibodies. We now show that Salp15 from both Ixodes ricinus and Ixodes scapularis protects serum-sensitive isolates of Borrelia burgdorferi sensu lato against complement-mediated killing. I. ricinus Salp15 show...

  3. Inhibition of serum cholesterol oxidation by dietary vitamin C and selenium intake in high fat fed rats.

    Science.gov (United States)

    Menéndez-Carreño, M; Ansorena, D; Milagro, F I; Campión, J; Martínez, J A; Astiasarán, I

    2008-04-01

    Cholesterol oxidation products (COPs) have been considered as specific in vivo markers of oxidative stress. In this study, an increased oxidative status was induced in Wistar rats by feeding them a high-fat diet (cafeteria diet). Another group of animals received the same diet supplemented with a combination of two different antioxidants, ascorbic acid (100 mg/kg rat/day) and sodium selenite (200 microg/kg rat/day) and a third group fed on a control diet. Total and individual COPs analysis of the different diets showed no differences among them. At the end of the experimental trial, rats were sacrificed and serum cholesterol, triglycerides and COPs were measured. None of the diets induced changes in rats body weight, total cholesterol and triglycerides levels. Serum total COPs in rats fed on the high-fat diet were 1.01 microg/ml, two times the amount of the control rats (0.47 microg/ml). When dietary antioxidant supplementation was given, serum total COPs concentration (0.44 microg/ml) showed the same levels than those of the rats on control diet. 7beta-hydroxycholesterol, formed non-enzymatically via cholesterol peroxidation in the presence of reactive oxygen species, showed slightly lower values in the antioxidant-supplemented animals compared to the control ones. This study confirms the importance of dietary antioxidants as protective factors against the formation of oxysterols.

  4. New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

    Science.gov (United States)

    Greig, Nigel H; Reale, Marcella; Tata, Ada M

    2013-08-01

    receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer's disease drugs.

  5. Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada.

    Directory of Open Access Journals (Sweden)

    Thibault B Ali

    Full Text Available This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS and the Canada Vigilance Adverse Reaction Database (CVARD concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR. A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001 and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001 databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

  6. Liquid chromatography-tandem mass spectrometry method for the measurement of serum mevalonic acid: a novel marker of hydroxymethylglutaryl coenzyme A reductase inhibition by statins.

    Science.gov (United States)

    Waldron, Jenna; Webster, Craig

    2011-05-01

    Mevalonic acid (MVA) is synthesized at an early and rate-limiting step in the biosynthesis of cholesterol by the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, and is a useful measure of statin efficacy or treatment. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum MVA has been developed. Following the in vitro conversion of MVA to mevalonic acid lactone (MVAL) in the serum, MVAL and a deuterated internal standard were extracted using an online solid-phase extraction procedure. Chromatographic separation was achieved using a Luna PFP column (Phenomenex), with enhanced selectivity and improved resolution for polar compounds. A gradient system was used, with mobile phase comprising methanol and water (5 mmol/L ammonium formate buffer, pH 2.5). Analysis was performed using an API 5000 tandem mass spectrometer (Applied Biosystems) in positive electrospray ionization mode. The method showed excellent recoveries (98 ± 8%) and imprecision (intra-assay coefficient of variation of 2.2% [6.5 ng/mL] and 2.6% [10.5 ng/mL], and inter-assay coefficient of variation of 9% [10.5 ng/mL]). The assay provides a calibration range up to 50 ng/mL with a limit of detection at 0.1 ng/mL. A simple, rapid and analytically specific method has been developed for the measurement of serum MVA, in the form of MVAL. The high analytical sensitivity of the method allows for accurate quantitation of MVAL in serum samples, both at the endogenous levels found in healthy individuals and in statin-treated patients where normal levels are expected to be greatly reduced through the inhibition of HMG-CoA reductase.

  7. Enhancement of anti-cholinesterase activity of Zingiber cassumunar essential oil using a microemulsion technique.

    Science.gov (United States)

    Okonogi, S; Chaiyana, W

    2012-10-01

    The aim of the present study was to enhance the cholinesterase inhibitory activity of Zingiber cassumunar (ZC) oil using a microemulsion (ME) technique. Pseudoternary phase diagrams of the oil, water, and surfactant/co-surfactant mixture were constructed using a water titration method. Effects of co-surfactant, surfactant/co-surfactant ratio, ionic strength, and pH were examined by means of the microemulsion region which existed in the phase diagrams. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were tested by Ellman's colorimetric assay. It was found that ZC oil possesses inhibitory activity against not only AChE but also BChE. Formulation of ZC oil as ME revealed that alkyl chain length and number of hydroxyl groups of co-surfactant exhibited a remarkable effect on the pseudoternary phase diagram. Longer alkyl chains and more hydroxyl groups gave smaller regions of MEs. Ionic strength also affected the ME region. However, the phase behavior was hardly influenced by pH. The suitable ZC oil ME was composed of Triton X-114 in combination with propylene glycol. The anti-cholinesterase activity of this ME was much higher than that of native ZC oil. It exhibited twenty times and twenty five times higher inhibitory activity against AChE and BChE, respectively. ZC oil loaded ME is an attractive formulation for further characterization and an in vivo study in an animal model with Alzheimer's disease.

  8. Structure-Based Search for New Inhibitors of Cholinesterases

    Directory of Open Access Journals (Sweden)

    Barbara Malawska

    2013-03-01

    Full Text Available Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC50 values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

  9. Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor.

    Science.gov (United States)

    Sagi, Yotam; Weinstock, Marta; Youdim, Moussa B H

    2003-07-01

    (R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.

  10. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus)

    International Nuclear Information System (INIS)

    Yuan, Lilai; Li, Jiasu; Zha, Jinmiao; Wang, Zijian

    2016-01-01

    Organophosphate flame retardants (OPFRs) have been detected at high concentrations in various environmental and biotic samples, but little is known about their toxicity. In this study, the potential neurotoxicity of three OPFRs (TCEP, TDCPP, and TPP) and Chlorpyrifos (CPF, an organophosphate pesticide) were compared in Chinese rare minnow using an acute toxicity test and a 21-day fish assay. The acute test demonstrated significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by CPF. Although significant AChE inhibition at high concentration of TPP was also observed, none of the OPFRs had effects similar to CPF on these enzymes, indicating that their acute toxicities to Chinese rare minnow may be unrelated to cholinesterase inhibition. In addition, the 21-day fish assay with TDCPP demonstrated no significant effects on cholinesterase activities or neurotransmitter levels. Nonetheless, this OPFR exhibited widespread effects on the neurotrophic factors and their receptors (e.g., ntf3, ntrk1, ntrk2, ngfr, and fgf2, fgf11, fgf22, fgfr4), indicating that TDCPP or other OPFRs may elicit neurological effects by targeting neurotrophic factors and their receptors in Chinese rare minnow. - Highlights: • Significant inhibition of AChE and BChE activities by CPF was observed. • None of the OPFRs had similar effects on the cholinesterase like the CPF. • TDCPP showed significant effects on the neurotrophic factor genes in rare minnow. - Although none of the tested OPFRs showed any significant effects on cholinesterase activities and neurotransmitter levels, TDCPP did elicit widespread effects on neurotrophic factor genes.

  11. Acetyl-cholinesterase Enzyme Inhibitory Effect of Calophyllum species

    African Journals Online (AJOL)

    Purpose: To search for new acetylcholinesterase enzyme inhibitors from Calopyllum species. Methods: Six stem bark extracts of Calophyllum inophyllum, C. soulattri, C. teysmannii, C. lowii, C. benjaminum and C. javanicum were subjected to anti-cholinesterase analysis against acetylcholinesterase (AChE) enzyme using ...

  12. Tritium labeling of a powerful methylphosphonate inhibitor of cholinesterase: synthesis and biological applications

    International Nuclear Information System (INIS)

    Balan, A.; Barness, I.; Simon, G.; Levy, D.; Ashani, Y.

    1988-01-01

    7-(Methylethoxy phosphinyloxy)-1-methyl-quinolinium iodide (MEPQ), a powerful anti-cholinesterase methylphosphonate ester, was labeled with tritium (9 Ci/mmol) at the methylphosphonyl moiety (TCH2P(O)(OR)X) by an iodine-tritium replacement reaction. Kinetic measurements of the rate of inhibition of acetylcholinesterase (AChE) by [ 3 H]MEPQ and its rate of hydrolysis in alkaline solution confirmed the identity of [ 3 H]MEPQ with authentic MEPQ, which was prepared by the same reaction sequences. Gel-filtration experiments verified the radiospecificity of [ 3 H]MEPQ. In vitro radiolabeling of both AChE and butyrylcholinesterase along with the whole-body autoradiography of [ 3 H]MEPQ-treated mice suggests that [ 3 H]MEPQ is a convenient marker for studying biological systems containing these esterases

  13. Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity

    Directory of Open Access Journals (Sweden)

    Nelson Jeng-Yeou Chear

    2016-04-01

    Full Text Available Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences.

  14. Edaravone protects against oxygen-glucose-serum deprivation/restoration-induced apoptosis in spinal cord astrocytes by inhibiting integrated stress response

    Directory of Open Access Journals (Sweden)

    Bin Dai

    2017-01-01

    Full Text Available We previously found that oxygen-glucose-serum deprivation/restoration (OGSD/R induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase (PERK, eukaryotic initiation factor 2-alpha (eIF2α and activating transcription factor 4 (ATF4. We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone (0.1, 1, 10, 100 μM treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated (p-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.

  15. Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model.

    Science.gov (United States)

    Nakada, Tomohisa; Kudo, Toshiyuki; Kume, Toshiyuki; Kusuhara, Hiroyuki; Ito, Kiyomi

    2018-02-01

    Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL cre ), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  16. [Reference values for erythrocyte cholinesterase activity in the working population of Antioquia, Colombia, according to the Michel and EQM techniques].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2003-11-01

    To establish reference values for erythrocyte cholinesterase (EC 3.1.1.7) activity for the active working population of two regions of the department of Antioquia, Colombia, that are located at different altitudes above sea level. We took representative samples from populations of active working persons 18 to 59 years old from two regions in the department of Antioquia: (1) the Aburrá Valley (1 540 m above sea level) and (2) the near east of the department (2 150 m above sea level). We excluded workers who were using cholinesterase-inhibiting substances in their work or at home, those who had a disease that altered their cholinesterase levels, and those who said they were not in good health. We measured the erythrocyte cholinesterase activity using two methods: (1) the Michel method and (2) the EQM method (EQM Research, Cincinnati, Ohio, United States of America). We carried out the measurements with 827 people, 415 from the Aburrá Valley and 412 from the near east region. We compared proportions using the chi-square test and Fisher's exact test. We utilized the Student's t test for independent samples to compare two averages. To simultaneously compare three or more averages, analysis of variance was used, followed by the Newman-Keuls multiple-range test. When the variables were not normally distributed or when the variances were not homogeneous, Kruskal-Wallis nonparametric analysis of variance was used to compare the medians. Three computer software programs were used in the statistical analysis: SPSS 9.0, SGPlus 7.1, and Epi Info 6.04. In all the statistical tests the level of significance was set at P EQM method was 35.21 U/g hemoglobin (95% CI: 34.82 to 35.60). With the Michel method: (1) the enzymatic activity differed significantly between the two regions, according to the Newman-Keuls test; (2) within each region, the enzymatic activity was significantly higher among males than among females, according to the Newman-Keuls test; and (3) in none of the

  17. The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

    Science.gov (United States)

    Chu, Xiaoyan; Bleasby, Kelly; Chan, Grace Hoyee; Nunes, Irene; Evers, Raymond

    2016-09-01

    In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  18. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

    Directory of Open Access Journals (Sweden)

    Kimia Hirbod

    2017-06-01

    Full Text Available Objective(s: To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole using dibromoalkanes 3a-m. Final compounds were evaluated against acetylcholinesterase (AChE and butyrylcholinesterase (BuChE by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 µM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.

  19. Butyryl- and acetyl-cholinesterase inhibitory activities in essential oils of Salvia species and their constituents.

    Science.gov (United States)

    Savelev, Sergey U; Okello, Edward J; Perry, Elaine K

    2004-04-01

    Extracts of Salvia (sage) species have been reported to have cholinergic activities relevant to the treatment of Alzheimer's disease. A lack of information on the inhibition of the enzyme butyrylcholinesterase, also considered to be a target in the treatment of the disease, prompted this in vitro investigation of the essential oils of S. fruticosa, S. lavandulaefolia, S. of ficinalis and S. of ficinalis var. purpurea for anti-butyrylcholinesterase activity. Dose-dependent inhibition of human cholinesterases by the extracts and constituents was determined using the method of Ellman. A time dependent increase in the inhibition of butyrylcholinesterase by the oils of S. fruticosa and S. of ficinalis var. purpurea was evident. IC(50) values decreased from 0.15 +/- 0.007 and 0.14 +/- 0.007 mg/mL after 5 min to 0.035 +/- 0.016 and 0.06 +/- 0.018 mg/mL after 90 min incubation time respectively. The slow onset of inhibition of butyrylcholinesterase was also shown by individual constituents, such as 3-carene and beta-pinene. Analyses of the chemical composition of the oils and anti-butyrylcholinesterase activity of their constituents revealed that none of the compounds tested would account for the total activity of the oils and that synergy is likely. Copyright 2004 John Wiley & Sons, Ltd.

  20. The kinetics of the phospholipase A2-catalyzed hydrolysis of Egg phosphatidylcholine in unilamellar vesicles. Product inhibition and its relief by serum albumin.

    Science.gov (United States)

    Kupferberg, J P; Yokoyama, S; Kézdy, F J

    1981-06-25

    Only the lecithin in the outer leaflet (representing 70% of the total) of egg lecithin unilamellar vesicles is hydrolyzed by Crotalus atrox phospholipase A2. Hydrolyzed vesicles remain intact and impermeable to ionic solutes. The fatty acids produced in the hydrolysis remain on the vesicle and are only partially ionized at neutral pH due to electrostatic repulsions. About 40% of the lysolecithin product is desorbed from the vesicle. In the presence of a large excess of bovine serum albumin, the reaction is first order with respect to both the enzyme and the substrate. At 21 degrees C, pH 7.2, I = 0.16 M, and [Ca2+] = 7 mM, the second order rate constant is kex(2) = 1.5 X 10(6) M-1 s-1. In the absence of albumin, the reaction is inhibited competitively by both the monomeric (KIm = 4.5 X 10(-8) M) and micellar (nKIa = 3.7 X 10(-7) M) forms of lysolecithin ([critical micelle concentration] = 4.3 X 10(-6) M). Bovine serum albumin complexes two molecules of lysolecithin with a dissociation constant, Kb = 5 X 10(-8) M. With substoichiometric albumin, the reaction is biphasic, and, when the albumin is saturated with lysolecithin, the kinetics become similar to those observed in the absence of albumin. The action of phospholipase A2 shows that in unilamellar vesicles there is only one major lecithin conformation in the outer leaflet, or that all conformations are rapidly interconvertible.

  1. Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer's disease.

    Science.gov (United States)

    Lan, Jin-Shuai; Hou, Jian-Wei; Liu, Yun; Ding, Yue; Zhang, Yong; Li, Ling; Zhang, Tong

    2017-12-01

    A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC 50 , 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 μM for eqBuChE and 4.4 μM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aβ (1-42) aggregation (64.7% at 20 μM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer's diseases.

  2. Histochemical localization of cholinesterase activity in the dental epithelium of guinea pig teeth.

    Science.gov (United States)

    Jayawardena, C K; Takano, Y

    2004-07-01

    Cholinesterase is known for its remarkable diversity in distribution and function. An association of this enzyme with proliferative and morpho-differentiating tissues has been reported in several species. Here we report on the first evidence of the presence of cholinesterase in the enamel organ of continuously erupting incisors and molars of the guinea pig. Frozen sections of the incisors and molars of the guinea pig were incubated for histochemical demonstration of cholinesterase activity by means of the thiocholine method as described by Karnovsky and Root. The cholinesterase activity was observed in several types of cells of the dental epithelium; cells forming the basal portion of the enamel organ, outer enamel epithelium and maturation stage ameloblasts of both the incisors and molars. In the crown analogue side, the outer enamel epithelial cells gained strong reactions for cholinesterase and maintained the reaction throughout the secretory and maturation stages of amelogenesis. In contrast, cholinesterase reactions were lacking in the inner enamel epithelium, pre-ameloblasts, and secretory ameloblasts. In the early stage of enamel maturation, ameloblasts began to show positive reactions for cholinesterase, which was upregulated in the incisal direction. Although both tooth types showed similar reactive patterns for cholinesterase at the growing ends, maturation ameloblasts depicted a different pattern of staining displaying the reactions only sporadically in molars. These data indicate the role of cholinesterase in the enamel organ in tooth morphogenesis and function of guinea pig teeth. Copyright 2004 Springer-Verlag

  3. Cholinesterase inhibitory activity and structure elucidation of a new phytol derivative and a new cinnamic acid ester from Pycnanthus angolensis

    Directory of Open Access Journals (Sweden)

    Taiwo O. Elufioye

    Full Text Available ABSTRACT The leaves of Pycnanthus angolensis (Welw. Warb., Myristicaceae, are used as memory enhancer and anti-ageing in Nigerian ethnomedicine. This study aimed at evaluating the cholinesterase inhibitory property as well as isolates the bioactive compounds from the plant. The acetylcholinesterase and butyrylcholinesterase inhibitory potentials of extracts, fractions, and isolated compounds were evaluated by colorimetric and TLC bioautographic assay techniques. The extract inhibited both enzymes with activity increasing with purification, ethyl acetate fraction being most active fraction at 65.66 ± 1.06% and 49.38 ± 1.66% against acetylcholinesterase and butyrylcholinesterase, respectively while the supernatant had 77.44 ± 1.18 inhibition against acetylcholinesterase. Two new bioactive compounds, (2E, 18E-3,7,11,15,18-pentamethylhenicosa-2,18-dien-1-ol (named eluptol and [12-(4-hydroxy-3-methyl-oxo-cyclopenta-1,3-dien-1yl-11-methyl-dodecyl](E-3-(3,4-dimethylphenylprop-2-enoate (named omifoate A were isolated from the plant with IC50 of 22.26 µg/ml (AChE, 34.61 µg/ml (BuChE and 6.51 µg/ml (AChE, 9.07 µg/ml (BuChE respectively. The results showed that the plant has cholinesterase inhibitory activity which might be responsible for its memory enhancing action, thus justifying its inclusion in traditional memory enhancing preparations

  4. Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease.

    Science.gov (United States)

    Chioua, Mourad; Pérez, Marta; Bautista-Aguilera, Oscar M; Yañez, Matilde; López, Manuela G; Romero, Alejandro; Cacabelos, Ramón; de la Bellacasa, Raimon Puig; Brogi, Simone; Butini, Stefania; Borrell, José I; Marco-Contelles, Jose

    2015-01-01

    This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.

  5. Advances toward multifunctional cholinesterase and β-amyloid aggregation inhibitors.

    Science.gov (United States)

    Panek, Dawid; Wichur, Tomasz; Godyń, Justyna; Pasieka, Anna; Malawska, Barbara

    2017-10-01

    The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with β-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-β-secretase or τ-antiaggregation activity.

  6. Dual inhibitors of cholinesterases and monoamine oxidases for Alzheimer's disease.

    Science.gov (United States)

    Knez, Damijan; Sova, Matej; Košak, Urban; Gobec, Stanislav

    2017-05-01

    Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field. The aim of this review is to provide an update on the novel dual inhibitors identified recently and to shed light on their therapeutic potential.

  7. [Levels of plasma cholinesterase in Colombian working-class populations].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2003-12-01

    Levels of plasma cholinesterase in Colombian working-class populations Reference values for plasma cholinesterase (EC 3.1.1.8) are not available for Colombian populations. A representative sample of a working-class population was used to establish these values to provide reference data for use by the social security system. Two working-class populations were sampled from the Aburrá Valley (Aburrá) and eastern Antioquia (Oriente). Cholinesterase activity was measured in 827 workers, with ages spanning 18-49 years, 415 from Aburrá and 412 people from Oriente. Three methods were used to measure cholinesterase: Michel, EQM and Monotest The average values by Michel and EQM were not statistically different between regions (Michel: Aburrá, 1.11, and East, 1.13 deltas pH/hora; EQM: Aburrá, 2.55, and Oriente, 2.48 U/ml). By the Monotest, the enzyme average was statistically higher in Aburra than in Oriente (5,743 and 5,459 U/L respectively; p = 0 .012). By region and technique, men had significantly higher enzymatic levels than women. Within both regions and sexes, no statistically significant difference among the three aged groups was noted. Our obtained Colombian values differed significantly from foreign reference values: Michel and Monotest levels were higher and EQM levels were lower. For making clinical and epidemiologic decisions in Colombia related to these data, the values obtained for the Colombian populations are preferred over values derived from external sources.

  8. [Insect cholinesterases and irreversible inhibitors. Statistical treatment of the data].

    Science.gov (United States)

    Moralev, S N

    2010-01-01

    The data on sensitivity of cholinesterases (ChE) of different insects to reversible inhibitors, as well as the data on physico-chemical parameters of amino acids constituting their active centers, were treated by factor analysis and juxtaposed. It is shown that both these characteristics are related to taxonomical belonging of insects. It is revealed the "material substrate" of the factors determining inhibitor action specificity, which are specific sites in ChE active center.

  9. Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems.

    Science.gov (United States)

    Darvesh, Sultan; Macdonald, Ian R; Martin, Earl

    2013-07-01

    Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. The relationship between total cholinesterase activity and mortality in four butterfly species

    Science.gov (United States)

    Bargar, Timothy A.

    2012-01-01

    The relationship between total cholinesterase activity (TChE) and mortality in four butterfly species (great southern white [Ascia monuste], common buckeye [Junonia coenia], painted lady [Vanessa cardui], and julia butterflies [Dryas julia]) was investigated. Acute contact toxicity studies were conducted to evaluate the response (median lethal dose [LD50] and TChE) of the four species following exposure to the organophosphate insecticide naled. The LD50 for these butterflies ranged from 2.3 to 7.6 μg/g. The average level of TChE inhibition associated with significant mortality ranged from 26 to 67%, depending on the species. The lower bounds of normal TChE activity (2 standard deviations less than the average TChE for reference butterflies) ranged from 8.4 to 12.3 μM/min/g. As a percentage of the average reference TChE activity for the respective species, the lower bounds were similar to the inhibition levels associated with significant mortality, indicating there was little difference between the dose resulting in significant TChE inhibition and that resulting in mortality.

  11. Evaluation of Candidate Genes for cholinesterase Activity in Farmworkers Exposed to organophosphorous Pesticides-Association of SNPs in BCHE

    Science.gov (United States)

    Background: Organophosphate pesticides act as cholinesterase inhibitors, and as such may give rise to potential neurological effects. Cholinesterase activity is a useful, indirect measurement of pesticide exposure, especially in high-risk individuals such as farmworkers. To und...

  12. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

    OpenAIRE

    Kaduszkiewicz, Hanna; Zimmermann, Thomas; Beck-Bornholdt, Hans-Peter; van den Bussche, Hendrik

    2005-01-01

    Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.

  13. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

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    Martin Krátký

    2016-02-01

    Full Text Available Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thiocarbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE. O-Aromatic (thiocarbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thiocarbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenylcarbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM, while 2-(phenylcarbamoylphenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM. Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  14. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors

    Science.gov (United States)

    Greig, Nigel H.; Reale, Marcella; Tata, Ada Maria

    2016-01-01

    receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer’s disease drugs. PMID:23597304

  15. Plasma cholinesterase activity of rats, western grey kangaroos, alpacas, sheep, cattle, and horses.

    Science.gov (United States)

    Mayberry, Chris; Mawson, Peter; Maloney, Shane K

    2015-01-01

    Plasma cholinesterase activity levels of various species may be of interest to toxicologists or pathologists working with chemicals that interfere with the activity of plasma cholinesterase. We used a pH titration method to measure the plasma cholinesterase activity of six mammalian species. Plasma cholinesterase activity varied up to 50-fold between species: sheep (88 ± 45 nM acetylcholine degraded per ml of test plasma per minute), cattle (94 ± 35), western grey kangaroos (126 ± 92), alpaca (364 ± 70), rats (390 ± 118) and horses (4539 ± 721). We present a simple, effective technique for the assay of plasma cholinesterase activity levels from a range of species. Although labour-intensive, it requires only basic laboratory equipment. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Globular Adiponectin Inhibits the Apoptosis of Mesenchymal Stem Cells Induced by Hypoxia and Serum Deprivation via the AdipoR1-Mediated Pathway

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    Xia-Qiu Tian

    2016-02-01

    Full Text Available Background/Aims: Poor viability of transplanted mesenchymal stem cells (MSCs within the ischemic heart limits their therapeutic potential for cardiac repair. Globular adiponectin (gAPN exerts anti-apoptotic effects on several types of stem cells. Herein, we investigated the effect of gAPN on the MSCs against apoptosis induced by hypoxia and serum deprivation (H/SD. Methods: MSCs exposed to H/SD conditions were treated with different concentrations of gAPN. To identify the main type of receptor, MSCs were transfected with siRNA targeting adiponectin receptor 1 or 2 (AdipoR1 or AdipoR2. To elucidate the downstream pathway, MSCs were pre-incubated with AMPK inhibitor Compound C. Apoptosis, caspase-3 activity and mitochondrial membrane potential were evaluated. Results: H/SD-induced MSCs apoptosis and caspase-3 activation were attenuated by gAPN in a concentration-dependent manner. gAPN increased Bcl-2 and decreased Bax expressions. The loss of mitochondrial membrane potential induced by H/SD was also abolished by gAPN. The protective effect of gAPN was significantly attenuated after the knockdown of AdipoR1 rather than AdipoR2. Moreover, Compound C partly suppressed the anti-apoptotic effect of gAPN. Conclusions: gAPN inhibits H/SD-induced apoptosis in MSCs via AdipoR1-mediated pathway, possibly linked to the activation of AMPK. gAPN may be a novel survival factor for MSCs in the ischemic engraftment environment.

  17. Globular Adiponectin Inhibits the Apoptosis of Mesenchymal Stem Cells Induced by Hypoxia and Serum Deprivation via the AdipoR1-Mediated Pathway.

    Science.gov (United States)

    Tian, Xia-Qiu; Yang, Yue-Jin; Li, Qing; Huang, Pei-Sen; Li, Xiang-Dong; Jin, Chen; Qi, Kang; Jiang, Lei-Pei; Chen, Gui-Hao

    2016-01-01

    Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Globular adiponectin (gAPN) exerts anti-apoptotic effects on several types of stem cells. Herein, we investigated the effect of gAPN on the MSCs against apoptosis induced by hypoxia and serum deprivation (H/SD). MSCs exposed to H/SD conditions were treated with different concentrations of gAPN. To identify the main type of receptor, MSCs were transfected with siRNA targeting adiponectin receptor 1 or 2 (AdipoR1 or AdipoR2). To elucidate the downstream pathway, MSCs were pre-incubated with AMPK inhibitor Compound C. Apoptosis, caspase-3 activity and mitochondrial membrane potential were evaluated. H/SD-induced MSCs apoptosis and caspase-3 activation were attenuated by gAPN in a concentration-dependent manner. gAPN increased Bcl-2 and decreased Bax expressions. The loss of mitochondrial membrane potential induced by H/SD was also abolished by gAPN. The protective effect of gAPN was significantly attenuated after the knockdown of AdipoR1 rather than AdipoR2. Moreover, Compound C partly suppressed the anti-apoptotic effect of gAPN. gAPN inhibits H/SD-induced apoptosis in MSCs via AdipoR1-mediated pathway, possibly linked to the activation of AMPK. gAPN may be a novel survival factor for MSCs in the ischemic engraftment environment. © 2016 The Author(s) Published by S. Karger AG, Basel.

  18. Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

    Science.gov (United States)

    Rodríguez, Yeray A; Gutiérrez, Margarita; Ramírez, David; Alzate-Morales, Jans; Bernal, Cristian C; Güiza, Fausto M; Romero Bohórquez, Arnold R

    2016-10-01

    New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 μm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 μm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

  19. Plasma Cholinesterase Activity in Female Green Turtles Chelonia mydas Nesting in Laguna de Terminos, Mexico Related to Organochlorine Pesticides in Their Eggs.

    Science.gov (United States)

    Rivas-Hernández, Gerardo; May-Uc, Yaneli; Noreña-Barroso, Elsa; Cobos-Gasca, Víctor; Rodríguez-Fuentes, Gabriela

    2018-01-01

    The inhibition of cholinesterase (ChE) activity has been used as a biomarker of exposure to organophosphate and carbamate insecticides. ChE of nesting female green turtles (Chelonia mydas) were biochemically characterized using two substrates, acetylthiocholine iodide and butyrylthiocholine iodide, and three ChE inhibitors (eserine sulfate, BW284C51 and iso-OMPA). The results indicated that BChE is the predominant plasma ChE in female C. mydas, but with atypical properties that differ from those found in human BChE. Eggs from green turtles nesting at two sites in Laguna de Terminos contained µg g -1 (wet weight) quantities of organochlorine (OC) pesticides. Drins (aldrin, dieldrin, endrin, endrin ketone, endrin aldehyde) were found at the highest concentrations with no significant differences in the concentrations in eggs collected at the two sampling sites. A negative relationship was found between levels of OC pesticides in eggs and BChE activity in the plasma of female turtles laying the eggs. Since OC pesticides are not cholinesterase inhibitors, we hypothesized that this inverse relationship may be related to an antagonistic effect between OCs and organophosphate pesticides and mobilization of OCs from the fatty tissues of the female turtles into their eggs. However, further study is required to verify the hypothesis. It is also possible that other contaminants, such as petroleum hydrocarbons are responsible for the modulation of cholinesterase activity in female turtles.

  20. Cholinesterase inhibitor (Altenuene) from an endophytic fungus Alternaria alternata: optimization, purification and characterization.

    Science.gov (United States)

    Bhagat, J; Kaur, A; Kaur, R; Yadav, A K; Sharma, V; Chadha, B S

    2016-10-01

    The aim of this study was to screen endophytic fungi isolated from Vinca rosea for their potential to produce acetylcholinesterase (AChE) inhibitors. Endophytic fungi isolated from V. rosea (Catharanthus roseus), were screened for AChE inhibitor production using Ellman's method. Maximum inhibition against AChE (78%) was observed in an isolate VS-10, identified to be Alternaria alternata on morphological and molecular basis. The isolate also inhibited butyrylcholinesterase (73%). Significant increase (1·3 fold) was achieved after optimization of process parameters using one variable at time approach. The inhibitor was purified using chromatographic techniques. The structure elucidation of the inhibitor was carried out using spectroscopic techniques and was identified to be 'altenuene'. The purified inhibitor possessed antioxidant potential as revealed by dot blot assay. The insecticidal potential of purified inhibitor was evaluated by feeding Spodoptora litura on diet amended with inhibitor. It evinced significant larval mortality. Endophytic A. alternata can serve as a source of dual cholinesterase inhibitor 'altenuene' with significant antioxidant and insecticidal activity. This is the first report on acetylcholinestearse inhibitory activity of altenuene. Alternaria alternata has the potential to produce a dual ChE inhibitor with antioxidant activity useful in the treatment of neurodegenerative disorders and in agriculture as biocontrol agent. © 2016 The Society for Applied Microbiology.

  1. H2O2 treatment or serum deprivation induces autophagy and apoptosis in naked mole-rat skin fibroblasts by inhibiting the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Zhao, Shanmin; Li, Li; Wang, Shiyong; Yu, Chenlin; Xiao, Bang; Lin, Lifang; Cong, Wei; Cheng, Jishuai; Yang, Wenjing; Sun, Wei; Cui, Shufang

    2016-12-20

    Naked mole-rats (NMR; Heterocephalus glaber) display extreme longevity and resistance to cancer. Here, we examined whether autophagy contributes to the longevity of NMRs by assessing the effects of the PI3K/Akt pathway inhibitor LY294002 and the autophagy inhibitor chloroquine (CQ) on autophagy and apoptosis in NMR skin fibroblasts. Serum starvation, H2O2 treatment, and LY294002 treatment all increased the LC3-II/LC3-I ratio and numbers of double-membraned autophagosomes and autophagic vacuoles, and decreased levels of p70S6K, p-AktSer473, and p-AktThr308. By contrast, CQ treatment decreased p70S6K, AktSer473, and AktThr308 levels. The Bax/Bcl-2 ratio increased after 12 h of exposure to LY294002 or CQ. These data show that inhibiting the Akt pathway promotes autophagy and apoptosis in NMR skin fibroblasts. Furthermore, LY294002 or CQ treatment decreased caspase-3, p53, and HIF1-α levels, suggesting that serum starvation or H2O2 treatment increase autophagy and apoptosis in NMR skin fibroblasts by inhibiting the PI3K/Akt pathway. CQ-induced inhibition of late autophagy stages also prevented Akt activation and induced apoptosis. Finally, the HIF-1α and p53 pathways were involved in serum starvation- or H2O2-induced autophagy in NMR skin fibroblasts.

  2. Neuroprotective effect of seaweeds inhabiting South Indian coastal area (Hare Island, Gulf of Mannar Marine Biosphere Reserve): Cholinesterase inhibitory effect of Hypnea valentiae and Ulva reticulata.

    Science.gov (United States)

    Suganthy, N; Karutha Pandian, S; Pandima Devi, K

    2010-01-14

    Alzheimer's disease (AD) is the most common form of dementia, which is one of the four leading causes of death in developed nations. Until date the only symptomatic treatment for this disease is based on the "cholinergic hypothesis" where the drugs enhance acetylcholine levels in the brain by inhibiting acetylcholinesterase (AChE). In the course for screening cholinesterase inhibitors about eight seaweeds, with wide pharmaceutical applications, were collected from Hare Island, Gulf of Mannar, Marine Biosphere Reserve, Tamil Nadu, India. Inhibitory effect of methanol extract of the seaweeds was studied in vitro by incubating various concentration of the extract with AChE or butyryl cholinesterase (BuChE) and assessing their activities by Ellman's colorimetric method. Kinetic parameters like IC(50), K(i) and V(max) were also analyzed. The results showed that of the eight seaweeds screened Hypnea valentiae, Padina gymnospora, Ulva reticulata and Gracilaria edulis exhibited inhibitory activity to AChE with IC(50) value of 2.6, 3.5, 10 and 3mg/ml respectively, while H. valentiae, Enteromorpha intestinalis, Dictyota dichotoma and U. reticulata showed 50% inhibition to BuChE at concentration 3.9, 7, 6.5 and 10mg/ml respectively. The inhibitory activities of the seaweed extracts were comparable to the standard drug donepezil. Enzyme kinetic analysis showed that algal extracts exhibited mixed type inhibition (partial noncompetitive inhibition). Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  3. Planarian cholinesterase: in vitro characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity and reactivation.

    Science.gov (United States)

    Hagstrom, Danielle; Hirokawa, Hideto; Zhang, Limin; Radic, Zoran; Taylor, Palmer; Collins, Eva-Maria S

    2017-08-01

    The freshwater planarian Dugesia japonica has recently emerged as an animal model for developmental neurotoxicology and found to be sensitive to organophosphorus (OP) pesticides. While previous activity staining of D. japonica, which possess a discrete cholinergic nervous system, has shown acylthiocholine catalysis, it is unknown whether this is accomplished through an acetylcholinesterase (AChE), butyrylcholinesterase (BChE), or a hybrid esterase and how OP exposure affects esterase activity. Here, we show that the majority of D. japonica cholinesterase (DjChE) activity departs from conventional AChE and BChE classifications. Inhibition by classic protonable amine and quaternary reversible inhibitors (ethopropazine, donepezil, tacrine, edrophonium, BW284c51, propidium) shows that DjChE is far less sensitive to these inhibitors than human AChE, suggesting discrete differences in active center and peripheral site recognition and structures. Additionally, we find that different OPs (chlorpyrifos oxon, paraoxon, dichlorvos, diazinon oxon, malaoxon) and carbamylating agents (carbaryl, neostigmine, physostigmine, pyridostigmine) differentially inhibit DjChE activity in vitro. DjChE was most sensitive to diazinon oxon and neostigmine and least sensitive to malaoxon and carbaryl. Diazinon oxon-inhibited DjChE could be reactivated by the quaternary oxime, pralidoxime (2-PAM), and the zwitterionic oxime, RS194B, with RS194B being significantly more potent. Sodium fluoride (NaF) reactivates OP-DjChE faster than 2-PAM. As one of the most ancient true cholinesterases, DjChE provides insight into the evolution of a hybrid enzyme before the separation into distinct AChE and BChE enzymes found in higher vertebrates. The sensitivity of DjChE to OPs and capacity for reactivation validate the use of planarians for OP toxicology studies.

  4. The effect of diminazene aceturate on cholinesterase activity in dogs with canine babesiosis

    Directory of Open Access Journals (Sweden)

    R.J. Milner

    1997-07-01

    Full Text Available A clinical trial was designed to evaluate the effects of diminazene aceturate and its stabiliser antipyrine on serum pseudocholinesterase (PChE and red blood cell acetylcholinesterase (RBC AChE in dogs with babesiosis. The trial was conducted on naturally occurring, uncomplicated cases of babesiosis (n = 20 that were randomly allocated to groups receiving a standard therapeutic dose of diminazene aceturate with antipyrine stabiliser (n = 10 or antipyrine alone (n = 10. Blood was drawn immediately before and every 15 minutes for 1 hour after treatment. Plasma PChE showed a 4 % decrease between 0 and 60 min within the treatment group (p < 0.05. No statistically significant differences were found between the treatment and control groups at any of the time intervals for PChE. There was an increase in RBC AChE activity at 15 min in the treatment group (p < 0.05. No significant differences were found between the treatment and control groups at any time interval for RBC AChE. In view of the difference in PChE, samples from additional, new cases (n = 10 of canine babesiosis were collected to identify the affect of the drug over 12 hours. No significant depression was identified over this time interval. The results suggests that the underlying mechanism in producing side-effects, when they do occur, is unlikely to be through cholinesterase depression.

  5. Cholinesterase activity in the cup oyster Saccostrea sp. exposed to chlorpyrifos, imidacloprid, cadmium and copper.

    Science.gov (United States)

    Moncaleano-Niño, Angela M; Luna-Acosta, Andrea; Gómez-Cubillos, Maria Camila; Villamil, Luisa; Ahrens, Michael J

    2018-04-30

    In the present study, the sensitivity and concentration dependence of three functionally-defined components of cholinesterase activity (total: T-ChE; eserine-sensitive: Es-ChE; and eserine-resistant: Er-ChE) were quantified in the gill, digestive gland and adductor muscle of the tropical cup oyster Saccostrea sp., following acute (96h) aqueous exposure to commercial formulations of the organophosphate (OP) insecticide chlorpyrifos and the neonicotinoid (NN) imidacloprid (concentration range: 0.1-100mg/L), as well as to dissolved cadmium and copper (concentration range: 1-1000μg/L). Oysters (1.5-5.0cm shell length), field-collected from a boating marina in Santa Marta, Colombia (Caribbean Sea) were exposed in the laboratory to each substance at five concentrations. T-ChE, Es-ChE, and Er-ChE activity were quantified in the three tissues in pools of 5 individuals (3 replicates per concentration), before and after inhibition with the total cholinesterase inhibitor eserine (physostigmine, 100µM). Oysters exposed to chlorpyrifos, imidacloprid and Cd showed reduced T-ChE and Es-ChE activity in gills at highest exposure concentrations, with Es-ChE activity being inhibited proportionally more so than T-ChE, whereas Er-ChE activity showed no significant concentration-response. Digestive gland also showed diminished T-ChE, Es-ChE and Er-ChE activity for highest chlorpyrifos and Cd concentrations relative to controls, but an increase of T-ChE and Er-ChE activity at the highest imidacloprid concentration (100mg/L). For Cu, T-ChE, Es-ChE and Er-ChE activities in gills and digestive gland were elevated relative to controls in oysters exposed to Cu concentrations > 100µg/L. In adductor muscle, T-ChE, Es-ChE and Er-ChE activity showed no apparent pattern for any of the four xenobiotics and concentration levels tested. Although this study confirms acute (96h) concentration-dependent reduction of tissue T-ChE and Es-ChE activity in gills and digestive glands of Saccostrea sp

  6. Development of square wave voltammetry method for the assessment of organophosphorus compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol as a redox indicator.

    Science.gov (United States)

    Qiu, Jingxia; Chen, Jin; Ma, Qianqian; Miao, Yuqing

    2009-09-01

    A square wave voltammetry method was developed for the assessment of organophosphorus (OPs) compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol (2,6-DCIP) as a redox indicator. The substrate of acetylthiocholine is hydrolysed by the cholinesterase (ChE) from soil animal pheretima, and the produced thiocholine reacts with the 2,6-DCIP to give obvious shift of electrochemical signal. The inhibition of ChE was assessed by measuring the enzyme activity before and after incubating with parathion-methyl. The reduction peak current of 2,6-DCIP decreases with the time of enzymatical reaction. The ChE loses almost 32.74% activity after 10 min incubation with 1ng mL(-1) paraoxon and 54.62% with 10 microg mL(-1) paraoxon, while the activity that corresponds to 100 microg mL(-1) paraoxon was nearly completely inhibited. This method can be employed to assess the inhibition of ChE and investigate OPs impact on environmental animals.

  7. Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

    Science.gov (United States)

    Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

    2017-12-01

    Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ 42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP 695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

  8. Cholinesterase activities in the scallop Pecten jacobaeus: Characterization and effects of exposure to aquatic contaminants

    International Nuclear Information System (INIS)

    Stefano, Bonacci; Ilaria, Corsi; Silvano, Focardi

    2008-01-01

    Nearshore marine environments of industrialized countries are increasingly threatened by anthropogenic pollution. It is therefore a priority task to investigate the sensitivity of new ecotoxicological warning signals of the occurrence and effects of aquatic pollutants. The main aims of the present study were: 1) to characterize the biochemical properties of ChEs in tissues of the bivalve Pecten jacobaeus, using different specific substrates and selective inhibitors; 2) to measure sensitivity of ChE activities to in vitro exposure to the OPs azamethiphos and DFP and to the heavy metals cadmium and zinc. Our final aim was to carry out a preliminary evaluation of the suitability of ChEs measurement in tissues of the scallop for monitoring marine environmental quality and neurotoxic compounds contamination in the Mediterranean Sea. Responses to specific inhibitors have suggested that ChEs in adductor muscle share many characteristics with vertebrate acetylcholinesterase. Dose-dependent inhibition of ChE was observed in response to in vitro exposure to environmental contaminants such as cadmium and azamethiphos. Sensitivity to zinc and DFP was lower. ChEs in P. jacobaeus might therefore have potential as a sensitive biomarker for monitoring marine pollution. Results of the present study will be useful to focus further experiment of exposure to pollutants under in vivo conditions. Capsule: Cholinesterase activities in scallop Pecten jacobaeus were observed to be sensitive to contaminants in vitro and may therefore have potential as biomarkers for monitoring water pollution

  9. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

    Directory of Open Access Journals (Sweden)

    Michalina Hebda

    2016-03-01

    Full Text Available Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM. Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM, and it inhibits amyloid beta aggregation (35.8% at 10 μM. Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

  10. Cholinesterase activities in the scallop Pecten jacobaeus: Characterization and effects of exposure to aquatic contaminants

    Energy Technology Data Exchange (ETDEWEB)

    Stefano, Bonacci [Department of Environmental Sciences ' G. Sarfatti' , University of Siena, Via P.A. Mattioli 4, I-53100 Siena (Italy)], E-mail: bonacci@unisi.it; Ilaria, Corsi [Department of Environmental Sciences ' G. Sarfatti' , University of Siena, Via P.A. Mattioli 4, I-53100 Siena (Italy)], E-mail: corsii@unisi.it; Silvano, Focardi [Department of Environmental Sciences ' G. Sarfatti' , University of Siena, Via P.A. Mattioli 4, I-53100 Siena (Italy)], E-mail: focardi@unisi.it

    2008-03-15

    Nearshore marine environments of industrialized countries are increasingly threatened by anthropogenic pollution. It is therefore a priority task to investigate the sensitivity of new ecotoxicological warning signals of the occurrence and effects of aquatic pollutants. The main aims of the present study were: 1) to characterize the biochemical properties of ChEs in tissues of the bivalve Pecten jacobaeus, using different specific substrates and selective inhibitors; 2) to measure sensitivity of ChE activities to in vitro exposure to the OPs azamethiphos and DFP and to the heavy metals cadmium and zinc. Our final aim was to carry out a preliminary evaluation of the suitability of ChEs measurement in tissues of the scallop for monitoring marine environmental quality and neurotoxic compounds contamination in the Mediterranean Sea. Responses to specific inhibitors have suggested that ChEs in adductor muscle share many characteristics with vertebrate acetylcholinesterase. Dose-dependent inhibition of ChE was observed in response to in vitro exposure to environmental contaminants such as cadmium and azamethiphos. Sensitivity to zinc and DFP was lower. ChEs in P. jacobaeus might therefore have potential as a sensitive biomarker for monitoring marine pollution. Results of the present study will be useful to focus further experiment of exposure to pollutants under in vivo conditions. Capsule: Cholinesterase activities in scallop Pecten jacobaeus were observed to be sensitive to contaminants in vitro and may therefore have potential as biomarkers for monitoring water pollution.

  11. Characterization of catalytic efficiency parameters of brain cholinesterases in tropical fish.

    Science.gov (United States)

    de Assis, Caio Rodrigo Dias; Linhares, Amanda Guedes; Oliveira, Vagne Melo; França, Renata Cristina Penha; Santos, Juliana Ferreira; Marcuschi, Marina; Carvalho, Elba Verônica Matoso Maciel; Bezerra, Ranilson Souza; Carvalho, Luiz Bezerra

    2014-12-01

    Brain cholinesterases from four fish (Arapaima gigas, Colossoma macropomum, Rachycentron canadum and Oreochromis niloticus) were characterized using specific substrates and selective inhibitors. Parameters of catalytic efficiency such as activation energy (AE), k(cat) and k(cat)/k(m) as well as rate enhancements produced by these enzymes were estimated by a method using crude extracts described here. Despite the BChE-like activity, specific substrate kinetic analysis pointed to the existence of only acetylcholinesterase (AChE) in brain of the species studied. Selective inhibition suggests that C. macropomum brain AChE presents atypical activity regarding its behavior in the presence of selective inhibitors. AE data showed that the enzymes increased the rate of reactions up to 10(12) in relation to the uncatalyzed reactions. Zymograms showed the presence of AChE isoforms with molecular weights ranging from 202 to 299 kDa. Values of k(cat) and k(cat)/k(m) were similar to those found in the literature.

  12. Early appearance and possible roles of non-neuromuscular cholinesterases.

    Directory of Open Access Journals (Sweden)

    Carla eFalugi

    2012-04-01

    Full Text Available The biological function of the cholinesterase (ChE enzymes is well known and has been studied since the beginning of the XXth century; in particular, acetylcholinesterase (AChE, E.C. 3.1.1.7 is an enzyme playing a key role in the modulation of neuromuscular impulse transmission. However, in the past decades, there has been increasing interest concerning its role in regulating non-neuromuscular cell-to-cell interactions mediated by intracellular ion concentration changes, like the ones occurring during gamete interaction and embryonic development. An understanding of the mechanisms of the cholinergic regulation of these events can help us foresee the possible impact on environmental and human health, including gamete efficiency and possible teratogenic effects on different models, and help elucidate the extent to which exposure to ChE inhibitors may affect human health.

  13. Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure.

    Science.gov (United States)

    Nigg, H N; Knaak, J B

    2000-01-01

    The organophosphorus pesticides of this review were discovered in 1936 during the search for a replacement for nicotine for cockroach control. The basic biochemical characteristics of RBC AChE and BChE were determined in the 1940s. The mechanism of inhibition of both enzymes and other serine esterases was known in the 1940s and, in general, defined in the 1950s. In 1949, the death of a parathion mixer-loader dictated blood enzyme monitoring to prevent acute illness from organophosphorus pesticide intoxication. However, many of the chemical and biochemical steps for serine enzyme inhibition by OP compounds remain unknown today. The possible mechanisms of this inhibition are presented kinetically beginning with simple (by comparison) Michaelis-Menten substrate enzyme interaction kinetics. As complicated as the inhibition kinetics appear here, PBPK model kinetics will be more complex. The determination of inter- and intraindividual variation in RBC ChE and BChE was recognized early as critical knowledge for a blood esterase monitoring program. Because of the relatively constant production of RBCs, variation in RBC AChE was determined by about 1970. The source of plasma (or serum) BChE was shown to be the liver in the 1960s with the change in BChE phenotype to the donor in liver transplant patients. BChE activity was more variable than RBC AChE, and only in the 1990s have BChE individual variation questions been answered. We have reviewed the chemistry, metabolism, and toxicity of organophosphorus insecticides along with their inhibitory action toward tissue acetyl- and butyrylcholinesterases. On the basis of the review, a monitoring program for individuals mixing-loading and applying OP pesticides for commercial applicators was recommended. Approximately 41 OPs are currently registered for use by USEPA in the United States. Under agricultural working conditions, OPs primarily are absorbed through the skin. Liver P-450 isozymes catalyze the desulfurization of

  14. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    Energy Technology Data Exchange (ETDEWEB)

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.; Munro, N.B.; Linnabary, R.D. (Environmental Sciences Division, Oak Ridge National Laboratory, TN (United States))

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.

  15. Accumulation of phenolic compounds in in vitro cultures and wild plants of Lavandula viridis L'Hér and their antioxidant and anti-cholinesterase potential.

    Science.gov (United States)

    Costa, Patrícia; Gonçalves, Sandra; Valentão, Patrícia; Andrade, Paula B; Romano, Anabela

    2013-07-01

    In this study, we evaluated the phenolic profile, antioxidant and anti-cholinesterase potential of different extracts from wild plants and in vitro cultures of Lavandula viridis L'Hér. The HPLC-DAD analysis allowed the identification and quantification of 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids, and luteolin and pinocembrin. Water/ethanol extract from in vitro cultures contained the highest amount of the identified phenolic compounds (51652.92 mg/kg). To investigate the antioxidant activity we used Trolox equivalent antioxidant capacity, oxygen radical absorbance capacity, Fe(2+) chelation activity and the inhibition of Fe(2+)-induced lipid peroxidation in mouse brain homogenates (in vitro). Overall, all the extracts from both wild plants and in vitro cultures exhibited ability to scavenge free radicals, to chelate Fe(2+) and to protect against lipid peroxidation. In addition, the extracts from L. viridis were active in inhibiting both acetylcholinesterase and butyrylcholinesterase (Ellman's method). Our findings suggest that L. viridis in vitro cultures represent a promising alternative for the production of active metabolites with antioxidant and anti-cholinesterase activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. BINDING EFFICACY AND ELUCIDATION OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP OF ACETANILIDE AND ITS DERIVATIVES WITH BOVINE SERUM ALBUMIN AND THEIR INHIBITION AGAINST COX1

    OpenAIRE

    Dr. Violet Dhayabaran et al

    2012-01-01

    Serum albumins are the most abundant proteins in plasma with many physiological functions. Among them, BSA has a wide range of functions involving the binding, transport and delivery of fatty acids, porphyrins, bilirubin, steroids, etc and it is home to specific binding sites for metals, pharmaceuticals and dyes. Recently, nanotechnology has become a popular term in the current science and technology. Nanotechnology has been introduced for the food and drug industry, including encapsulations ...

  17. A direct method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels

    Directory of Open Access Journals (Sweden)

    Boopathy Rathanam

    2000-12-01

    Full Text Available Abstract Background In vertebrates, two types of cholinesterases exist, acetylcholinesterase and butyrylcholinesterase. The function of acetylcholinesterase is to hydrolyse acetylcholine, thereby terminating the neurotransmission at cholinergic synapse, while the precise physiological function of butyrylcholinesterase has not been identified. The presence of cholinesterases in tissues that are not cholinergically innervated indicate that cholinesterases may have functions unrelated to neurotransmission. Furthermore, cholinesterases display a genuine aryl acylamidase activity apart from their predominant acylcholine hydrolase activity. The physiological significance of this aryl acylamidase activity is also not known. The study on the aryl acylamidase has been, in part hampered by the lack of a specific method to visualise this activity. We have developed a method to visualise the aryl acylamidase activity on cholinesterase in polyacrylamide gels. Results The o-nitroaniline liberated from o-nitroacetanilide by the action of aryl acylamidase activity on cholinesterases, in the presence of nitrous acid formed a diazonium compound. This compound gave an azo dye complex with N-(1-napthyl-ethylenediamine, which appeared as purple bands in polyacrylamide gels. Treating the stained gels with trichloroacetic acid followed by Tris-HCl buffer helped in fixation of the stain in the gels. By using specific inhibitors for acetylcholinesterase and butyrylcholinesterase, respectively, differential staining for the aryl acylamidase activities on butyrylcholinesterase and acetylcholinesterase in a sample containing both these enzymes has been demonstrated. A linear relationship between the intensity of colour developed and activity of the enzyme was obtained. Conclusions A novel method to visualise the aryl acylamidase activity on cholinesterases in polyacrylamide gels has been developed.

  18. Measurement of K-27, an oxime-type cholinesterase reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.

    Science.gov (United States)

    Gyenge, Melinda; Kalász, Huba; Petroianu, George A; Laufer, Rudolf; Kuca, Kamil; Tekes, Kornélia

    2007-08-17

    K-27 is a bisquaternary asymmetric pyridinium aldoxime-type cholinesterase reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type cholinesterase reactivators.

  19. Globular Adiponectin Inhibits the Apoptosis of Mesenchymal Stem Cells Induced by Hypoxia and Serum Deprivation via the AdipoR1-Mediated Pathway

    OpenAIRE

    Xia-Qiu Tian; Yue-Jin Yang; Qing Li; Pei-Sen Huang; Xiang-Dong Li; Chen Jin; Kang Qi; Lei-Pei Jiang; Gui-Hao Chen

    2016-01-01

    Background/Aims: Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Globular adiponectin (gAPN) exerts anti-apoptotic effects on several types of stem cells. Herein, we investigated the effect of gAPN on the MSCs against apoptosis induced by hypoxia and serum deprivation (H/SD). Methods: MSCs exposed to H/SD conditions were treated with different concentrations of gAPN. To identify the main type of rece...

  20. Fetuin-A/albumin-mineral complexes resembling serum calcium granules and putative nanobacteria: demonstration of a dual inhibition-seeding concept.

    Directory of Open Access Journals (Sweden)

    Cheng-Yeu Wu

    2009-11-01

    Full Text Available Serum-derived granulations and purported nanobacteria (NB are pleomorphic apatite structures shown to resemble calcium granules widely distributed in nature. They appear to be assembled through a dual inhibitory-seeding mechanism involving proteinaceous factors, as determined by protease (trypsin and chymotrypsin and heat inactivation studies. When inoculated into cell culture medium, the purified proteins fetuin-A and albumin fail to induce mineralization, but they will readily combine with exogenously added calcium and phosphate, even in submillimolar amounts, to form complexes that will undergo morphological transitions from nanoparticles to spindles, films, and aggregates. As a mineralization inhibitor, fetuin-A is much more potent than albumin, and it will only seed particles at higher mineral-to-protein concentrations. Both proteins display a bell-shaped, dose-dependent relationship, indicative of the same dual inhibitory-seeding mechanism seen with whole serum. As ascertained by both seeding experiments and gel electrophoresis, fetuin-A is not only more dominant but it appears to compete avidly for nanoparticle binding at the expense of albumin. The nanoparticles formed in the presence of fetuin-A are smaller than their albumin counterparts, and they have a greater tendency to display a multi-layered ring morphology. In comparison, the particles seeded by albumin appear mostly incomplete, with single walls. Chemically, spectroscopically, and morphologically, the protein-mineral particles resemble closely serum granules and NB. These particles are thus seen to undergo an amorphous to crystalline transformation, the kinetics and completeness of which depend on the protein-to-mineral ratios, with low ratios favoring faster conversion to crystals. Our results point to a dual inhibitory-seeding, de-repression model for the assembly of particles in supersaturated solutions like serum. The presence of proteins and other inhibitory factors tend

  1. Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon.

    Science.gov (United States)

    Jarvie, Emma M; Cellek, Selim; Sanger, Gareth J

    2008-01-01

    Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.

  2. Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2-PAM).

    Science.gov (United States)

    John, Harald; Blum, Marc-Michael

    2012-01-01

    Pralidoxime (2-PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2-PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2-PAM was introduced. In this time (mid-1950s until the end of the 1970s) 2-PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size-exclusion, reversed-phase, and ligand-exchange chromatography have been introduced. Today, the most popular method for 2-PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied. This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2-PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2-PAM are provided. Copyright © 2011 John Wiley & Sons, Ltd.

  3. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    Science.gov (United States)

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

  4. Acetylcholine turnover in mouse brain: influence of cholinesterase inhibitors

    International Nuclear Information System (INIS)

    Karlen, B.; Holmstedt, B.; Lundgren, G.; Lundin, J.

    1986-01-01

    The authors determine whether the irreversible cholinesterase inhibitors soman, sarin or FX, which are thought to increase brain ACh concentration by a mechanism different to that of the muscarinic receptor agonist oxotremorine, also would decrease the turnover rate of brain ACh. Male albino mice were used in the study. N-(2-hydroxyethyl-N,N,N-tri-( 2 H 3 )methylammonium iodide and N-(2-acetoxyethyl)-N,N,N-tri-( 2 H 3 )methylammonium iodide were used as internal standards. N-(2-acetoxyethyl)-N,N,N,-tri-( 2 H 3 ), ( 1 H)methylammonium iodide was used for calibration purposes. The concentrations of Ch, ACh and their deuterated variants found in whole brain and striatum after pretreatment with saline, soman, sarin and FX are shown. In whole brain the endogeneous concentration of Ach was not affected by sarin and only to a slight but significant extent by Fs, while soman increased the level to about 30 nmol/g. All three substances increased the ch level in comparison to controls

  5. Characterization of cholinesterases in Chironomus riparius and the effects of three herbicides on chlorpyrifos toxicity.

    Science.gov (United States)

    Pérez, Joanne; Monteiro, Marta S; Quintaneiro, Carla; Soares, Amadeu M V M; Loureiro, Susana

    2013-11-15

    In this study, the toxicities of four pesticides (the herbicides atrazine, terbuthylazine, metolachlor and the insecticide chlorpyrifos) previously detected in the Alqueva reservoir/dam (south of Portugal) were evaluated individually and in binary combinations of the herbicides and the insecticide using fourth-instar larvae of the aquatic midge Chironomus riparius. Chlorpyrifos induced toxicity to midges in all the 48 h toxicity bioassays performed. The swimming behaviour of the larvae was impaired, with EC50 values ranging from 0.15 to 0.17 μg/L. However, neither s-triazine (atrazine and terbuthylazine) herbicides nor metolachlor alone at concentrations up to 200 μg/L caused significant toxicity to C. riparius. When combined with both s-triazine herbicides, chlorpyrifos toxicity was enhanced by approximately 2-fold when tested in a binary mixture experimental setup, at the 50% effective concentration levels. To evaluate how chlorpyrifos toxicity was being increased, the cholinesterases (ChE) were characterized biochemically using different substrates and selective inhibitors. The results obtained suggested that the main enzyme present in this species is acetylcholinesterase (AChE) and therefore it was assayed upon C. riparius exposures to all pesticides individually and as binary mixtures. Although atrazine and terbuthylazine are not effective inhibitors of AChE, the potentiation of chlorpyrifos toxicity by the two s-triazine herbicides was associated with a potentiation in the inhibition of AChE in midges; both s-triazine herbicides at 200 μg/L increased the inhibition of the AChE activity by 7 and 8-fold, respectively. A strong correlation was observed between swimming behaviour disturbances of larvae and the inhibition of the AChE activity. In contrast, metolachlor did not affect chlorpyrifos toxicity at any of the concentrations tested. Therefore, the herbicides atrazine and terbuthylazine can act as synergists in the presence of chlorpyrifos, increasing

  6. Evaluation of Cholinesterase Activities During in Vivo Intoxication Using an Electrochemical Sensor Strip – Correlation With Intoxication Symptoms

    Directory of Open Access Journals (Sweden)

    Jana Zdarova-Karasova

    2009-05-01

    Full Text Available Cholinesterase activity in blood of laboratory rats was monitored. Rats were intoxicated with paraoxon at dosis of 0 – 65 – 125 – 170 – 250 – 500 nmol. The 250 nmol dose was found to be the LD50. An electrochemical sensor was found useful to provide information about cholinesterase activity. The decrease of cholinesterase activity was correlated to intoxication symptoms and mortality level. It was found that the symptoms of intoxication are not observed while at least 50% of cholinesterase activity in blood remains. The minimal cholinesterase activity essential to survival is around 10%, when compared with the initial state. No changes in levels of low moleculary weight antioxidants were observed.

  7. Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease.

    Science.gov (United States)

    Xie, Sai-Sai; Wang, Xiao-Bing; Li, Jiang-Yan; Yang, Lei; Kong, Ling-Yi

    2013-06-01

    A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  8. Effects of eight weeks of an alleged aromatase inhibiting nutritional supplement 6-OXO (androst-4-ene-3,6,17-trione on serum hormone profiles and clinical safety markers in resistance-trained, eugonadal males

    Directory of Open Access Journals (Sweden)

    Kreider Richard

    2007-10-01

    Full Text Available Abstract The purpose of this study was to determine the effects of 6-OXO, a purported nutritional aromatase inhibitor, in a dose dependent manner on body composition, serum hormone levels, and clinical safety markers in resistance trained males. Sixteen males were supplemented with either 300 mg or 600 mg of 6-OXO in a double-blind manner for eight weeks. Blood and urine samples were obtained at weeks 0, 1, 3, 8, and 11 (after a 3-week washout period. Blood samples were analyzed for total testosterone (TT, free testosterone (FT, dihydrotestosterone (DHT, estradiol, estriol, estrone, SHBG, leutinizing hormone (LH, follicle stimulating hormone (FSH, growth hormone (GH, cortisol, FT/estradiol (T/E. Blood and urine were also analyzed for clinical chemistry markers. Data were analyzed with two-way MANOVA. For all of the serum hormones, there were no significant differences between groups (p > 0.05. Compared to baseline, free testosterone underwent overall increases of 90% for 300 mg 6-OXO and 84% for 600 mg, respectively (p 0.05 and clinical safety markers were not adversely affected with ingestion of either supplement dose (p > 0.05. While neither of the 6-OXO dosages appears to have any negative effects on clinical chemistry markers, supplementation at a daily dosage of 300 mg and 600 mg for eight weeks did not completely inhibit aromatase activity, yet significantly increased FT, DHT, and T/E.

  9. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study.

    Directory of Open Access Journals (Sweden)

    Laura Y Park-Wyllie

    2009-09-01

    Full Text Available BACKGROUND: Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia. METHODS AND FINDINGS: We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3:1 were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11% required a pacemaker during hospitalization, and six (4% died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29-3.51. The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18-4.28 and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16-4.71. We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%] who survived to discharge subsequently resumed cholinesterase inhibitor therapy. CONCLUSIONS: Among older patients, initiation of cholinesterase

  10. Black-bellied whistling duck (Dendrocygna autumnalis) brain cholinesterase characterization and diagnosis of anticholinesterase pesticide exposure in wild populations from Mexico.

    Science.gov (United States)

    Osten, Jaime Rendón-von; Soares, Amadeu M V M; Guilhermino, Lucia

    2005-02-01

    Rice is the main crop in the subbasin of the fluvial lagoon system of Palizada River (FLSPR) in the state of Campeche, Mexico. The pesticides used to control pests of this crop mainly are carbofuran, chlorpyrifos, and glyphosate. Black-bellied whistling duck (Dendrocygna autumnalis) is an ecologically and economically important species in the area. This duck is consumed by local inhabitants throughout the year, despite its potential exposure to pesticides. Due to its feeding habits, abundance, and nutritional value, D. autumnalis is a good indicator of environmental contamination and a potential route of human exposure to organophosphate and carbamate pesticides. In this study, the brain cholinesterase (ChE) in the frontal cerebral cortex of autochthonous ducks was characterized. In addition, the potential of the three locally used pesticides and mixtures to inhibit ChE activity was investigated and the exposure of the wild duck population during intensive pesticide applications in rice fields was evaluated. We found that acetylcholinesterase (AChE) seems to be the predominant ChE form in the biological fraction analyzed. Carbofuran was the most potent ChE inhibitor of D. autumnalis brain ChE activity from the three pesticides analyzed. Cholinesterase inhibition after exposure to pesticide mixtures predominantly was due to carbofuran. A decrease (p 30%) was apparent in wild ducks compared to reference ducks, with recovery of ChE inhibition in wild ducks occurring months later when no pesticides were applied in the field. Dendrocygna autumnalis brain ChE is a suitable parameter for inclusion in biomonitoring programs for both environmental protection and human safety.

  11. Baked corn (Zea mays L.) and bean (Phaseolus vulgaris L.) snack consumption lowered serum lipids and differentiated liver gene expression in C57BL/6 mice fed a high-fat diet by inhibiting PPARγ and SREBF2.

    Science.gov (United States)

    Dominguez-Uscanga, Astrid; Loarca-Piña, Guadalupe; Gonzalez de Mejia, Elvira

    2017-12-01

    The aim was to determine the effect of consuming a baked white corn/bean snack (70/30% blend) on improving diet-induced dyslipidemia and liver differential gene expression in mice fed a high-fat diet (HFD). C57BL/6 mice were randomized into six groups and different doses of the snack (0.5-2.0 g/d) supplemented to a basal HFD for 12 weeks. Unsupplemented HFD and a standard diet were used as positive and negative controls, respectively. Groups receiving HFD1.0, HFD1.5 and HFD2.0 showed attenuation in body weight gain (20%). Serum cholesterol and triglycerides were reduced (Psnack. Histological analysis showed a reduction in adipocyte diameters (PSnack consumption induced differential expression of 529 genes in the liver; RGS16 was the highest up-regulated molecule (+15-fold change). Increased expression of this gene could have improved glucose metabolism in HFD2.0. Ingenuity Pathway Analysis downstream analysis showed a predicted inhibition of target genes of peroxisome PPARγ and key regulators of lipogenic genes in the liver. The results suggest that consumption of a white corn/bean snack (70%/30% blend) attenuates weight gain, fat mass accumulation, adipocyte size and nonalcoholic fatty liver disease in HFD-fed mice by inhibiting PPARγ and SREBF2. The study proposes that this type of product might be beneficial by preventing dyslipidemia, obesity and hepatic steatosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Fatty Acid-Mediated Inhibition of Metal Binding to the Multi-Metal Site on Serum Albumin: Implications for Cardiovascular Disease.

    Science.gov (United States)

    Blindauer, Claudia A; Khazaipoul, Siavash; Yu, Ruitao; Stewart, Alan J

    2016-01-01

    Human serum albumin (HSA) is the major protein in blood plasma and is responsible for circulatory transport of a range of small molecules including fatty acids, metal ions and drugs. We previously identified the major plasma Zn2+ transport site on HSA and revealed that fatty-acid binding (at a distinct site called the FA2 site) and Zn2+ binding are interdependent via an allosteric mechanism. Since binding affinities of long-chain fatty acids exceed those of plasma Zn2+, this means that under certain circumstances the binding of fatty acid molecules to HSA is likely to diminish HSA Zn2+-binding, and hence affects the control of circulatory and cellular Zn2+ dynamics. This relationship between circulatory fatty acid and Zn2+ dynamics is likely to have important physiological and pathological implications, especially since it has been recognised that Zn2+ acts as a signalling agent in many cell types. Fatty acid levels in the blood are dynamic, but most importantly, chronic elevation of plasma fatty acid levels is associated with some metabolic disorders and disease states - including myocardial infarction and other cardiovascular diseases. In this article, we briefly review the metal-binding properties of albumin and highlight the importance of their interplay with fatty acid binding. We also consider the impact of this dynamic link upon levels and speciation of plasma Zn2+, its effect upon cellular Zn2+ homeostasis and its relevance to cardiovascular and circulatory processes in health and disease.

  13. Novel Nucleophilic Compounds with Oxime Group as Reactivators of Paraoxon-Inhibited Cholinesterases

    Czech Academy of Sciences Publication Activity Database

    Musilová, L.; Jun, D.; Paleček, J.; Církva, Vladimír; Musílek, K.; Paar, M.; Hrabinová, M.; Pohanka, M.; Kuca, K.

    2010-01-01

    Roč. 7, č. 4 (2010), s. 260-264 ISSN 1570-1808 Grant - others:GA MO(CZ) OVUOFVZ200902 Program:OV Institutional research plan: CEZ:AV0Z40720504 Keywords : acetylcholinesterase * butyrylcholinesterase * nerve agent Subject RIV: CC - Organic Chemistry Impact factor: 0.668, year: 2010

  14. Design and Synthesis of Bifunctional Oxime Reactivators of OP- inhibited Cholinesterase

    Science.gov (United States)

    2013-08-01

    N O O OH N O O O O N OH O O N N O O N N N O N N N N N O N+ N N N OH MeOH/APS THP NaBH4 MsCl HN N p-Toluenesulfonic Acid Swern Oxidation H2N O S O O O...pendant general acid groups. Compound 8 has been delivered to ICD for testing (synthesis and characterization below). This strategy is in place to...as a THP ether and the trifluoromethylketone installed by coupling the organolithium with trifluoroacetylpiperidine. We again used our direct

  15. PATTERN OF CHOLINESTERASE INHIBITION IN ADULT, MALE RATS CHRONICALLY EXPOSED TO DIETARY CHLORPYRIFOS.

    Science.gov (United States)

    Very little is known about the effects of chronic exposure to relatively low levels of anticholinesterase insecticides or how the effects of chronic exposure compare to higher, intermittent exposure of the same compound for the same duration. To that end, we exposed adult male ra...

  16. Differential swimming performance of two natricine snakes exposed to a cholinesterase-inhibiting pesticide.

    Science.gov (United States)

    Hopkins, W A; Winne, C T; DuRant, S E

    2005-02-01

    Environmental contaminants have direct effects on organisms at the molecular, cellular, and tissue levels, but the net results of these sub-organismal effects are only consequential to exposed populations if they alter organism-level traits that ultimately influence fitness (e.g., growth, locomotor performance, reproduction, and survival). Here, we explore the possibility that the swimming performance of neonate black swamp snakes (Seminatrix pygaea) and diamondback water snakes (Nerodia rhombifer) may be affected by exposure to carbaryl (2.5 and 5.0 mg/L). The highest concentration of carbaryl caused greater reductions in swim velocity in S. pygaea than in N. rhombifer. Most individuals recovered from the effects of carbaryl on swimming performance within 96 h, but recovery was significantly slower in S. pygaea than in N. rhombifer. We hypothesize that the sensitivity of S. pygaea may arise from its highly permeable integument compared to other natricines. Our findings suggest that performance can serve as an ecologically relevant response to contaminant exposure in reptiles and warrants further study.

  17. Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation

    Science.gov (United States)

    2005-05-01

    analysed by combinatorial mutations and enantiomeric phosphonates Zrinka KOVARIK*t1, Zoran RADI6*, Harvey A. BERMANf, Vera SIMEON-RUDOLFt, Elsa REINERt and...Harvey A. Berman,1’ Vera Simeon-Rudolf,§ Elsa Reiner,§ and Palmer Taylbr*4’ Department qf Pharmacology, Univeitirv ofCalffornia at San Diego, La...and refinement statistics A N TZ2PA6 isomer complexed to mAChE anti1 synl Data collection* Beamline (European Synchrotron ID14-EH1 ID14-EH2 Radiation

  18. Silica-Immobilized Enzyme Reactors; Application to Cholinesterase-Inhibition Studies

    National Research Council Canada - National Science Library

    Luckarift, Heather R; Johnson, Glenn R; Spain, Jim C

    2006-01-01

    ...) using silica-encapsulated equine butyrycholinestearse (BuChE) as a model system. Peptide-mediated silica formation was used to encapsulate BuChE, directly immobilizing the enzyme within a commercial pre-packed column...

  19. Crystal Structure of the Extracellular Cholinesterase-Like Domain from Neuroligin-2

    Energy Technology Data Exchange (ETDEWEB)

    Koehnke,J.; Jin, X.; Budreck, E.; Posy, S.; Scheiffele, P.; Hnoig, B.; Shapiro, L.

    2008-01-01

    Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3- Angstroms crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions.

  20. The intracellular domain of the Drosophila cholinesterase-like neural adhesion protein, gliotactin, is natively unfolded

    NARCIS (Netherlands)

    Zeev-Ben-Mordehai, T; Rydberg, EH; Solomon, A.; Toker, L; Auld, VJ; Silman, I.; Botti, S; Sussman, J.L.

    2003-01-01

    Drosophila gliotactin (Gli) is a 109-kDa transmembrane, cholinesterase-like adhesion molecule (CLAM), expressed in peripheral glia, that is crucial for formation of the blood-nerve barrier. The intracellular portion (Gli-cyt) was cloned and expressed in the cytosolic fraction of Escherichia coli

  1. Effects of Cholinesterase Inhibitors in Parkinson's Disease Dementia : A Review of Clinical Data

    NARCIS (Netherlands)

    van Laar, Teus; De Deyn, Peter Paul; Aarsland, Dag; Barone, Paolo; Galvin, James E.

    2011-01-01

    Aims: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available

  2. Caregiver Acceptance of Adverse Effects and Use of Cholinesterase Inhibitors in Alzheimer's Disease

    Science.gov (United States)

    Oremus, Mark; Wolfson, Christina; Vandal, Alain C.; Bergman, Howard; Xie, Qihao

    2007-01-01

    Caregivers play a determining role in choosing treatments for persons with Alzheimer's disease. The objective of this study was to examine caregivers' willingness to have persons with Alzheimer's disease continue taking cholinesterase inhibitors in the event that any 1 of 11 adverse effects was to occur. Data were gathered via postal questionnaire…

  3. Potentially hazardous substances in surface waters. II. Cholinesterase inhibitors in Dutch surface waters

    NARCIS (Netherlands)

    Greve, P.A.; Freudenthal, J.; Wit, S.L.

    1972-01-01

    Several analytical methods were employed to determine the concentrations of cholinesterase inhibitors in several Dutch surface waters. An Auto-Analyzer method was used for screening purposes; thin-layer chromatography and gas-liquid chromatography-mass spectrometry were used for identification and

  4. Acute Consumption of Bordo Grape Juice and Wine Improves Serum Antioxidant Status in Healthy Individuals and Inhibits Reactive Oxygen Species Production in Human Neuron-Like Cells.

    Science.gov (United States)

    Copetti, Cristiane; Franco, Fernanda Wouters; Machado, Eduarda da Rosa; Soquetta, Marcela Bromberger; Quatrin, Andréia; Ramos, Vitor de Miranda; Moreira, José Cláudio Fonseca; Emanuelli, Tatiana; Sautter, Cláudia Kaehler; Penna, Neidi Garcia

    2018-01-01

    Few studies investigated the biological effects of American grape cultivars. We investigated the metabolic response after acute consumption of grape juice or wine from Bordo grapes ( Vitis labrusca ) in a placebo-controlled crossover study with fifteen healthy volunteers. Blood samples were collected 1 hour after the intake of 100 mL of water, juice, or wine to measure TBARS, ABTS, FRAP, glucose, and uric acid levels. To evaluate differences in cellular response, intracellular reactive species production (DCFH-DA) and metabolic mitochondrial viability (MTT) were assessed after exposure of human neuron-like cells (SH-SY5Y) to juice or wine. Glycemia was reduced after juice or wine consumption, whereas blood levels of uric acid were reduced after juice consumption but increased after wine consumption. Juice and wine consumption reduced plasma lipid peroxidation and increased plasma antioxidant capacity (ABTS and FRAP assays). Furthermore, juice inhibited H 2 O 2 -induced intracellular production of reactive species (RS) and increased the viability of SH-SY5Y cells. In contrast, wine (dealcoholized) exhibited a per se effect by inducing the production of RS and reducing cell viability. These results indicate a positive impact of acute consumption of Bordo juice and wine on human oxidative status, whereas only juice had protective effects against oxidative stress-induced cytotoxicity.

  5. Acute Consumption of Bordo Grape Juice and Wine Improves Serum Antioxidant Status in Healthy Individuals and Inhibits Reactive Oxygen Species Production in Human Neuron-Like Cells

    Directory of Open Access Journals (Sweden)

    Cristiane Copetti

    2018-01-01

    Full Text Available Few studies investigated the biological effects of American grape cultivars. We investigated the metabolic response after acute consumption of grape juice or wine from Bordo grapes (Vitis labrusca in a placebo-controlled crossover study with fifteen healthy volunteers. Blood samples were collected 1 hour after the intake of 100 mL of water, juice, or wine to measure TBARS, ABTS, FRAP, glucose, and uric acid levels. To evaluate differences in cellular response, intracellular reactive species production (DCFH-DA and metabolic mitochondrial viability (MTT were assessed after exposure of human neuron-like cells (SH-SY5Y to juice or wine. Glycemia was reduced after juice or wine consumption, whereas blood levels of uric acid were reduced after juice consumption but increased after wine consumption. Juice and wine consumption reduced plasma lipid peroxidation and increased plasma antioxidant capacity (ABTS and FRAP assays. Furthermore, juice inhibited H2O2-induced intracellular production of reactive species (RS and increased the viability of SH-SY5Y cells. In contrast, wine (dealcoholized exhibited a per se effect by inducing the production of RS and reducing cell viability. These results indicate a positive impact of acute consumption of Bordo juice and wine on human oxidative status, whereas only juice had protective effects against oxidative stress-induced cytotoxicity.

  6. Comparative Effects of Oral Chlorpyrifos Exposure on Cholinesterase Activity and Muscarinic Receptor Binding in Neonatal and Adult Rat Heart

    Science.gov (United States)

    Howard, Marcia D.; Mirajkar, Nikita; Karanth, Subramanya; Pope, Carey N.

    2010-01-01

    Organophosphorus (OP) pesticides elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for inactivating acetylcholine (ACh) at cholinergic synapses. A number of OP toxicants have also been reported to interact directly with muscarinic receptors, in particular the M2 muscarinic subtype. Parasympathetic innervation to the heart primarily regulates cardiac function by activating M2 receptors in the sinus node, atrial-ventricular node and conducting tissues. Thus, OP insecticides can potentially influence cardiac function in a receptor–mediated manner indirectly by inhibiting acetylcholinesterase and directly by binding to muscarinic M2 receptors. Young animals are generally more sensitive than adults to the acute toxicity of OP insecticides and age related differences in potency of direct binding to muscarinic receptors by some OP toxicants have been reported. We thus compared the effects of the common OP insecticide chlorpyrifos (CPF) on functional signs of toxicity and cardiac ChE activity and muscarinic receptor binding in neonatal and adult rats. Dosages were based on acute lethality (i.e., 0.5 and 1 × LD10: neonates, 7.5 and 15 mg/kg; adults, 68 and 136 mg/kg). Dose- and time-related changes in body weight and cholinergic signs of toxicity (involuntary movements) were noted in both age groups. With 1 × LD10, relatively similar maximal reductions in ChE activity (95%) and muscarinic receptor binding (≈ 30%) were noted, but receptor binding reductions appeared earlier in adults and were more prolonged in neonates. In vitro inhibition studies indicated that ChE in neonatal tissues was markedly more sensitive to inhibition by the active metabolite of chlorpyrifos (i.e., chlorpyrifos oxon, CPO) than enzyme in adult tissues (IC50 values: neonates, 17 nM; adults, 200 nM). Chelation of free calcium with EDTA had relatively little effect on in vitro cholinesterase inhibition, suggesting that differential A-esterase activity was not

  7. Long term exposure to low dose neurotoxic pesticides affects hatching, viability and cholinesterase activity of Artemia sp.

    Science.gov (United States)

    Gambardella, Chiara; Nichino, Daniela; Iacometti, Camillo; Ferrando, Sara; Falugi, Carla; Faimali, Marco

    2018-03-01

    The brine shrimp Artemia was used as a model organism to test toxicity of several neuroactive pesticides (chlorpyrifos (CLP), chlorpyrifos oxon (CLP ox), diazinon (DZN), carbaryl (CBR)) following exposure to far below than lethal doses. Cysts were exposed to the pesticides in order to test a scenario similar to actual coastal environment contamination, by analyzing different responses. Cysts were rehydrated in water containing the pesticides at concentrations ranging from 10 -11 to 10 -5  M, for 72, 96 and 192 h, respectively. For these exposure times, morpho-functional and biochemical parameters, such as hatching speed and viability were investigated in the larvae together with cholinesterase (ChE) activity quantification and histochemical localization. Finally, ChE inhibition was also compared with conventional selective ChE inhibitors. Results showed that CLP ox and CBR caused a significant dose-dependent decrease in hatching speed, followed by high percentages of larval death, while CLP and DZN were responsible for irregular hatching patterns. In addition, the pesticides mostly caused larval death some days post-hatching, whereas this effect was negligible for the specific ChE inhibitors, suggesting that part of pesticide toxicity may be due to molecules other than the primary target. ChE activity was observed in the protocerebrum lobes, linked to the development of pair eyes. Such activity was inhibited in larvae exposed to all pesticides. When compared to conventional selective inhibitors of ChE activities, this inhibition demonstrated that the selected pesticides mainly affect acetylcholinesterase and, to a lesser extent, pseudocholinesterases. In conclusion, the brine shrimp is a good model to test the environmental toxicity of long term exposure to cholinergic pesticides, since changes in hatching speed, viability and ChE activity were observed. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

    Energy Technology Data Exchange (ETDEWEB)

    Du, Dan; Wang, Jun; Wang, Limin; Lu, Donglai; Lin, Yuehe

    2012-02-08

    An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. The proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.

  9. Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents.

    Science.gov (United States)

    Lushchekina, Sofya V; Schopfer, Lawrence M; Grigorenko, Bella L; Nemukhin, Alexander V; Varfolomeev, Sergei D; Lockridge, Oksana; Masson, Patrick

    2018-01-01

    Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme. Second generation bioscavengers are catalytic bioscavengers capable of detoxifying OPs with a turnover. High bimolecular rate constants ( k cat / K m > 10 6 M -1 min -1 ) are required, so that low enzyme doses can be administered. Cholinesterases (ChE) are attractive candidates because OPs are hemi-substrates. Moderate OP hydrolase (OPase) activity has been observed for certain natural ChEs and for G117H-based human BChE mutants made by site-directed mutagenesis. However, before mutated ChEs can become operational catalytic bioscavengers their dephosphylation rate constant must be increased by several orders of magnitude. New strategies for converting ChEs into fast OPase are based either on combinational approaches or on computer redesign of enzyme. The keystone for rational conversion of ChEs into OPases is to understand the reaction mechanisms with OPs. In the present work we propose that efficient OP hydrolysis can be achieved by re-designing the configuration of enzyme active center residues and by creating specific routes for attack of water molecules and proton transfer. Four directions for nucleophilic attack of water on phosphorus atom were defined. Changes must lead to a novel enzyme, wherein OP hydrolysis wins over competing aging reactions. Kinetic, crystallographic, and computational data have been accumulated that describe mechanisms of reactions involving ChEs. From these studies, it appears that introducing

  10. Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents

    Directory of Open Access Journals (Sweden)

    Sofya V. Lushchekina

    2018-03-01

    Full Text Available Organophosphorus agents (OPs are irreversible inhibitors of acetylcholinesterase (AChE. OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme. Second generation bioscavengers are catalytic bioscavengers capable of detoxifying OPs with a turnover. High bimolecular rate constants (kcat/Km > 106 M−1min−1 are required, so that low enzyme doses can be administered. Cholinesterases (ChE are attractive candidates because OPs are hemi-substrates. Moderate OP hydrolase (OPase activity has been observed for certain natural ChEs and for G117H-based human BChE mutants made by site-directed mutagenesis. However, before mutated ChEs can become operational catalytic bioscavengers their dephosphylation rate constant must be increased by several orders of magnitude. New strategies for converting ChEs into fast OPase are based either on combinational approaches or on computer redesign of enzyme. The keystone for rational conversion of ChEs into OPases is to understand the reaction mechanisms with OPs. In the present work we propose that efficient OP hydrolysis can be achieved by re-designing the configuration of enzyme active center residues and by creating specific routes for attack of water molecules and proton transfer. Four directions for nucleophilic attack of water on phosphorus atom were defined. Changes must lead to a novel enzyme, wherein OP hydrolysis wins over competing aging reactions. Kinetic, crystallographic, and computational data have been accumulated that describe mechanisms of reactions involving ChEs. From these studies, it appears that

  11. Pro-2-PAM therapy for central and peripheral cholinesterases.

    Science.gov (United States)

    Demar, James C; Clarkson, Edward D; Ratcliffe, Ruthie H; Campbell, Amy J; Thangavelu, Sonia G; Herdman, Christine A; Leader, Haim; Schulz, Susan M; Marek, Elizabeth; Medynets, Marie A; Ku, Therese C; Evans, Sarah A; Khan, Farhat A; Owens, Roberta R; Nambiar, Madhusoodana P; Gordon, Richard K

    2010-09-06

    Novel therapeutics to overcome the toxic effects of organophosphorus (OP) chemical agents are needed due to the documented use of OPs in warfare (e.g. 1980-1988 Iran/Iraq war) and terrorism (e.g. 1995 Tokyo subway attacks). Standard OP exposure therapy in the United States consists of atropine sulfate (to block muscarinic receptors), the acetylcholinesterase (AChE) reactivator (oxime) pralidoxime chloride (2-PAM), and a benzodiazepine anticonvulsant to ameliorate seizures. A major disadvantage is that quaternary nitrogen charged oximes, including 2-PAM, do not cross the blood brain barrier (BBB) to treat brain AChE. Therefore, we have synthesized and evaluated pro-2-PAM (a lipid permeable 2-PAM derivative) that can enter the brain and reactivate CNS AChE, preventing seizures in guinea pigs after exposure to OPs. The protective effects of the pro-2-PAM after OP exposure were shown using (a) surgically implanted radiotelemetry probes for electroencephalogram (EEG), (b) neurohistopathology of brain, (c) cholinesterase activities in the PNS and CNS, and (d) survivability. The PNS oxime 2-PAM was ineffective at reducing seizures/status epilepticus (SE) in diisopropylfluorophosphate (DFP)-exposed animals. In contrast, pro-2-PAM significantly suppressed and then eliminated seizure activity. In OP-exposed guinea pigs, there was a significant reduction in neurological damage with pro-2-PAM but not 2-PAM. Distinct regional areas of the brains showed significantly higher AChE activity 1.5h after OP exposure in pro-2-PAM treated animals compared to the 2-PAM treated ones. However, blood and diaphragm showed similar AChE activities in animals treated with either oxime, as both 2-PAM and pro-2-PAM are PNS active oximes. In conclusion, pro-2-PAM can cross the BBB, is rapidly metabolized inside the brain to 2-PAM, and protects against OP-induced SE through restoration of brain AChE activity. Pro-2-PAM represents the first non-invasive means of administering a CNS therapeutic for

  12. O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation.

    Science.gov (United States)

    Mao, Fei; Huang, Ling; Luo, Zonghua; Liu, Anqiu; Lu, Chuanjun; Xie, Zhiyong; Li, Xingshu

    2012-10-01

    In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer's disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2-aminobenzaldehyde. These compounds were then evaluated as multifunctional anti-Alzheimer's disease agents. All of the hybrids are potential biometal chelators, and in addition, most of them were better antioxidants and inhibitors of cholinesterases and amyloid-β (Aβ) aggregation than the lead compound tacrine. Compound 7c has the potential to be a candidate for AD therapy: it is a much better inhibitor of acetylcholinesterase (AChE) than tacrine (IC(50): 0.55 nM vs 109 nM), has good biometal chelation ability, is able to inhibit Aβ aggregation and has moderate antioxidant activity (1.22 Trolox equivalents). Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists.

    Science.gov (United States)

    Tomassoli, Isabelle; Ismaili, Lhassane; Pudlo, Marc; de Los Ríos, Cristóbal; Soriano, Elena; Colmena, Inés; Gandía, Luis; Rivas, Luis; Samadi, Abdelouahid; Marco-Contelles, José; Refouvelet, Bernard

    2011-01-01

    The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K(+)-induced calcium signals in bovine chromaffin cells. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  14. (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy.

    Science.gov (United States)

    Cheng, Shaobing; Zheng, Wei; Gong, Ping; Zhou, Qiang; Xie, Qiong; Yu, Lining; Zhang, Peiyi; Chen, Liangkang; Li, Juan; Chen, Jianxing; Chen, Hailin; Chen, Hongzhuan

    2015-07-01

    The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-β (Aβ) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aβ self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives.

    Science.gov (United States)

    Wang, Yali; Sun, Yang; Guo, Yueyan; Wang, Zechen; Huang, Ling; Li, Xingshu

    2016-01-01

    Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound 10 provided a desired balance of AChE and hMAO-B inhibition activities, with IC50 value of 3.94 and 3.44 μM, respectively. Further studies revealed that compound 10 was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that 10 was a promising dual functional agent for the treatment of AD.

  16. Chemical Composition of Volatiles; Antimicrobial, Antioxidant and Cholinesterase Inhibitory Activity of Chaerophyllum aromaticum L. (Apiaceae) Essential Oils and Extracts.

    Science.gov (United States)

    Petrović, Goran M; Stamenković, Jelena G; Kostevski, Ivana R; Stojanović, Gordana S; Mitić, Violeta D; Zlatković, Bojan K

    2017-05-01

    The present study reports the chemical composition of the headspace volatiles (HS) and essential oils obtained from fresh Chaerophyllum aromaticum root and aerial parts in full vegetative phase, as well as biological activities of their essential oils and MeOH extracts. In HS samples, the most dominant components were monoterpene hydrocarbons. On the other hand, the essential oils consisted mainly of sesquiterpenoids, representing 73.4% of the root and 63.4% of the aerial parts essential oil. The results of antibacterial assay showed that the aerial parts essential oil and MeOH extract have no antibacterial activity, while the root essential oil and extract showed some activity. Both of the tested essential oils exhibited anticholinesterase activity (47.65% and 50.88%, respectively); MeOH extract of the root showed only 8.40% inhibition, while aerial part extract acted as an activator of cholinesterase. Regarding the antioxidant activity, extracts were found to be more effective than the essential oils. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  17. Recombinant butyryl-cholinesterase (RBuChe) therapy following VX poisoning by the percutaneous route: preliminary studies

    International Nuclear Information System (INIS)

    Speakman, P.; Armstrong, S.

    2009-01-01

    Medical countermeasures to prevent or mitigate the effects of nerve agent poisoning are part of the UK MoD's integrated approach to CBRN defence. Protexia is currently in advanced development as a pretreatment for nerve agent poisoning by PharmAthene in collaboration with US DoD. The principle of its use in this context has been demonstrated in a model of inhalation exposure. Nerve agent poisoning by the percutaneous route poses additional challenges for medical countermeasures. The present study investigates the effects of non-pegylated rBuChE administered following poisoning by VX in an animal model of percutaneous exposure. This investigation is part of an ongoing programme of work assessing the potential of candidate medical interventions. Male guinea pigs implanted with dermal and blood microdialysis probes were maintained under anaesthesia. VX (296 micro g/kg or 740 micro g/kg) was applied to the dorsal skin and non-pegylated rBuChE or placebo was administered (i.v.) 30 minutes later. Dialysate fractions were collected for 8 hours and VX was analysed by LC-MS-MS. Cholinesterase levels were measured in selected tissues post mortem. Following VX (296 micro g/kg), non-pegylated rBuChE significantly reduced the concentration of VX in the blood but had no effect on dermal concentrations; additionally following VX (740 micro g/kg), non-pegylated rBuChE prevented lethality. Tissue cholinesterase activity was inhibited following VX exposure but in those animals treated with rhBuChE, activities were similar to control values. To our knowledge these results provide the first evidence of the mechanism of therapeutic intervention with rBuChE. Further work is necessary to increase confidence in these preliminary observations by conducting confirmatory studies. Crown Copyright 2008. This work was carried out as part of the UK MoD NBC Research Programme. Non-pegylated rBuChE was supplied by PharmAthene under a materials transfer and non-disclosure agreement. (author)

  18. Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study

    Directory of Open Access Journals (Sweden)

    Hedbäck Bo

    2009-06-01

    Full Text Available Abstract Background Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment. Methods With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B2 (TXB2-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis. Results The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5'-diphosphate (ADP-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r2 = 0.49. In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN

  19. Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study

    Science.gov (United States)

    Eriksson, Andreas C; Jonasson, Lena; Lindahl, Tomas L; Hedbäck, Bo; Whiss, Per A

    2009-01-01

    Background Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment. Methods With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B2 (TXB2)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis. Results The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5'-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r2 = 0.49). In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow

  20. Serum sickness

    Science.gov (United States)

    ... the problem should be stopped. Avoid using that medicine or antiserum in the future. ... Call your provider if you received medicine or antiserum in the last 4 weeks and have symptoms of serum sickness.

  1. Endochondral Ossification Is Accelerated in Cholinesterase-Deficient Mice and in Avian Mesenchymal Micromass Cultures.

    Directory of Open Access Journals (Sweden)

    Janine Spieker

    Full Text Available Most components of the cholinergic system are detected in skeletogenic cell types in vitro, yet the function of this system in skeletogenesis remains unclear. Here, we analyzed endochondral ossification in mutant murine fetuses, in which genes of the rate-limiting cholinergic enzymes acetyl- (AChE, or butyrylcholinesterase (BChE, or both were deleted (called here A-B+, A+B-, A-B-, respectively. In all mutant embryos bone growth and cartilage remodeling into mineralizing bone were accelerated, as revealed by Alcian blue (A-blu and Alizarin red (A-red staining. In A+B- and A-B- onset of mineralization was observed before E13.5, about 2 days earlier than in wild type and A-B+ mice. In all mutants between E18.5 to birth A-blu staining disappeared from epiphyses prematurely. Instead, A-blu+ cells were dislocated into diaphyses, most pronounced so in A-B- mutants, indicating additive effects of both missing ChEs in A-B- mutant mice. The remodeling effects were supported by in situ hybridization (ISH experiments performed on cryosections from A-B- mice, in which Ihh, Runx2, MMP-13, ALP, Col-II and Col-X were considerably decreased, or had disappeared between E18.5 and P0. With a second approach, we applied an improved in vitro micromass model from chicken limb buds that allowed histological distinction between areas of cartilage, apoptosis and mineralization. When treated with the AChE inhibitor BW284c51, or with nicotine, there was decrease in cartilage and accelerated mineralization, suggesting that these effects were mediated through nicotinic receptors (α7-nAChR. We conclude that due to absence of either one or both cholinesterases in KO mice, or inhibition of AChE in chicken micromass cultures, there is increase in cholinergic signalling, which leads to increased chondroblast production and premature mineralization, at the expense of incomplete chondrogenic differentiation. This emphasizes the importance of cholinergic signalling in cartilage and

  2. Blood cholinesterase activity levels of farmers in winter and hot season of Mae Taeng District, Chiang Mai Province, Thailand.

    Science.gov (United States)

    Hongsibsong, Surat; Kerdnoi, Tanyaporn; Polyiem, Watcharapon; Srinual, Niphan; Patarasiriwong, Vanvimol; Prapamontol, Tippawan

    2018-03-01

    Organophosphate and carbamate pesticides have been widely used by farmers for crop protection and pest control. Inhibition of acetylcholinesterase (AChE) in erythrocyte and butyrylcholinesterase (BChE) in plasma is the predominant toxic effect of organophosphate and carbamate pesticides. Mae Taeng District, Chiang Mai Province, is one of the large areas of growing vegetables and fruits. Due to their regular exposure to these pesticides, the farmers are affected by this toxicity. The objective of the study was to examine the AChE and the BChE activity levels in the blood of 102 farmers for comparison of exposure in two cropping seasons, winter and hot. Blood samples were collected in December 2013 (winter) and April-June 2014 (hot). A total of 102 farmers joined the study, represented by 76 males (74.5 %) and 26 females (25.5 %). The age of most of the farmers was 53.4 ± 8.7 years. Out of 102, 21 farmers used carbamate pesticides. The results showed that the AChE and the BChE activity levels of all the farmers were 3.27 ± 0.84 Unit/mL and 2.15 ± 0.58 Unit/mL, respectively. The AChE and the BChE activity levels in males were 3.31 ± 0.88 Unit/mL and 1.97 ± 0.60 U/mL, respectively, during winter and 3.27 ± 0.82 Unit/mL and 2.15 ± 0.58 U/mL, respectively, during the hot season, and AChE and the BChE activity levels in females were 3.27 ± 0.82 U/mL and 2.44 ± 0.56 U/mL, respectively, during the hot season. The cholinesterase activity levels, both AChE and BChE, in the male farmers' blood had significant difference between the two seasons, while in the case of the female farmers, there was significant difference in the BChE activity levels, at p < 0.05. The BChE activity level was found to significantly correlate with self-spray (p < 0.05), which implies that the BChE activity decreased when they sprayed by themselves. The cholinesterase activity levels of the present study were lower than those of the other

  3. Assay techniques for detection of exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide. Technical bulletin

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-05-01

    This technical bulletin provides analytical techniques to identify toxic chemical agents in urine or blood samples. It is intended to provide the clinician with laboratory tests to detect exposure to sulfur mustard, cholinesterase inhibitors, sarin, soman, GF, and cyanide.

  4. Esterase metabolism of cholinesterase inhibitors using rat liver in vitro

    Science.gov (United States)

    A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species...

  5. Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Li, Yuxing; Qiang, Xiaoming; Li, Yan; Yang, Xia; Luo, Li; Xiao, Ganyuan; Cao, Zhongcheng; Tan, Zhenghuai; Deng, Yong

    2016-04-15

    A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ1-42 aggregation and HuAChE-induced Aβ1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 μM) and good inhibition of BuChE (IC50=28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors

    DEFF Research Database (Denmark)

    Wu, Gaochan; Gao, Yun; Kang, Dongwei

    2018-01-01

    acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) as potential drug targets for Alzheimer's disease (AD). Among the designed compounds, compound 8a2 exhibited potent inhibition against AChE and BChE with IC50 values of 4.89 μM and 3.61 μM, respectively. Further structure-activity relationship...

  7. Aqueous extracts of avocado pear (Persea americana Mill.) leaves and seeds exhibit anti-cholinesterases and antioxidant activities in vitro.

    Science.gov (United States)

    Oboh, Ganiyu; Odubanjo, Veronica O; Bello, Fatai; Ademosun, Ayokunle O; Oyeleye, Sunday I; Nwanna, Emem E; Ademiluyi, Adedayo O

    2016-03-01

    Avocado pear (Persea americana Mill.) leaves and seeds are used in traditional medicine for the treatment/management of Alzheimer disease (AD); however, information on the mechanism of actions is limited. This study sought to investigate the effect of P. americana leaf and seed aqueous extracts on some enzymes linked with AD (acetylcholinesterase [AChE] and butyrylcholinesterase [BChE] activities) and their antioxidant potentials in vitro. The inhibitory effects of extracts on AChE and BChE activities and antioxidant potentials (inhibition of Fe2+- and sodium nitroprusside-induced thiobarbiturate reactive species [TBARS] production in rat brain homogenates, radicals [1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and nitric oxide] scavenging and iron [Fe] chelation abilities) were investigated. Phenolic content and phytochemical screening were carried out. Alkaloid profile was also determined using gas chromatography coupled with flame ionization detector (GC-FID). The extracts inhibited AChE and BChE activities and prooxidant-induced TBARS production in a dose-dependent manner, with the seed extract having the highest inhibitory effect and the leaf extract exhibiting higher phenolic content and radical scavenging abilities, but lower Fe chelation ability compared with that of the seed. The phytochemical screening revealed the presence of saponins, alkaloids, and terpenoids in both extracts, whereas the total alkaloid profile was higher in the seed extract than in the leaf extract, as revealed by GC-FID. The anti-cholinesterase and antioxidant activities of avocado leaf and seed could be linked to their phytoconstituents and might be the possible mechanisms underlying their use as a cheap and natural treatment/management of AD. However, these extracts should be further investigated in vivo.

  8. Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

    Science.gov (United States)

    Sultana, Nargis; Sarfraz, Muhammad; Tanoli, Saba Tahir; Akram, Muhammad Safwan; Sadiq, Abdul; Rashid, Umer; Tariq, Muhammad Ilyas

    2017-06-01

    Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N 1 -substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC 50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.

    Science.gov (United States)

    Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Heart rate variability analysis in acute poisoning by cholinesterase inhibitors

    OpenAIRE

    JEONG, JINWOO; KIM, YONGIN

    2017-01-01

    Heart rate variability (HRV) has been associated with a variety of clinical situations. However, few studies have examined the association between HRV and acute poisoning. Organophosphate (OP) and carbamate inhibit esterase enzymes, particularly acetylcholinesterase, resulting in an accumulation of acetylcholine and thereby promoting excessive activation of corresponding receptors. Because diagnosis and treatment of OP and carbamate poisoning greatly depend on...

  11. Ivermectin resistant and susceptible third-stage larvae of Haemonchus contortus: cholinesterase and phosphatase activities

    Directory of Open Access Journals (Sweden)

    Consuelo Giménez-Pardo

    2004-03-01

    Full Text Available Cholinesterase and acid phosphatase (AP, but not alkaline phosphatase activities, were detected in cytosolic and membrane-bound fractions of ivermectin resistant and susceptible Haemonchus contortus infective-stage larvae. Some differences in acetylcholinesterase activity of cytosolic fractions and in the AP activity of these fractions as well as in the response to AP inhibitors by membrane-bound fractions were detected. Data are discussed.

  12. Copper (II) and zinc (II) complexes with flavanone derivatives: Identification of potential cholinesterase inhibitors by on-flow assays.

    Science.gov (United States)

    Sarria, André Lucio Franceschini; Vilela, Adriana Ferreira Lopes; Frugeri, Bárbara Mammana; Fernandes, João Batista; Carlos, Rose Maria; da Silva, Maria Fátima das Graças Fernandes; Cass, Quezia Bezerra; Cardoso, Carmen Lúcia

    2016-11-01

    Metal chelates strongly influence the nature and magnitude of pharmacological activities in flavonoids. In recent years, studies have shown that a promising class of flavanone-metal ion complexes can act as selective cholinesterase inhibitors (ChEIs), which has led our group to synthesize a new series of flavanone derivatives (hesperidin, hesperetin, naringin, and naringenin) complexed to either copper (II) or zinc (II) and to evaluate their potential use as selective ChEIs. Most of the synthesized complexes exhibited greater inhibitory activity against acetylcholinesterase (AChE) than against butyrylcholinesterase (BChE). Nine of these complexes constituted potent, reversible, and selective ChEIs with inhibitory potency (IC 50 ) and inhibitory constant (K i ) ranging from 0.02 to 4.5μM. Copper complexes with flavanone-bipyridine derivatives afforded the best inhibitory activity against AChE and BChE. The complex Cu(naringin)(2,2'-bipyridine) (11) gave IC 50 and K i values of 0.012±0.002 and 0.07±0.01μM for huAChE, respectively, which were lower than the inhibitory values obtained for standard galanthamine (IC 50 =206±30.0 and K i =126±18.0μM). Evaluation of the inhibitory activity of this complex against butyrylcholinesterase from human serum (huBChE) gave IC 50 and K i values of 8.0±1.4 and 2.0±0.1μM, respectively. A Liquid Chromatography-Immobilized Capillary Enzyme Reactor by UV detection (LC-ICER-UV) assay allowed us to determine the IC 50 and K i values and the type of mechanism for the best inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. UHPLC-ESI-ORBITRAP-MS analysis of the native Mapuche medicinal plant palo negro (Leptocarpha rivularis DC. - Asteraceae) and evaluation of its antioxidant and cholinesterase inhibitory properties.

    Science.gov (United States)

    Jiménez-González, Andrea; Quispe, Cristina; Bórquez, Jorge; Sepúlveda, Beatriz; Riveros, Felipe; Areche, Carlos; Nagles, Edgar; García-Beltrán, Olimpo; Simirgiotis, Mario J

    2018-12-01

    UHPLC/ESI/MS identification of organic compounds is the first step in the majority of screening techniques for the characterization of biologically active metabolites in natural sources. This paper describes a method for the fast identification and characterisation of secondary metabolites in Leptocarpha rivularis DC. (Palo negro) extracts by HPLC/UV (DAD)-Mass Spectrometry (HPLC/MS). The plant is used for the treatment of several diseases since pre-hispanic Mapuche times. Thirty-seven compounds were detected in the aqueous edible extract for the first time including 4 sesquiterpenes, 10 flavonoids, 9 oxylipins, 2 organic acids, and 11 phenolic acids. In addition, phenolic content antioxidant and cholinesterase inhibitory activities were measured for the first time using the edible infusion. The total polyphenol content of the infusion was 230.76 ± 2.5 mmol GAE/kg dry weight, while the antioxidant activity was 176.51 ± 28.84; 195.28 ± 4.83; and 223.92 ± 2.95 mmol TE/kg dry weight, for the DPPH, ABTS, and FRAP assays, respectively. The cholinesterase inhibitory activity was 7.38 ± 0.03 and 5.74 ± 0.06 mmol GALAE/kg, for the inhibition of acetylcholinesterase AChE and BChE, respectively, showing that this plant is a candidate for the isolation of compounds that can be useful for the treatment of neurodegenerative diseases. Furthermore, this plant could serve also as a raw material for the production of dietary supplements, due to its content of polyphenolic compounds.

  14. Activities of cholinesterase enzyme among diazinon and sevin insecticides sprayers in the western part of Iran

    Directory of Open Access Journals (Sweden)

    Ali Jalilian

    2016-10-01

    Full Text Available Objective: To measure the activities of cholinesterase enzyme among farmers who used the selected insecticides for the purpose of preventing the growth of agricultural pests on their farms. Methods: A total of 21 people used diazinon to spray their agricultural lands and 13 people also used sevin to spray theirs in western part of Iran. Lovi Bond method was used for the measurement of cholinesterase activity. Results: Results revealed that the enzyme level before spraying with diazinon was 100.0% among 3 workers and 87.5% in 18 of them. This level decreased to 75.0% among 13 workers and 67.5% in 5 workers. The number of workers that had headache, pale, dizziness with headache, nausea, diarrhea with cramps and stomachache were 5, 9, 5, 3, 4 and 7 respectively. These symptoms decreased after 72 h. Out of 13 workers who sprayed with sevin, the enzyme level before spraying was normal (100.0% among 5 workers and 87.5% in 8 workers. After spraying, the enzyme level was 87.5% in 5 workers, 75.0% in 5 workers and 67.5% in 3 workers. Conclusions: These workers were in danger of chemical poisoning. Measurement of precholinesterase and post-cholinesterase exposures is recommended in order to compare the values after pesticide application.

  15. Synthesis, biological evaluation and docking studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as inhibitors of cholinesterases.

    Science.gov (United States)

    Sarfraz, Muhammad; Sultana, Nargis; Rashid, Umer; Akram, Muhammad Safwan; Sadiq, Abdul; Tariq, Muhammad Ilyas

    2017-02-01

    In search of potent inhibitors of cholinesterases, we have synthesized and evaluate a number of 2,3-dihydroquinazolin-4(1H)-one derivatives. The synthetic approach provided an efficient synthesis of the target molecules with excellent yield. All the tested compounds showed activity against both the enzymes in micromolar range. In many case, the inhibition of both enzymes are higher than or comparable to the standard drug galatamine. With the selectivity index of 2.3 for AChE, compound 5f can be considered as a potential lead compound with a feature of dual AChE/BChE inhibition with IC 50 =1.6±0.10μM (AChE) and 3.7±0.18μM (BChE). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. The computed binding modes of these compounds in the active site of AChE and BChE provide an insight into the mechanism of inhibition of these two enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Qian Yang Yu Yin Granule-containing serum inhibits angiotensin II-induced proliferation, reactive oxygen species production, and inflammation in human mesangial cells via an NADPH oxidase 4-dependent pathway.

    Science.gov (United States)

    Ding, Kang; Wang, Yan; Jiang, Weimin; Zhang, Yu; Yin, Hongping; Fang, Zhuyuan

    2015-03-25

    Qian Yang Yu Yin Granule (QYYYG), a traditional Chinese herbal medicine, has been indicated for renal damage in hypertension for decades in China, but little remains known regarding its underlying molecular mechanism. Therefore, we performed the current study in order to investigate the underlying molecular mechanism of QYYYG in the treatment of hypertensive renal damage. We hypothesize that QYYYG relieves hypertensive renal injury through an angiotensin II (Ang II)-nicotinamide adenine dinucleotide phosphate (NAPDH)-oxidase (NOX)-reactive oxygen species (ROS) pathway. In this study, we investigated the effects of QYYYG-containing serum (QYGS) in human mesangial cells (HMCs) against Ang II-induced cell proliferation, ROS production, and inflammation through the seropharmacological method. We found that QYGS could inhibit cell proliferation in Ang II-treated HMCs. In addition, QYGS considerably suppressed production of ROS, decreased mRNA and protein expression of NAPDH-oxidase 4 (NOX4), p22 (phox) , and activated Ras-related C3 botulinum toxin substrate 1 (GTP-Rac1); as well as counteracted the up-regulation of inflammatory markers including tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) p65, and interleukin 6 (IL-6). These effects were further confirmed in HMCs transfected with specific small interfering RNA (siRNA) targeting NOX4. Taken together, these results suggest that a NOX4-dependent pathway plays an important role in regulating the inhibitory effect of QYGS. Our findings provide new insights into the molecular mechanisms of QYYYG and their role in the treatment of hypertensive nephropathy.

  17. Acetylcholinesterase assay for cerebrospinal fluid using bupivacaine to inhibit butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Anders Jens

    2001-12-01

    Full Text Available Abstract Background Most test systems for acetylcholinesterase activity (E.C.3.1.1.7. are using toxic inhibitors (BW284c51 and iso-OMPA to distinguish the enzyme from butyrylcholinesterase (E.C.3.1.1.8. which occurs simultaneously in the cerebrospinal fluid. Applying Ellman's colorimetric method, we were looking for a non-toxic inhibitor to restrain butyrylcholinesterase activity. Based on results of previous in vitro studies bupivacaine emerged to be a suitable inhibitor. Results Pharmacokinetic investigations with purified cholinesterases have shown maximum inhibition of butyrylcholinesterase activity and minimal interference with acetylcholinesterase activity at bupivacaine final concentrations between 0.1 and 0.5 mmol/l. Based on detailed analysis of pharmacokinetic data we developed three equations representing enzyme inhibition at bupivacaine concentrations of 0.1, 0.2 and 0.5 mmol/l. These equations allow us to calculate the acetylcholinesterase activity in solutions containing both cholinesterases utilizing the extinction differences measured spectrophotometrically in samples with and without bupivacaine. The accuracy of the bupivacaine-inhibition test could be confirmed by investigations on solutions of both purified cholinesterases and on samples of human cerebrospinal fluid. If butyrylcholinesterase activity has to be assessed simultaneously an independent test using butyrylthiocholine iodide as substrate (final concentration 5 mmol/l has to be conducted. Conclusions The bupivacaine-inhibition test is a reliable method using spectrophotometrical techniques to measure acetylcholinesterase activity in cerebrospinal fluid. It avoids the use of toxic inhibitors for differentiation of acetylcholinesterase from butyrylcholinesterase in fluids containing both enzymes. Our investigations suggest that bupivacaine concentrations of 0.1, 0.2 or 0.5 mmol/l can be applied with the same effect using 1 mmol/l acetylthiocholine iodide as substrate.

  18. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Jan, Yi-Hua [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Baker, Angela A. [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Mishin, Vladimir [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Department of Environmental Health Science, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  19. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    International Nuclear Information System (INIS)

    Jan, Yi-Hua; Richardson, Jason R.; Baker, Angela A.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2015-01-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  20. Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.

    Science.gov (United States)

    Schwarz, Stefan; Lucas, Susana Dias; Sommerwerk, Sven; Csuk, René

    2014-07-01

    The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Characterization of the In Vitro Kinetic Interaction of Chlorpyrifos-Oxon with Rat Salivary Cholinesterase: A Potential Biomonitoring Matrix

    Energy Technology Data Exchange (ETDEWEB)

    Kousba, Ahmed A.(BATTELLE (PACIFIC NW LAB)); Poet, Torka S.(BATTELLE (PACIFIC NW LAB)); Timchalk, Charles (Pacific Northwest National Laboratory)

    2003-02-12

    Chlorpyrifos (CPF) is a commonly used organophosphate insecticide (OP). The primary mechanism of action for CPF involves the inhibition of acetylcholinesterase (AChE) by the active metabolite, CPF-oxon, with subsequent accumulation of acetylcholine (ACh) resulting in a wide range of neutotoxicity. CPF-oxon, can likewise inhibit other non-target cholinesterases (ChE) such as butyrylcholinesterase (BuChE), which represents a detoxification mechanism and a potential biomarker of exposure/response. Biological monitoring for OPs has focused on measuring parent chemical or metabolite in blood and urine or blood ChE inhibition. Salivary biomonitoring has recently been explored as a practical method for examination of chemical exposure; however, there are a limited number of studies exploring its use for OPs. To evaluate the use of salivary ChE as a biological monitor for OP exposure, the current study characterized salivary ChE activity in Sprague-Dawley rats through its comparison with brain and plasma ChE using BW284C51 and iso-OMPA as selective inhibitors of AChE and BuChE, respectively. The study also estimated the kinetic constants describing BuChE interaction with CPF-oxon. A modified Ellman assay in conjunction with pharmacodynamic (PD) modeling was used to characterize the in vitro titration of diluted rat salivary ChE enzyme with CPF-oxon. The results indicated that, more than 95% of rat salivary ChE activity was associated with BuChE activity, total BuChE active site concentration was 0.0012 0.00013 nmol/ml saliva, reactivation rate constant (Kr) was 0.068 0.008 h-1 and inhibitory (Ki) rate constant of 8.825 and 9.80 nM-1h-1 determined experimentally and using model optimization respectively. These study results would be helpful for further evaluating the potential utility of salivary ChE as a practical tool for biological monitor of OP exposures.

  2. New Insights into Butyrylcholinesterase Activity Assay: Serum Dilution Factor as a Crucial Parameter.

    Directory of Open Access Journals (Sweden)

    Joanna Jońca

    Full Text Available Butyrylcholinesterase (BChE activity assay and inhibitor phenotyping can help to identify patients at risk of prolonged paralysis following the administration of neuromuscular blocking agents. The assay plays an important role in clinical chemistry as a good diagnostic marker for intoxication with pesticides and nerve agents. Furthermore, the assay is also commonly used for in vitro characterization of cholinesterases, their toxins and drugs. There is still lack of standardized procedure for measurement of BChE activity and many laboratories use different substrates at various concentrations. The purpose of this study was to validate the BChE activity assay to determine the best dilution of human serum and the most optimal concentration of substrates and inhibitors. Serum BChE activity was measured using modified Ellman's method applicable for a microplate reader. We present our experience and new insights into the protocol for high-throughput routine assays of human plasma cholinesterase activities adapted to a microplate reader. During our routine assays used for the determination of BChE activity, we have observed that serum dilution factor influences the results obtained. We show that a 400-fold dilution of serum and 5mM S-butyrylthiocholine iodide can be successfully used for the accurate measurement of BChE activity in human serum. We also discuss usage of various concentrations of dibucaine and fluoride in BChE phenotyping. This study indicates that some factors of such a multicomponent clinical material like serum can influence kinetic parameters of the BChE. The observed inhibitory effect is dependent on serum dilution factor used in the assay.

  3. Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment.

    Science.gov (United States)

    Musilek, Kamil; Komloova, Marketa; Holas, Ondrej; Hrabinova, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Nachon, Florian; Dolezal, Martin; Kuca, Kamil

    2011-02-01

    Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π-π or π-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  4. New Indole Alkaloids from the Bark of Rauvolfia Reflexa and their Cholinesterase Inhibitory Activity

    Directory of Open Access Journals (Sweden)

    Mehran Fadaeinasab

    2015-11-01

    Full Text Available Background/Aims: Rauvolfia reflexa is a member of the Apocynaceae family. Plants from the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders Methods and Results: Two new indole alkaloids, rauvolfine C (1 and 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-β-carboline (2, along with five known, macusine B (3, vinorine (4, undulifoline (5, isoresrpiline (6 and rescinnamine (7 were isolated from the bark of Rauvolfia reflexa. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 µM. Compound 7 was found to be the most potent inhibitor of both acetylcholinesterase (AChE and butyrylcholinesterase (BChE. Compounds 1, 2, 5 and 6 were found to be selective towards BChE, while compounds 3, 4 and 7 were dual inhibitors, having almost equal inhibitory activity on both AChE and BChE. Molecular docking revealed that compounds 6 and 7 interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding. In AChE, the indole moiety of both compounds interacted with the residues lining the peripheral anionic site, whereas in BChE, their methoxy groups are primarily responsible for the strong inhibitory activity via interactions with residues at the active site of the enzyme. Conclusion: Two new and five known indole alkaloids were isolated from R. reflexa. Among the compounds, 7 and 6 showed the most potent and promising cholinesterase inhibitory activity, worthy for further investigations.

  5. New Indole Alkaloids from the Bark of Rauvolfia Reflexa and their Cholinesterase Inhibitory Activity.

    Science.gov (United States)

    Fadaeinasab, Mehran; Basiri, Alireza; Kia, Yalda; Karimian, Hamed; Ali, Hapipah Mohd; Murugaiyah, Vikneswaran

    2015-01-01

    Rauvolfia reflexa is a member of the Apocynaceae family. Plants from the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders Methods and Results: Two new indole alkaloids, rauvolfine C (1) and 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-β-carboline (2), along with five known, macusine B (3), vinorine (4), undulifoline (5), isoresrpiline (6) and rescinnamine (7) were isolated from the bark of Rauvolfia reflexa. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 µM. Compound 7 was found to be the most potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1, 2, 5 and 6 were found to be selective towards BChE, while compounds 3, 4 and 7 were dual inhibitors, having almost equal inhibitory activity on both AChE and BChE. Molecular docking revealed that compounds 6 and 7 interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding. In AChE, the indole moiety of both compounds interacted with the residues lining the peripheral anionic site, whereas in BChE, their methoxy groups are primarily responsible for the strong inhibitory activity via interactions with residues at the active site of the enzyme. Two new and five known indole alkaloids were isolated from R. reflexa. Among the compounds, 7 and 6 showed the most potent and promising cholinesterase inhibitory activity, worthy for further investigations. © 2015 S. Karger AG, Basel.

  6. [Correlation and interconversion between erythrocyte cholinesterase values obtained by the Michel and the EQM techniques].

    Science.gov (United States)

    Carmona-Fonseca, Jaime

    2006-12-01

    Several techniques are available to measure red cell cholinesterase; therefore, evaluations with several methods provide a measure of concordance. An equation was formulated to transform native data of reference values to reference units of cholinesterase activity as measured by Michel and EQM tests. The experimental design was descriptive, transversal and prospective. The group sampled was a representative adult working population, aged 18-75, without previous exposure to cholinesterase inhibitors pesticides. The individuals were affiliated to the Social Security System and resided in Valle de Aburrá and Cercano Oriente Antioqueño (Antioquia Province, northwestern Colombia). Of 827 individuals, quantitative erythrocytes (Michel y EQM) tests exhibited "r" coefficients between 0.67 and R2 coefficient of 44%.,This indicated that one test explained the results in other test in 44% of the cases. The corelation was higher in Aburrá than in Oriente. The linear model for the 827 individuals was as follows: EQM U/g oxy-hemoglobin = 9.575 U/ g oxy-hemoglobin + 29.791 (Michel delta pH/hour). Michel delta pH/hr = 0.3312 delta pH/hour + 0.0149 (EQM U/g oxy-hemoglobin), where EQM was expressed in U/g oxy-hemoglobin and Michel pH change/hr. Inter-sections (coefficient a) and inclines (coefficient b) were significant in this model. In the adjusted equations, after exclusion of 12 extreme data (1.5% of 827), the r coefficient increased from 0.67 to 0.72 The adjusted equations were as follows: EQM U/g oxy-hemoglobin = 8.1884 U/g oxy-hemoglobin + 31.3920 (Michel delta pH/hour); Michel delta pH/hr = 0.2925 delta pH/hr + 0.0161 (EQM U/g oxy-hemoglobin). This system of linear equations permitted the transformation of Michel (delta PH/ hr) units to EQM (U/g oxy-hemoglobin) units and vice versa. This will facilitate data comparisons by clinicians and epidemiologists who are using these methods of cholinesterase measurement.

  7. Serum ferritin

    International Nuclear Information System (INIS)

    Rochna Viola, E.M.; Diaz de Domingo, N.B.; Lazarowski, A.

    1981-01-01

    Serum ferritin (SF) concentration as determined by the immunoradiometric method allows the direct measurement of a fraction of the body ferritin pool. In normal subjects, SF is an excellent index of body iron stores. In certain conditions associated with increased ferritin synthesis (such as liver disease, inflammation, malignancy, chronic disorders, ineffective erythropoiesis, or during ferrotherapy), SF may not accurately reflect body iron stores. In hyposideremic anemias SF concentration permits to differentiate those due to iron deficiency from those due to chronic disorders. With a good assay quality, subnormal SF levels are incontrovertible in the diagnosis of iron deficiency. SF determination has been investigated as possible tumor marker. When performed in combination with the alpha-fetoprotein assay, SF enhances the specificity of serodiagnosis of hepatoma. SF results must be interpreted bearing in mind the possible participation of circumstances that i) modify the body iron stores and ii) lead to increased ferritin synthesis. (author) [es

  8. Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.

    Science.gov (United States)

    Samadi, Abdelouahid; de los Ríos, Cristóbal; Bolea, Irene; Chioua, Mourad; Iriepa, Isabel; Moraleda, Ignacio; Bartolini, Manuela; Andrisano, Vincenza; Gálvez, Enrique; Valderas, Carolina; Unzeta, Mercedes; Marco-Contelles, José

    2012-06-01

    The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 ± 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aβ aggregation induced by hAChE by 30.6%. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  9. Evaluation of Antioxidant, Anti-cholinesterase, and Anti-inflammatory Effects of Culinary Mushroom Pleurotus pulmonarius.

    Science.gov (United States)

    Nguyen, Trung Kien; Im, Kyung Hoan; Choi, Jaehyuk; Shin, Pyung Gyun; Lee, Tae Soo

    2016-12-01

    Culinary mushroom Pleurotus pulmonarius has been popular in Asian countries. In this study, the anti-oxidant, cholinesterase, and inflammation inhibitory activities of methanol extract (ME) of fruiting bodies of P. pulmonarius were evaluted. The 1,1-diphenyl-2-picryl-hydrazy free radical scavenging activity of ME at 2.0 mg/mL was comparable to that of butylated hydroxytoluene, the standard reference. The ME exhibited significantly higher hydroxyl radical scavenging activity than butylated hydroxytoluene. ME showed slightly lower but moderate inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase than galantamine, a standard AChE inhibitor. It also exhibited protective effect against cytotoxicity to PC-12 cells induced by glutamate (10~100 µg/mL), inhibitory effect on nitric oxide (NO) production and inducible nitric oxide synthase protein expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, and carrageenan-induced paw edema in a rat model. High-performance liquid chromatography analysis revealed the ME of P. pulmonarius contained at least 10 phenolic compounds and some of them were identified by the comparison with known standard phenolics. Taken together, our results demonstrate that fruiting bodies of P. pulmonarius possess antioxidant, anti-cholinesterase, and inflammation inhibitory activities.

  10. Terpenes, Phenylpropanoids, Sulfur and Other Essential Oil Constituents as Inhibitors of Cholinesterases.

    Science.gov (United States)

    Burcul, Franko; Blazevic, Ivica; Radan, Mila; Politeo, Olivera

    2018-03-29

    Essential oils constituents are a diverse family of low molecular weight organic compounds with comprehensive biological activity. According to their chemical structure these active compounds can be divided into four major groups: terpenes, terpenoids, phenylpropenes, and "others". In addition, they may contain diverse functional groups according to which they can be classified as hydrocarbons (monoterpenes, sesquiterpenes, and aliphatic hydrocarbons); oxygenated compounds (monoterpene and sesquiterpene alcohols, aldehydes, ketones, esters, and other oxygenated compounds); and sulfur and/or nitrogen sulfur-containing compounds (thioesters, sulfides, isothiocyantes, nitriles, and others). Compounds that act as cholinesterase inhibitors still represent the only pharmacological treatment of Alzheimer´s disease. Numerous in vitro studies showed that some compounds, found in essential oils, have a promising cholinesterase inhibitory activity, such as α-pinene, δ-3-carene, 1,8-cineole, carvacrol, thymohydroquinone, α- and β-asarone, anethole, etc. This review summarizes the most relevant research published to date on essential oil constituents and their acetylcholinesterase/butyrylcholinesterase inhibitory potential as well as their structure related activity, synergistic and antagonistic effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. A fine structural localization of the non-specific cholinesterase activity in glomerular nerve formations (endings).

    Science.gov (United States)

    Dubový, P

    1990-01-01

    Snout glabrous skin (rhinarium) of the cat is innervated not only by typical simple lamellar corpuscles but also glomerular formations. In contrast to simple lamellar corpuscles, glomerular nerve formations are located away the dermal papillae. In cross sections, glomerular nerve formation consists of several axonal profiles enveloped by 1-2 cytoplasmic lamellae of Schwann cells. The space among them is filled by collagenous microfibrils and the basal lamina-like material. Capsule was composed from fibroblast-like cells without definite basal lamina. An electron-dense reaction product due to non-specific cholinesterase activity was associated with Schwann cells and their processes surrounding unmyelinated terminal portion of the sensory axons. Abundant reaction product was bound to the collagenous microfibrils and was deposited in extracellular matrix between Schwann cell processes. These results are further evidence for the presence of the non-specific cholinesterase molecules as integral component of the extracellular matrix in sensory corpuscles. On the basis of histochemical study two possible explanation are considered for functional involving of this enzyme in sensory nerve formations.

  12. Regional cholinesterase activity in white-throated sparrow brain is differentially affected by acephate (Orthene®)

    Science.gov (United States)

    Vyas, N.B.; Kuenzel, W.J.; Hill, E.F.; Romo, G.A.; Komaragiri, M.V.S.

    1996-01-01

    Effects of a 14-day dietary exposure to an organophosphorus pesticide, acephate (acetylphosphoramidothioic acid O,S-dimethyl ester), were determined on cholinesterase activity in three regions (basal ganglia, hippocampus, and hypothalamus) of the white-throated sparrow, Zonotrichia albicollis, brain. All three regions experienced depressed cholinesterase activity between 0.5–2 ppm acephate. The regions exhibited cholinesterase recovery at 2–16 ppm acephate; however, cholinesterase activity dropped and showed no recovery at higher dietary levels (>16 ppm acephate). Evidence indicates that the recovery is initiated by the magnitude of depression, not the duration. In general, as acephate concentration increased, differences in ChE activity among brain regions decreased. Three terms are introduced to describe ChE response to acephate exposure: 1) ChE resistance threshold, 2) ChE compensation threshold, and 3) ChE depression threshold. It is hypothesized that adverse effects to birds in the field may occur at pesticide exposure levels customarily considered negligible.

  13. Initial cognitive response to cholinesterase inhibitors and subsequent long-term course in patients with mild Alzheimer's disease

    NARCIS (Netherlands)

    Droogsma, Erika; van Asselt, Dieneke; Diekhuis, Marjolein; Veeger, Nic; van der Hooft, Cornelis; De Deyn, Peter Paul

    Background: Some guidelines recommend to discontinue treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) without an initial response to ChEI treatment. Evidence supporting this recommendation, however, is limited. This study aimed to investigate the relation

  14. In Vitro Ability of Currently Available Oximes to Reactivate Organophosphate Pesticide-Inhibited Human Acetylcholinesterase and Butyrylcholinesterase

    OpenAIRE

    Kamil Musilek; Kamil Kuca; Daniel Jun; Lucie Musilova

    2011-01-01

    We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a “pseudocatalytic...

  15. Potential anti-cholinesterase and β-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits.

    Science.gov (United States)

    Bhakta, Himanshu Kumar; Park, Chan Hum; Yokozawa, Takako; Tanaka, Takashi; Jung, Hyun Ah; Choi, Jae Sue

    2017-07-01

    Cholinesterase (ChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer's disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-β-D-glucose, 1,2,3,6-tetra-O-galloyl-β-D-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1. All of the compounds displayed concentration-dependent in vitro inhibitory activity toward the ChEs and BACE1. Among them, tellimagrandin II exhibited the best inhibitory activity toward ChEs, whereas the best BACE1 inhibitor was 1,2,3,6-tetra-O-galloyl-β-D-glucose. Isoterchebin and polymeric proanthocyanidins were also significant ChE inhibitors. The kinetic and docking studies demonstrated that all compounds interacted with both the catalytic active sites and the peripheral anionic sites of the ChEs and BACE1. Tellimagrandin II, isoterchebin, and the polymeric proanthocyanidins exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. In conclusion, we identified significant ChE and BACE1 inhibitors from Corni Fructus that could have value as new multi-targeted compounds for anti-AD agents.

  16. Correlación y conversión entre los valores de actividad de la colinesterasa plasmática medida por tres técnicas diferentes Correlation and conversion of plasma cholinesterase activity values using three techniques

    Directory of Open Access Journals (Sweden)

    Jaime Carmona-Fonseca

    2007-07-01

    Full Text Available OBJETIVO: Determinar las relaciones matemáticas entre tres técnicas cuantitativas empleadas para medir la actividad de la colinesterasa plasmática, a partir de los valores de referencia ya establecidos para dos poblaciones de Antioquia, Colombia. MÉTODOS:Diseño descriptivo, transversal y prospectivo. Se conformaron dos muestras independientes representativas de la población laboral adulta (18-65 años, no expuesta a plaguicidas inhibidores de la colinesterasa y vinculada al Seguro Social, del valle de Aburrá (415 personas y del cercano oriente antioqueño (412 personas, del departamento de Antioquia, Colombia. La colinesterasa plasmática (EC 3.1.1.8 se midió mediante tres técnicas cuantitativas: Michel, EQM® y Monotest®. Se elaboraron ecuaciones de regresión que relacionaran entre sí los resultados de las tres técnicas estudiadas. RESULTADOS: Se definieron seis ecuaciones de regresión lineal simple que permitieron relacionar los resultados de las tres técnicas de medición de colinesterasa plasmática analizadas. La correlación entre las técnicas fue moderada (r: de 0,686 a 0,771, pero aumentó (r: de 0,744 a 0,811 al eliminar 12 (1,5% valores extremos. Las asociaciones entre las técnicas fueron altamente significativas (P OBJECTIVES: To determine mathematical correlations of three quantitative techniques to measure plasma cholinesterase, using reference values already established for two populations in the department of Antioquia, Colombia. METHODS: In this descriptive, cross-sectional, prospective study, two independent, representative samples of working adults (18 to 65 years old were examined. In both samples the adults worked for businesses associated with Colombia’s Social Security system. Adults in the two samples had not been exposed to cholinesterase-inhibiting pesticides. The samples were from two neighboring regions of the department of Antioquia: one sample (415 adults was from the Aburrá Valley, and the other

  17. A phosphoinositide 3-kinase (PI3K)-serum- and glucocorticoid-inducible kinase 1 (SGK1) pathway promotes Kv7.1 channel surface expression by inhibiting Nedd4-2 protein

    DEFF Research Database (Denmark)

    Andersen, Martin Nybo; Krzystanek, Katarzyna; Petersen, Frederic

    2013-01-01

    Epithelial cell polarization involves several kinase signaling cascades that eventually divide the surface membrane into an apical and a basolateral part. One kinase, which is activated during the polarization process, is phosphoinositide 3-kinase (PI3K). In MDCK cells, the basolateral potassium...... channel Kv7.1 requires PI3K activity for surface-expression during the polarization process. Here, we demonstrate that Kv7.1 surface expression requires tonic PI3K activity as PI3K inhibition triggers endocytosis of these channels in polarized MDCK. Pharmacological inhibition of SGK1 gave similar results...... as PI3K inhibition, whereas overexpression of constitutively active SGK1 overruled it, suggesting that SGK1 is the primary downstream target of PI3K in this process. Furthermore, knockdown of the ubiquitin ligase Nedd4-2 overruled PI3K inhibition, whereas a Nedd4-2 interaction-deficient Kv7.1 mutant...

  18. Cholinesterase as inflammatory markers in a experimental infection by Trypanosoma evansi in rabbits

    Directory of Open Access Journals (Sweden)

    Márcio M. Costa

    2012-12-01

    Full Text Available The aim of this study is to evaluate the role of cholinesterases as an inflammatory marker in acute and chronic infection by Trypanosoma evansi in rabbits experimentally infected. Twelve adult female New Zealand rabbits were used and divided into two groups with 6 animals each: control group (rabbits 1-6 and infected group (rabbits 7-12. Infected group received intraperitoneally 0.5 mL of blood from a rat containing 108 parasites per animal. Blood samples used for cholinesterases evaluation were collected on days 0, 2, 7, 12, 27, 42, 57, 87, 102 and 118 days post-inoculation (PI. Increased activity (P0.05 was observed in the encephalic structures. The increased activities of AChE and BChE probably have a pro-inflammatory purpose, attempting to reduce the concentration of acetylcholine, a neurotransmitter which has an anti-inflammatory property. Therefore, cholinesterase may be inflammatory markers in infection with T. evansi in rabbits.O objetivo do presente estudo é avaliar o papel das colinesterases como marcadores inflamatórios nas fases aguda e crônica da infecção por T. evansi em coelhos infectados experimentalmente. Foram utilizados 12 coelhos adultos, fêmeas, da raça Nova Zelândia, divididos em dois grupos: um grupo controle, com seis animais (coelhos 1-6, e um grupo infectado, com seis animais (coelhos 7-12. Os animais pertencentes ao grupo infectados receberam, pela via intraperitoneal, 0,5 mL de sangue de rato contendo 108 tripanossomas por animal. Amostras do sangue utilizado para avaliação das colinesterases foram coletadas nos dias 0, 2, 7, 12, 27, 42, 57, 87, 102 e 118 pós-inoculação (PI. Aumento (P0,05 foi observada nas estruturas encefálicas. O aumento de atividade da AChE e BChE provavelmente tenha finalidade pró-inflamatória, a fim de reduzir as concentrações de acetilcolina, neurotransmissor que apresenta propriedade anti-inflamatória. Portanto, as colinesterases podem ser marcadores inflamatórios na infec

  19. Cholinesterase activity in blood and pesticide presence in sweat as biomarkers of children`s environmental exposure to crop protection chemicals

    Directory of Open Access Journals (Sweden)

    Lucyna Kapka-Skrzypczak

    2015-09-01

    Altogether, the study indicated that cholinesterase activity is a sensitive marker of the children’s environmental exposure to pesticides, whereas sweat patches are useful devices for collecting samples to be analysed for the presence of the pesticides.

  20. HUBUNGAN ANTARA PERILAKU DALAM PENGELOLAAN PESTISIDA DENGAN AKTIVITAS ENZIM CHOLINESTERASE DARAH PADA PETANI CABE DI DESA SANTANA MEKAR KECAMATAN CISAYONG KABUPATEN TASIKMALAYA

    Directory of Open Access Journals (Sweden)

    Ai Sukmawati

    2012-11-01

    Full Text Available A study on use pesticide was conducted in Santana Mekar village, Tasikmalaya regency in June 2003. The aim of this study was to find out the relationship between knowledge, attitude and practice of pesticide use and blood cholinesterase enzyme activities. The study used survey method and cross sectional approach. The result showed that 34.5% from 61 respondents have normal blood cholinesterase enzyme activity. Most of the respondents have good knowledge, attitude and practice on using pesticides. Rank spearman correlation analysis shows that a positive relation was found between knowledge, attitude and practice on using pesticides with blood cholinesterase enzyme activity (p=0.001, a=0.1 .   Keywords : behavior, pesticide, blood cholinesterase enzyme activity

  1. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids.

    Science.gov (United States)

    Bautista-Aguilera, Oscar M; Esteban, Gerard; Chioua, Mourad; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Soriano, Elena; Samadi, Abdelouahid; Unzeta, Mercedes; Marco-Contelles, José

    2014-01-01

    The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective h

  2. Analysis of Amaryllidaceae alkaloids from Zephyranthes grandiflora by GC/MS and their cholinesterase activity

    Directory of Open Access Journals (Sweden)

    Lucie Cahlíková

    2011-05-01

    Full Text Available Amaryllidaceae are known as ornamental plants, furthermore some species of this family contain galanthamine, an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, and other alkaloids with interesting pharmacological activity. The chemical composition of alkaloids from Zephyranthes grandiflora Lindl. was analyzed by GC/MS. Seven known compounds, belonging to five structural types of Amaryllidaceae alkaloids, were identified. The alkaloid extract from the bulbs showed promising cholinesterase inhibitory activities against human blood acetylcholinesterase (HuAChE; IC50 39.2±3.0 µg/mL and human plasma butyrylcholinesterase (HuBuChE; IC50 356±9.3 µg/mL.

  3. Analysis of Amaryllidaceae alkaloids from Zephyranthes grandiflora by GC/MS and their cholinesterase activity

    Directory of Open Access Journals (Sweden)

    Lucie Cahlíková

    2011-08-01

    Full Text Available Amaryllidaceae are known as ornamental plants, furthermore some species of this family contain galanthamine, an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, and other alkaloids with interesting pharmacological activity. The chemical composition of alkaloids from Zephyranthes grandiflora Lindl. was analyzed by GC/MS. Seven known compounds, belonging to five structural types of Amaryllidaceae alkaloids, were identified. The alkaloid extract from the bulbs showed promising cholinesterase inhibitory activities against human blood acetylcholinesterase (HuAChE; IC50 39.2±3.0 µg/mL and human plasma butyrylcholinesterase (HuBuChE; IC50 356±9.3 µg/mL.

  4. Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

    Directory of Open Access Journals (Sweden)

    Lam Benjamin

    2009-12-01

    Full Text Available Abstract This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD and Lewy body disease (LBD as it pertains to the use of cholinesterase inhibitors (ChEI. AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs.

  5. 14C-labeling of a tetrahydroacridine, a novel CNS-selective cholinesterase inhibitor

    International Nuclear Information System (INIS)

    Nishioka, Kazuhiko; Kamada, Takeshi; Kanamaru, Hiroshi

    1992-01-01

    9-Amino-8-fluoro-2,4-methano-1,2,3,4-tetrahydroacridine citrate (SM-10888), a novel cholinesterase inhibitor, was labeled with carbon-14 at C9 of the tetrahydroacridine ring for use in metabolic studies. Carbonation of 2,6-difluorophenyllithium (3) with [ 14 C]carbon dioxide gave the acid (4). Chlorination of 4 followed by treatment of the resulting acid chloride with ammonia afforded the amide (5). Dehydration of 5 with thionyl chloride and subsequent displacement reaction with ammonia gave the aminobenzonitrile (7). Condensation of 7 with the ketone (8) in the presence of anhydrous zinc chloride yielded the aminoacridine (9), which was treated with citric acid to afford [9- 14 C]SM-10888 (1). The overall yield of 1 was 37% from 2, and the specific activity was 1.35 GBq/mmol. (author)

  6. [sup 14]C-labeling of a tetrahydroacridine, a novel CNS-selective cholinesterase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Nishioka, Kazuhiko; Kamada, Takeshi; Kanamaru, Hiroshi (Sumitomo Chemical Co., Ltd., Takatsukasa, Takarazuka (Japan). Environmental Health Science Lab.)

    1992-06-01

    9-Amino-8-fluoro-2,4-methano-1,2,3,4-tetrahydroacridine citrate (SM-10888), a novel cholinesterase inhibitor, was labeled with carbon-14 at C9 of the tetrahydroacridine ring for use in metabolic studies. Carbonation of 2,6-difluorophenyllithium (3) with [[sup 14]C]carbon dioxide gave the acid (4). Chlorination of 4 followed by treatment of the resulting acid chloride with ammonia afforded the amide (5). Dehydration of 5 with thionyl chloride and subsequent displacement reaction with ammonia gave the aminobenzonitrile (7). Condensation of 7 with the ketone (8) in the presence of anhydrous zinc chloride yielded the aminoacridine (9), which was treated with citric acid to afford [9-[sup 14]C]SM-10888 (1). The overall yield of 1 was 37% from 2, and the specific activity was 1.35 GBq/mmol. (author).

  7. [Isomeric derivatives of lupinine and epilupinine--organophosphorus inhibitors of cholinesterases].

    Science.gov (United States)

    Basova, N E; Kormilitsyn, B N; Perchenok, A Iu; Rosengart, E V; Saakov, V S; Suvorov, A A

    2012-01-01

    The isomeric-structure analysis data of anticholinesterase action of organophosphorous inhibitors with similar structure help in the search of specific effectors and detection of differences in reactivity of various animals' enzymes. This study compared the data of efficacy in respect of 4 mammal and 5 arthropoda cholinesterase preparations for 26 quinolizidine inhibitors, which molecules contain both the isomeric unbranched and branched alkoxyl radicals in the phosphoryl group, and the epimeric lupinine and epilupinine derivatives in the leaving group. The changes in the alkoxyl radical structure of inhibitor molecules act on their efficacy only with respect to the mammal enzymes ("group" inhibitor specificity). The differences between lupinine and epilupinine derivatives were revealed. Highly specific inhibitors of different enzymes were detected among the tested compounds.

  8. Development of organophosphate hydrolase activity in a bacterial homolog of human cholinesterase

    Science.gov (United States)

    Legler, Patricia; Boisvert, Susanne; Compton, Jaimee; Millard, Charles

    2014-07-01

    We applied a combination of rational design and directed evolution (DE) to Bacillus subtilis p-nitrobenzyl esterase (pNBE) with the goal of enhancing organophosphorus acid anhydride hydrolase (OPAAH) activity. DE started with a designed variant, pNBE A107H, carrying a histidine homologous with human butyrylcholinesterase G117H to find complementary mutations that further enhance its OPAAH activity. Five sites were selected (G105, G106, A107, A190, and A400) within a 6.7 Å radius of the nucleophilic serine O?. All 95 variants were screened for esterase activity with a set of five substrates: pNP-acetate, pNP-butyrate, acetylthiocholine, butyrylthiocholine, or benzoylthiocholine. A microscale assay for OPAAH activity was developed for screening DE libraries. Reductions in esterase activity were generally concomitant with enhancements in OPAAH activity. One variant, A107K, showed an unexpected 7-fold increase in its kcat/Km for benzoylthiocholine, demonstrating that it is also possible to enhance the cholinesterase activity of pNBE. Moreover, DE resulted in at least three variants with modestly enhanced OPAAH activity compared to wild type pNBE. A107H/A190C showed a 50-fold increase in paraoxonase activity and underwent a slow time- and temperature-dependent change affecting the hydrolysis of OPAA and ester substrates. Structural analysis suggests that pNBE may represent a precursor leading to human cholinesterase and carboxylesterase 1 through extension of two vestigial specificity loops; a preliminary attempt to transfer the Ω-loop of BChE into pNBE is described. pNBE was tested as a surrogate scaffold for mammalian esterases. Unlike butyrylcholinesterase and pNBE, introducing a G143H mutation (equivalent to G117H) did not confer detectable OP hydrolase activity on human carboxylesterase 1. We discuss the importance of the oxyanion-hole residues for enhancing the OPAAH activity of selected serine hydrolases.

  9. The Suppression of Adjuvant-induced Inflammation and the Inhibition of the Serum and Tissue IL-17, TNF-α and IL-1β levels by Thymol and Carvacrol

    Directory of Open Access Journals (Sweden)

    Nasser Gholijani

    2017-06-01

    Full Text Available Background and Aim: Thymol and carvacrol are two important components of thyme that have multiple medicinal uses. This study investigates the in vivo effects of these natural products on adjuvant-induced inflammation and secretion of interleukin (IL-17 and key inflammatory cytokines in rats. Materials and Methods: We injected complete Freund’s adjuvant (CFA into the hind paws of rats in order to induce inflammation. Each of the CFA-treated rat groups received gavages of thymol, carvacrol, or vehicle (CFA-only group. Rats’ paws and ankle edema were measured and then we were able to determine an inflammatory score based on the results. After 72 h of inflammation induction, sera were collected and subsequently inflamed tissue extracts were prepared for cytokine assay by ELISA. Results: Both components significantly decreased paw edema in rats (p<0.01. Thymol decreased ankle edema to 61.6% of edema in CFA-only rats (p<0.001. We observed a decreased inflammatory score in the thymol and carvacrol-treated rats. The evaluation of the tissue and serum inflammatory cytokine levels showed that both components decreased tumor necrosis factor (TNF-α levels (p<0.05. Thymol and carvacrol reduced interleukin (IL-1β serum and tissue levels, respectively. These components reduced tissue levels of IL-17 from 148.4±13.4pg/ml in CFA-only rats to 90.1±18.9pg/ml (thymol and 82.3±9.2pg/ml (carvacrol. Both components decreased serum IL-17 levels in rats (p<0.05. In comparison, the anti-inflammatory drug, indomethacin, reduced the inflammatory score and decreased tissue TNF-α and IL-1β levels but did not affect IL-17 production. Conclusion: Carvacrol and thymol could relieve inflammation symptoms possibly by downregulating serum and tissue IL-17 expression in addition to key pro-inflammatory cytokines, TNFα and IL-1β.

  10. TLC-bioautographic evaluation of in vitro anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil.

    Science.gov (United States)

    Misra, Biswapriya B; Dey, Satyahari

    2013-02-01

    Sandalwood oil, rich in sesquiterpenoid alcohols, has been used in traditional medicinal systems as a relaxant and coolant. Besides, sandalwood oil is used as an ingredient in numerous skin fairness enhancing cosmetics. However, there is no available information on biological activities that relate to the above applications. Hence, the anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil were probed by both TLC-bioautographic and colorimetric methods. Results obtained from colorimetric assays indicated that sandalwood oil is a potent inhibitor of tyrosinase (IC50 = 171 microg mL(-1)) and cholinesterases (IC50 = 4.8-58 microg mL(-1)), in comparison with the positive controls used in the assays, kojic acid and physostigmine, respectively. The TLC-bioautographic assays indicated that alpha-santalol, the major constituent of the oil, is a strong inhibitor of both tyrosinase and cholinesterase. These in vitro results indicate that there is a great potential of this essential oil for use in the treatment of Alzheimer's disease, as well as in skin-care.

  11. Cognitive and affective changes in mild to moderate Alzheimer's disease patients undergoing switch of cholinesterase inhibitors: a 6-month observational study.

    Directory of Open Access Journals (Sweden)

    Gianfranco Spalletta

    Full Text Available Patients with Alzheimer's disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline, and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer's disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled

  12. Protein electrophoresis - serum

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003540.htm Protein electrophoresis - serum To use the sharing features on ... JavaScript. This lab test measures the types of protein in the fluid (serum) part of a blood ...

  13. Crystal structure, phytochemical study and enzyme inhibition activity of Ajaconine and Delectinine

    Science.gov (United States)

    Ahmad, Shujaat; Ahmad, Hanif; Khan, Hidayat Ullah; Shahzad, Adnan; Khan, Ezzat; Ali Shah, Syed Adnan; Ali, Mumtaz; Wadud, Abdul; Ghufran, Mehreen; Naz, Humera; Ahmad, Manzoor

    2016-11-01

    The Crystal structure, comparative DFT study and phytochemical investigation of atisine type C-20 diterpenoid alkaloid ajaconine (1) and lycoctonine type C-19 diterpenoid alkaloid delectinine (2) is reported here. These compounds were isolated from Delphinium chitralense. Both the natural products 1 and 2 crystallize in orthorhombic crystal system with identical space group of P212121. The geometric parameters of both compounds were calculated with the help of DFT using B3LYP/6-31+G (p) basis set and HOMO-LUMO energies, optimized band gaps, global hardness, ionization potential, electron affinity and global electrophilicity are calculated. The compounds 1 and 2 were screened for acetyl cholinesterase and butyryl cholinesterase inhibition activities in a dose dependent manner followed by molecular docking to explore the possible inhibitory mechanism of ajaconine (1) and delectinine (2). The IC50 values of tested compounds against AChE were observed as 12.61 μM (compound 1) and 5.04 μM (compound 2). The same experiments were performed for inhibition of BChE and IC50 was observed to be 10.18 μM (1) and 9.21 μM (2). Promising inhibition activity was shown by both the compounds against AChE and BChE in comparison with standard drugs available in the market such as allanzanthane and galanthamine. The inhibition efficiency of both the natural products was determined in a dose dependent manner.

  14. Fortification of Yogurts with Vitamin D and Calcium Enhances the Inhibition of Serum Parathyroid Hormone and Bone Resorption Markers: A Double Blind Randomized Controlled Trial in Women over 60 Living in a Community Dwelling Home.

    Science.gov (United States)

    Bonjour, J-P; Benoit, V; Atkin, S; Walrand, S

    2015-05-01

    To evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum parathyroid hormone (PTH) and bone resorption markers (BRM) as compared to iso-caloric and iso-protein dairy products in aged white women at risk of fragility fractures. A randomized double-blind controlled trial. A community dwelling home. Forty-eight women over 60 years (mean age 73.4). Consumption during 84 days of two 125 g servings of either vitamin D and calcium-fortified yogurts (FY) at supplemental levels of 10 µg vitamin D3/d and 520 mg/d of calcium (total=800 mg/d), or non fortified control yogurts (CY) providing 280 mg/d of calcium. Serum changes from baseline (D0) to D28, D56 and D84 in 25OHD, PTH and in two BRM: Tartrate-resistant-acid-phosphatase-isoform-5b (TRAP5b) and carboxy-terminal-cross-linked-telopeptide of type-I-collagen (CTX). The 10 years risk of major and hip fractures were 13.1 and 5.0%, and 12.9 and 4.2 %, in FY and CY groups, respectively. From D0 to D84, serum 25OHD increased (mean±SE) from 34.3±2.4 to 56.3±2.4 nmol/L in FY (n=24) and from 35.0±2.5 to 41.3±3.0 nmol/L in CY (n=24), (P=0.00001). The corresponding changes in PTH were from 64.1±5.1 to 47.4±3.8 ng/L in FY and from 63.5±4.6 to 60.7±4.2 ng/L in CY (P=0.0011). After D84, TRAP5b was reduced significantly (P=0.0228) and CTX fell though not significantly (P=0.0773) in FY compared to CY. This trial in aged white women living in a community dwelling home at risk for osteoporotic fractures confirms that fortification of dairy products with vitamin D3 and calcium should provide a greater prevention of secondary hyperparathyroidism and accelerated bone resorption as compared to non-fortified equivalent foods.

  15. Serum iron test

    Science.gov (United States)

    Fe+2; Ferric ion; Fe++; Ferrous ion; Iron - serum; Anemia - serum iron; Hemochromatosis - serum iron ... A blood sample is needed. Iron levels are highest in the morning. Your health care provider will likely have you do this test in the morning.

  16. SERUM PARAOXONASE ACTIVITY IN RENAL TRANSPLANT RECIPIENTS

    Directory of Open Access Journals (Sweden)

    Saritha Gadicherla

    2017-12-01

    Full Text Available BACKGROUND Serum paraoxonase is an enzyme synthesised in the liver. It is known to prevent atherosclerosis by inhibiting oxidation of lowdensity lipoprotein. Renal transplant recipients have increased tendency for developing atherosclerosis and cardiovascular disease. Reduced activity of serum paraoxonase contributes to accelerated atherosclerosis and increased cardiovascular complications in these patients. The aim of this study was to estimate serum paraoxonase activity in renal transplant recipients and compare it with healthy controls. MATERIALS AND METHODS 30 renal transplant recipients and 30 age and sex matched healthy controls were taken for the study. Serum paraoxonase activity, blood urea, serum creatinine and uric acid were estimated in these groups. The serum paraoxonase activity was correlated with urea, creatinine and uric acid levels. RESULTS Serum paraoxonase activity was reduced in renal transplant recipients compared to healthy controls. There was a negative correlation between paraoxonase activity and the levels of urea, creatinine and uric acid levels. CONCLUSION In this study, the paraoxonase activity was reduced in renal transplant recipients compared to controls. The increased cardiovascular disease in these patients could be due to reduced paraoxonase activity.

  17. Kinetics and molecular docking studies of loganin, morroniside and 7-O-galloyl-D-sedoheptulose derived from Corni fructus as cholinesterase and β-secretase 1 inhibitors.

    Science.gov (United States)

    Bhakta, Himanshu Kumar; Park, Chan Hum; Yokozawa, Takako; Min, Byung-Sun; Jung, Hyun Ah; Choi, Jae Sue

    2016-06-01

    We evaluated the major active components isolated from Corni Fructus: loganin, morroniside, and 7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer's disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-D-sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, loganin showed noncompetitive type inhibitory effects, while morroniside and 7-O-galloyl-D-sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO(-)-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer's disease treatment.

  18. Synthesis, biological evaluation, QSAR study and molecular docking of novel N-(4-amino carbonylpiperazinyl) (thio)phosphoramide derivatives as cholinesterase inhibitors.

    Science.gov (United States)

    Gholivand, Khodayar; Ebrahimi Valmoozi, Ali Asghar; Bonsaii, Mahyar

    2014-06-01

    Novel (thio)phosphoramidate derivatives based on piperidincarboxamide with the general formula of (NH2-C(O)-C5H9N)-P(X=O,S)R1R2 (1-5) and (NH2-C(O)-C5H9N)2-P(O)R (6-9) were synthesized and characterized by (31)P, (13)C, (1)H NMR, IR spectroscopy. Furthermore, the crystal structure of compound (NH2-C(O)-C5H9N)2-P(O)(OC6H5) (6) was investigated. The activities of derivatives on cholinesterases (ChE) were determined using a modified Ellman's method. Also the mixed-type mechanisms of these compounds were evaluated by Lineweaver-Burk plots. Molecular docking and quantitative structure-activity relationship (QSAR) were used to understand the relationship between molecular structural features and anti-ChE activity, and to predict the binding affinity of phosphoramido-piperidinecarboxamides (PAPCAs) to ChE receptors. From molecular docking analysis, noncovalent interactions especially hydrogen bonding as well as hydrophobic was found between PAPCAs and ChE. Based on the docking results, appropriate molecular structural parameters were adopted to develop a QSAR model. DFT-QSAR models for ChE enzymes demonstrated the importance of electrophilicity parameter in describing the anti-AChE and anti-BChE activities of the synthesized compounds. The correlation matrix of QSAR models and docking analysis confirmed that electrophilicity descriptor can control the influence of the hydrophobic properties of P=(O, S) and CO functional groups of PAPCA derivatives in the inhibition of human ChE enzymes. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Determination of esterase activity and characterization of cholinesterases in the reef fish Haemulon plumieri.

    Science.gov (United States)

    Leticia, Alpuche-Gual; Gerardo, Gold-Bouchot

    2008-11-01

    White grunt (Haemulon plumieri) has been proposed by the Mesoamerican Barrier Reef System (MBRS) Synoptic Monitoring Program as a bioindicator species. It is in this sense that the present study has a main goal to evaluate this organism's suitability as an indicator species. Individuals were captured during three seasons at the port of Sisal, Yucatan, Mexico which is located in an area that is considered to be weakly impacted by human activities such as agriculture or industry. Both cholinesterase (ChE) and carboxylesterase (CbE) activities were measured in brain, muscle, liver and eye of sampled individuals. Results indicated that ChE and CbE activities were greatest in the brain (256.3 ± 43) and in the liver (191 ± 21), respectively. Furthermore, ChEs detected in brain, liver and muscle were characterized, and results suggested that the acetylcholinesterase (AChE) type was more abundant relative to pseudocholinesterase (BChE) which was rare. In addition, K(m) and V(max) and IC(50) values were calculated from the Michaelis-Menten equation. Finally, an additional experiment in vitro showed a significant decrease in both ChE and CbE activities when different tissues were exposed to model xenobiotics, such as benzo[a]pyrene and Chlorpyrifos. In conclusion, findings from this study confirm the potential suitability of H. plumieri as an organic pollution bioindicator species, and thus of practical use for environmental biomonitoring purposes.

  20. A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease

    Science.gov (United States)

    S. Schneider, Lon

    2000-01-01

    Early research into Alzheimer's disease launched the cholinergic hypothesis, based on the correlation between central cholinergic deficiency and clinical measures of cognitive decline. This was epitomized in therapeutic strategies employing a variety of procholinergic agents, of which only the inhibitors of cholinesterase (ChE), the enzyme thai hydrolyzes acetylcholine in the synaptic cleft, have been proven clinically viable. Five such agents are reviewed: tacrine and donepezil, which act at the ionic subsite of acetylcholinesterase (AChE), and rivastigmine, galantamine, and metrifonate, which act at its catalytic esteratic subsite. Despite statistical evidence of efficacy from numerous well-controlled multicenter trials, important clinical utility issues remain outstanding: (i) number-needed-to-treat (NNT) analyses, quantifying the number of patients needing to be treated for one patient to show benefit, find values of 3 to 20; (ii) the pivotal trials themselves were conducted in nonrepreseniative populations, largely comprised of physically healthy outpatients with mildto-moderate Alzheimer's disease and a mean age of 72 years (thereby excluding over 30% of typical Alzheimer patients in State of California-funded clinics), treated for up to 6 months; and (Hi) tolerability is underreported and characterized by a positive correlation between dose, effect and cholinergic side effects - potentially serious adverse events include bradycardia, anorexia, weight loss and myasthenia with respiratory depression. Therapies thus require titration and constant monitoring. Nevertheless, acetylcholinesterase inhibitors (AChEls) constitute the first class of effective agents and are likely to remain so in the continuing absence of viable alternatives. PMID:22033801

  1. Excitant and depressant drugs modulate effects of environment on brain weight and cholinesterases

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, E.L.; Rosenzweig, M.R.; Wu, S.Y.C.

    1973-01-01

    Certain excitant drugs can enhance the effects of enriched experience on weights of brain sections and on the activities of acetylcholinesterase and cholinesterase in the brain, and certain depressants can lessen the brain weight effects. Most experiments were performed with prepubertal male rats. Some rats were exposed in groups of 12 to an enriched environmental condition (EC), usually for 2 h per day and over a 30-day period; others remained in their individual home cages (HC) throughout. Some received a drug injection and others received a saline injection before the daily EC period; HC controls received similar injections. The drug injections had no significant effects on brain values of HC rats, but they altered effects of EC, probably by influencing the animals' reactions to the environment. Methamphetamine and d-amphetamine enhanced the EC effects; metrazol had small positive effects; and strychnine was without effects. Phenobarbital depressed the brain weight effects but increased the enzymatic effects. Use of methamphetamine made it possible to find EC effects with short daily periods (30 min) or with a shortened experimental duration (15 days). In experiments with adult rats, methamphetamine did not modulate the brain weight effects. The results of this study may bear on the use of stimulants to promote recovery from brain damage.

  2. Inhibitor of DNA synthesis is present in normal chicken serum

    International Nuclear Information System (INIS)

    Franklin, R.A.; Davila, D.R.; Westly, H.J.; Kelley, K.W.

    1986-01-01

    The authors have found that heat-inactivated serum (57 0 C for 1 hour) from normal chickens reduces the proliferation of mitogen-stimulated chicken and murine splenocytes as well as some transformed mammalian lymphoblastoid cell lines. Greater than a 50% reduction in 3 H-thymidine incorporation was observed when concanavalin A (Con A)-activated chicken splenocytes that were cultured in the presence of 10% autologous or heterologous serum were compared to mitogen-stimulated cells cultured in the absence of serum. Normal chicken serum (10%) also caused greater than 95% suppression of 3 H-thymidine incorporation by bovine (EBL-1 and BL-3) and gibbon ape (MLA 144) transformed lymphoblastoid cell lines. The only cell line tested that was not inhibited by chicken serum was an IL-2-dependent, murine cell line. Chicken serum also inhibited both 3 H-thymidine incorporation and IL-2 synthesis by Con A-activated murine splenocytes. Suppression was caused by actions other than cytotoxicity because viability of chicken splenocytes was unaffected by increasing levels of chicken serum. Furthermore, dialyzed serum retained its activity, which suggested that thymidine in the serum was not inhibiting uptake of radiolabeled thymidine. Suppressive activity was not due to adrenal glucocorticoids circulating in plasma because neither physiologic nor pharmacologic doses of corticosterone had inhibitory effects on mitogen-stimulated chicken splenocytes. These data demonstrate that an endogenous factor that is found in normal chicken serum inhibits proliferation of T-cells from chickens and mice as well as some transformed mammalian lymphoblastoid cell lines

  3. The influence of cholinesterase inhibitor therapy for dementia on risk of cardiac pacemaker insertion: a retrospective, population-based, health administrative databases study in Ontario, Canada.

    Science.gov (United States)

    Huang, Allen R; Redpath, Calum J; van Walraven, Carl

    2015-04-28

    Cholinesterase inhibitors are used to treat the symptoms of dementia and can theoretically cause bradycardia. Previous studies suggest that patients taking these medications have an increased risk of undergoing pacemaker insertion. Since these drugs have a marginal impact on patient outcomes, it might be preferable to change drug treatment rather than implant a pacemaker. This population-based study determined the association of people with dementia exposed to cholinesterase inhibitor medication and pacemaker insertion. We used data from the Ontario health administrative databases from January 1, 1993 to June 30, 2012. We included all community-dwelling seniors who had a code for dementia and were exposed to cholinesterase inhibitors (donezepil, galantamine, and rivastigmine) and/or drugs used to treat co-morbidities of hypertension, diabetes, depression and hypothyroidism. We controlled for exposure to anti-arrhythmic drugs. Observation started at first exposure to any medication and continued until the earliest of pacemaker insertion, death, or end of study. 2,353,909 people were included with 96,000 (4.1%) undergoing pacemaker insertion during the observation period. Case-control analysis showed that pacemaker patients were less likely to be coded with dementia (unadjusted OR 0.42 [95%CI 0.41-0.42]) or exposed to cholinesterase inhibitors (unadjusted OR 0.39 [95%CI 0.37-0.41]). That Cohort analysis showed patients with dementia taking cholinesterase inhibitors had a decreased risk of pacemaker insertion (unadj-HR 0.58 [0.55-0.61]). Adjustment for patient age, sex, and other medications did not notably change results, as did restricting the analysis to incident users. Patients taking cholinesterase inhibitors rarely undergo, and have a significantly reduced risk of, cardiac pacemaker insertion.

  4. Acquisition and reinstatement of ethanol-induced conditioned place preference in rats: Effects of the cholinesterase inhibitors donepezil and rivastigmine.

    Science.gov (United States)

    Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Silberring, Jerzy; Kotlinska, Jolanta H

    2016-07-01

    The present study examined the influence of the cholinesterase inhibitors donepezil (a selective inhibitor of acetylcholinesterase) and rivastigmine (also an inhibitor of butyrylcholinesterase) on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in rats. Before the CPP procedure, animals received a single injection of ethanol (0.5 g/kg, 10% w/v, intraperitoneally [i.p.]) for 15 days. The ethanol-induced CPP (biased method) was developed by four injections of ethanol (0.5 g/kg, 10% w/v, i.p.) every second day. Control rats received saline instead of ethanol. Donepezil (0.5, 1 or 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5 or 1 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. The cholinesterase inhibitors were equally effective in increasing (dose dependently) the acquisition of ethanol-induced CPP. Furthermore, priming injections of both inhibitors reinstated (cross-reinstatement) the ethanol-induced CPP with similar efficacy. These effects of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist, but not by scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. Thus, our results show that the cholinergic system is involved in the reinforcing properties of ethanol, and nicotinic acetylcholine receptors play an important role in the relapse to ethanol-seeking behaviour. © The Author(s) 2016.

  5. [COMPARATIVE SENSITIVITY OF CHOLINESTERASES IN VERTEBRATES AND INVERTEBRATES TO HIGHLY SPECIFIC ORGANOPHOSPHORUS INHIBITORS DIISOPROPYL FLUOROPHOSPHATE (DFP) AND (2-ETHOXYMETHYL PHOSPHORYL THIOETHYL) ETHYL (METHYL) SULPHONIUM SULPHOMETHYLAT (GD-42)].

    Science.gov (United States)

    Basova, N E; Kormilitsyn, B N; Perchenok, A Yu; Rozengart, E V; Saakov, V S; Suvorov, A A

    2015-01-01

    The review presents data on comparative reactivity of 68 cholinesterase preparation from various organs and tissues in a number of vertebrates and invertebrates based on sensitivity to two highly specific and most studied organophosphorus inhibitors--diisopropyl fluorophosphates (DFP) and (2-ethoxymethyl phosphoryl thioethyl) ethyl (methyl) sulphonium sulphomethylat (GD-42). Analysis of these data suggests a great diversity in enzymologic characteristics of cholinesterase preparation in representatives of vertebrates and invertebrates, this variety observed even for closely related enzymes in animals of almost the same level of development.

  6. Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer’s disease cohort

    Directory of Open Access Journals (Sweden)

    Wattmo Carina

    2012-11-01

    Full Text Available Abstract Background Activities of daily living (ADL are an essential part of the diagnostic criteria for Alzheimer’s disease (AD. A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. Methods This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL scale, Physical Self-Maintenance Scale (PSMS and Mini-Mental State Examination (MMSE. Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. Results After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. Conclusions Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age

  7. Acetylcholine muscarinic receptors and response to anti-cholinesterase therapy in patients with Alzheimer's disease

    International Nuclear Information System (INIS)

    Brown, Derek; Chisholm, Jennifer A.; Patterson, Jim; Wyper, David; Owens, Jonathan; Pimlott, Sally

    2003-01-01

    An acetylcholine deficit remains the most consistent neurotransmitter abnormality found in Alzheimer's disease and various therapeutic agents have been targeted at this. In this study we investigated the action of Donepezil, a cholinesterase inhibitor that has few side-effects. In particular we set out to investigate whether muscarinic acetylcholine receptor (mAChR) availability influences the response to this therapy. We used the novel single-photon emission tomography (SPET) tracer (R,R)[ 123 I]I-quinuclidinyl benzilate (R,R[ 123 I]I-QNB), which has high affinity for the M1 subtype of mAChR. Regional cerebral perfusion was also assessed using technetium-99m hexamethylpropylene amine oxime. We investigated 20 patients on Donepezil treatment and ten age-matched controls. The results showed a reduction in (R,R)[ 123 I]I-QNB binding in the caudal anterior cingulate in patients compared with controls and relatively high binding in the putamen and rostral anterior cingulate, suggesting a relative sparing of mAChR in these regions. The main finding of the study was that mAChR availability as assessed by (R,R)[ 123 I]I-QNB binding did not distinguish responders from non-responders. Interestingly, we found that the extent of cognitive improvement showed no positive correlation with (R,R)[ 123 I]I-QNB binding in any brain region but was inversely related to binding in the insular cortex. This suggests that, within the advised cognitive performance band for use of Donepezil, response is greater in those patients with evidence of a more marked cholinergic deficit. A larger study should investigate this. (orig.)

  8. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors.

    Science.gov (United States)

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J; Borges, Fernanda

    2018-01-01

    Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN 1 (catechol derivative), and AntiOxBEN 2 (pyrogallol derivative) and compounds 15-18 , which have longer spacers. Compounds AntiOxBEN 1 and 15 , with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC 50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC 50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17 , no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN 1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

  9. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Catarina Oliveira

    2018-04-01

    Full Text Available Alzheimer's disease (AD is a multifactorial age-related disease associated with oxidative stress (OS and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative, and AntiOxBEN2 (pyrogallol derivative and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively, while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively. Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y and human hepatocarcinoma (HepG2 cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

  10. Hydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors

    Science.gov (United States)

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J.; Borges, Fernanda

    2018-04-01

    Alzheimer’s disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy towards AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a ten-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 nM, respectively). Interestingly, molecular modelling data pointed towards bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Αβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favourable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related disease

  11. Zinc in human serum

    International Nuclear Information System (INIS)

    Kiilerich, S.

    1987-01-01

    The zinc ion is essential for the living organism. Many pathological conditions have been described as a consequence of zinc deficiency. As zinc constitutes less than 0.01 per cent of the body weight, it conventionally belongs to the group of trace elements. The method of atomic absorption spectrophotometry is used to measure the concentration of zinc in serum and urine from healthy persons. The assumptions of the method is discussed. The importance of proteinbinding, diet and the diurnal variation of serum zinc concentration is presented. Serum versus plasma zinc concentration is discussed. Reference serum zinc values from 104 normal subjects are given. Zinc in serum is almost entirely bound to proteins. A preliminary model for the estimation of the distribution of zinc between serum albumin and α 2 -macroglobulin is set up. This estimate has been examined by an ultracentrufugation method. The binding of zinc to a α 2 -macroglobulin in normal persons is appoximately 7 per cent, in patients with cirrhosis of the liver of alcoholic origin approximately 6 per cent, in patients with insulin dependent diabetes mellitus approximately 5 per cent, and in patients with chronic renal failure approximately 2 per cent. It is concluded, therefore, that for clinical purposes it is sufficient to use the concentration of total serum zinc corrected for the concentration of serum albumin. (author)

  12. Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

    Directory of Open Access Journals (Sweden)

    Kamil Kuca

    2018-05-01

    Full Text Available Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7 and butyrylcholinesterase (BChE; EC 3.1.1.8, and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6 are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes” depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153 with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens AChE (HssACHE and BChE (HssBChE inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate. According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

  13. Piper betle leaves: profiling phenolic compounds by HPLC/DAD-ESI/MS(n) and anti-cholinesterase activity.

    Science.gov (United States)

    Ferreres, Federico; Oliveira, Andreia P; Gil-Izquierdo, Angel; Valentão, Patrícia; Andrade, Paula B

    2014-01-01

    Piper betle L. is a widely distributed plant in the tropical and subtropical regions, its leaves being largely consumed as a masticator and mouth freshener. The purposes of this work were to characterise the phenolic profile of this species and to improve knowledge of its anti-cholinesterase properties. The phenolic composition of P. betle leaf aqueous and ethanol extracts was characterised by HPLC coupled with a diode-array detector and combined with electrospray ionisation tandem MS, and in vitro cholinesterase inhibitory capacity of both extracts was assessed by spectrophotometric microassays. The effect on neuronal cells (SH-SY5Y) viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction and lactate dehydrogenase leakage. Twelve phenolic compounds, comprising a phenylpropanoid, five cinnamoyl and six flavonoids derivatives were identified in P. betle leaves. Hydroxychavicol was the major compound in both extracts; however, the aqueous extract presented a greater diversity of compounds. Both extracts showed strong activity against both acetyl- and butyrylcholinesterase, which can be due, at least partially, to the phenolic composition. Furthermore, the aqueous extract proved to be cytotoxic to human neuroblastoma cells at concentrations higher than 500 µg/mL. The results suggest that the consumption of P. betle leaves as an infusion can have a positive impact in the prevention and treatment of neurodegenerative diseases. Apigenin and luteolin derivatives are reported for the first time in this species. Copyright © 2014 John Wiley & Sons, Ltd.

  14. Risk Factors for Nursing Home Placement in Alzheimer's Disease: A Longitudinal Study of Cognition, ADL, Service Utilization, and Cholinesterase Inhibitor Treatment

    Science.gov (United States)

    Wattmo, Carina; Wallin, Asa K.; Londos, Elisabet; Minthon, Lennart

    2011-01-01

    Purpose of the Study: To identify risk factors for early nursing home placement (NHP) in Alzheimer's disease (AD), focusing on the impact of longitudinal change in cognition, activities of daily living (ADL), service utilization, and cholinesterase inhibitor treatment (ChEI). Design and Methods: In an open, 3-year, prospective, multicenter study…

  15. Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

    International Nuclear Information System (INIS)

    Antokhin, A M; Gainullina, E T; Taranchenko, V F; Ryzhikov, S B; Yavaeva, D K

    2010-01-01

    Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

  16. Adverse Drug Reactions Reported With Cholinesterase Inhibitors : An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

    NARCIS (Netherlands)

    Kroeger, Edeltraut; Mouls, Marie; Wilchesky, Machelle; Berkers, Mieke; Carmichael, Pierre-Hugues; van Marum, Rob; Souverein, Patrick; Egberts, Toine; Laroche, Marie-Laure

    2015-01-01

    Background: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market. Objective: To describe ChEI related ADRs in Alzheimer's disease

  17. Adverse Drug Reactions Reported With Cholinesterase Inhibitors: An Analysis of 16 Years of Individual Case Safety Reports From VigiBase

    NARCIS (Netherlands)

    Kroger, E.; Mouls, M.; Wilchesky, M.; Berkers, M.; Carmichael, P.H.; van Marum, R.J.; Souverein, P.; Egberts, T.; Laroche, M.L.

    2015-01-01

    Background: No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer’s disease has been conducted since their emergence on the market. Objective: To describe ChEI related ADRs in Alzheimer’s disease

  18. Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

    Energy Technology Data Exchange (ETDEWEB)

    Antokhin, A M; Gainullina, E T; Taranchenko, V F [Federal State Agency ' 27 Scientific Centre of Ministry of Defence of the Russian Federation' (Russian Federation); Ryzhikov, S B; Yavaeva, D K [Department of Physics, M.V.Lomonosov Moscow State University (Russian Federation)

    2010-10-19

    Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

  19. Characterization of cholinesterases present in brain and muscle tissues of juvenile blue shark (Prionace glauca

    Directory of Open Access Journals (Sweden)

    Luís Miguel Fonseca Alves

    2014-06-01

    Regarding the in vitro exposure to chlorpyrifos-oxon, we have observed a dose-response pattern showing higher ChE inhibitions with increasing pesticide concentrations and with more than 90% inhibition in the highest concentrations, which reveals the potential of this biomarker for biomonitoring studies and contaminant effect assessment in the blue shark.

  20. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  1. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

    Directory of Open Access Journals (Sweden)

    Roberto Raschetti

    2007-11-01

    Full Text Available Mild cognitive impairment (MCI refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD, in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine in delaying the conversion from MCI to Alzheimer disease or dementia.The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine. Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y to 25% (over 3 y among treated patients, and from 18% (over 2 y to 28% (over 3 y among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of

  2. Association between arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh

    Directory of Open Access Journals (Sweden)

    Karim Md Rezaul

    2010-07-01

    Full Text Available Abstract Background Arsenic is a potent pollutant that has caused an environmental catastrophe in certain parts of the world including Bangladesh where millions of people are presently at risk due to drinking water contaminated by arsenic. Chronic arsenic exposure has been scientifically shown as a cause for liver damage, cancers, neurological disorders and several other ailments. The relationship between plasma cholinesterase (PChE activity and arsenic exposure has not yet been clearly documented. However, decreased PChE activity has been found in patients suffering liver dysfunction, heart attack, cancer metastasis and neurotoxicity. Therefore, in this study, we evaluated the PChE activity in individuals exposed to arsenic via drinking water in Bangladesh. Methods A total of 141 Bangladeshi residents living in arsenic endemic areas with the mean arsenic exposure of 14.10 ± 3.27 years were selected as study subjects and split into tertile groups based on three water arsenic concentrations: low ( 265 μg/L. Study subjects were further sub-divided into two groups (≤50 μg/L and > 50 μg/L based on the recommended upper limit of water arsenic concentration (50 μg/L in Bangladesh. Blood samples were collected from the study subjects by venipuncture and arsenic concentrations in drinking water, hair and nail samples were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS. PChE activity was assayed by spectrophotometer. Results Arsenic concentrations in hair and nails were positively correlated with the arsenic levels in drinking water. Significant decreases in PChE activity were observed with increasing concentrations of arsenic in water, hair and nails. The average levels of PChE activity in low, medium and high arsenic exposure groups were also significantly different between each group. Lower levels of PChE activity were also observed in the > 50 μg/L group compared to the ≤50 μg/L group. Moreover, PChE activity was

  3. Inhibition of the mixed leukocyte reaction by alloantisera in man

    International Nuclear Information System (INIS)

    Jonker, M.; Leeuwen, A. van; Rood, J.J. van

    1977-01-01

    The incidence of MLC(mixed leukocyte culture)-inhibiting antibodies was determined in 42 pregnancy sera. MLC's were carried out between the cells from the serum donor and her husband in the presence of nonimmune AB serum and the test serum. Fifty per cent of the sera reduced the MLC response to less than 40% of the control values. Only four sera had lymphocytotoxic activity. The inhibition was strong against the specific immunizor, less strong against random unrelated cells and weak against cells which were SD(serologically defined)-identical with the serum donor. Absorptions with lymphocytes and platelets were carried out. Lymphocytes removed activity in three of the four sera tested. Platelets removed activity from one serum. It was concluded that both anti-LD(lymphocyte defined) and anti-SD antibodies were able to inhibit the MLR (mixed leukocyte reaction) at the stimulator cell level. (author)

  4. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer’s disease: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Noll Campbell

    2008-12-01

    Full Text Available Noll Campbell1, Amir Ayub2, Malaz A Boustani2, Chris Fox3, Martin Farlow4, Ian Maidment3, Robert Howard51Wishard Health Services, Indianapolis, Indiana; 2Indiana University Center for Aging Research, Regenstrief Institute, Inc., Indianapolis, Indiana; 3University of Kent, Kent, United Kingdom; 4Indiana University School of Medicine, Indianapolis, Indiana; 5King’s College, London, United KingdomObjective: To determine the efficacy of cholinesterase inhibitors (ChEIs in improving the behavioral and psychological symptoms of dementia (BPSD in patients with Alzheimer’s disease (AD.Data sources: We searched MEDLINE, Cochrane Registry, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL from 1966 to 2007. We limited our search to English Language, full text, published articles and human studies.Data extraction: We included randomized, double-blind, placebo-controlled trials evaluating the efficacy of donepezil, rivastigmine, or galantamine in managing BPSD displayed by AD patients. Using the United States Preventive Services Task Force (USPSTF guidelines, we critically appraised all studies and included only those with an attrition rate of less than 40%, concealed measurement of the outcomes, and intention to treat analysis of the collected data. All data were imputed into pre-defined evidence based tables and were pooled using the Review Manager 4.2.1 software for data synthesis.Results: We found 12 studies that met our inclusion criteria but only nine of them provided sufficient data for the meta-analysis. Among patients with mild to severe AD and in comparison to placebo, ChEIs as a class had a beneficial effects on reducing BPSD with a standard mean difference (SMD of −0.10 (95% confidence interval [CI]; −0.18, −0.01 and a weighted mean difference (WMD of −1.38 neuropsychiatry inventory point (95% CI; −2.30, −0.46. In studies with mild AD patients, the WMD was −1.92 (95% CI; −3.18, −0.66; and in studies

  5. Inhibition of the voltage-dependent chloride channel of Torpedo electric organ by diisopropylfluorophosphate and its reversal by oximes

    International Nuclear Information System (INIS)

    Abalis, I.M.; Chiang, P.K.; Wirtz, R.A.; Andre, R.G.

    1986-01-01

    Diisopropylfluorophosphate (DFP), a potent organophosphate inhibitor of cholinesterases, was found to inhibit the specific binding of [ 35 S]t-butylbicyclophosphorothionate (TBPS), specific chloride channels ligand, to the electric organ membranes of Torpedo, with a Ki of 21 +/- 3 μM. The binding sites of [ 35 S]TBPS in the Torpedo membranes were found not to be GABA receptors or nicotinic acetylcholine receptors as previously described. Interestingly, a stimulation of the binding of [ 35 S]TBPS was observed in the presence of atropine and three oximes, monopyridinium oxime 2-PAM, bispyridinium bis-oxime TMB-4 and H-oxime HI-6. The maximal stimulation was 300-500% of control, after which, the stimulation was reversed at higher concentrations. The three oximes protected by more than 95% the inhibition by 1 mM DFP of the binding of [ 35 S]TBPS to the voltage-dependent chloride channel. However, atropine protected only 20% of the inhibited channel. These results, thus, suggest that the protection against the toxic effects of DFP or other anticholinesterase agents by the tested oximes may not be solely a result of the reactivation of cholinesterases but also the protection of the voltage-dependent chloride channel

  6. Effect of induced epilepsy on some biochemical parameters in female rats

    Directory of Open Access Journals (Sweden)

    J.S. H. Ali

    2012-01-01

    Full Text Available The activity of cholinesterase and some biochemical parameters of blood such as glucose, cholesterol and phospholipids were estimated in 52 epilepsy induced females of Wister albino rats. Animals of this experiment were divided into two groups, group (I regarded as control and group (II administrated subcutaneously by pentylenetetrazole 100mg/kg and divided in to three sub-groups according to the time of samples collection 3 hrs, 24 hrs and 1 week. The results revealed that epilepsy induction caused a significant inhibition of serum cholinesterase activity 3 hrs after induction while in the brain, the activity of cholinesterase was significantly increased after 24 hrs Serum glucose level was significantly elevated after 3 hrs and 24 hrs of induction, total cholesterol and phospholipids were not changed. From the results obtained in this study, it can be concluded that epilepsy caused significant changes in cholinesterase activity in brain and serum in addition to the glucose level in the serum.

  7. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

    Science.gov (United States)

    Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-04-01

    Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. [Comparative analysis of sensitivity of proteases (chymotrypsin and trypsin) and cholinesterases of different origin to some organophosphorus inhibitors].

    Science.gov (United States)

    Rozengart, E V

    2009-01-01

    The antichymotrypsin, antitrypsin, and anticholinesterase efficiencies of four homologous series of organophosphorus inhibitors are compared: O-ethyl-S-(n-alkyl)methylthiophosphonates, O-(n-alkyl)-S-(n-butyl)methylthiophosphonates, O-(n-alkyl)-S-beta-(ethylmercaptoethylene)methylthiophosphonates, and their methylsulfomethylates. As sources of a-chymotrypsin and trypsin, commercial compounds of Worthington Biochemical Corporation and Leningrad Myasokombinat were tested. Bimolecular constant of the reaction rate was used as the measure of antienzyme efficiency. In all cases, the antichymotrypsin efficiency was lower, while the antitrypsin--essentially higher than the anticholinesterase activity of the studied inhibitors. These differences were found to much depend both on the inhibitor structure and on nature of the cholinesterase compounds.

  9. Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

    DEFF Research Database (Denmark)

    Schultz, K; Nilsson, K; Nielsen, Jørgen Erik

    2010-01-01

    BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients...... with dementia with Lewy bodies (DLB) with or without medication, as well as to reveal whether CSF TTR correlates with depression in dementia. METHODS: CSF samples from 59 patients with AD, 13 patients with DLB and 13 healthy controls were collected, and biochemical analysis was performed. Subjects were assessed...... for the presence of depression. RESULTS: No significant differences in CSF TTR were found between AD, DLB, and control subjects or between depressed and non-depressed dementia patients. Interestingly, we found a significant reduction in CSF TTR (14%) in AD patients who were medicated with cholinesterase inhibitors...

  10. In vitro inhibition of the paraoxonase from human serum with ...

    African Journals Online (AJOL)

    SERVER

    2008-03-04

    2000). ... Playfer JR, Eze CL, Bullen MF, Evans DAP (1976). Genetic polymor- phism and interethnic variability of plasma paraoxonase activity. J. Med. ... Senter PD, Marquardt H, Thomas BA, Hammock BD, Frank IS,. Svensson ...

  11. Association between blood cholinesterase activity, organophosphate pesticide residues on hands, and health effects among chili farmers in Ubon Ratchathani Province, northeastern Thailand

    Science.gov (United States)

    Nganchamung, Thitirat; Robson, Mark G; Siriwong, Wattasit

    Use of pesticides has been documented to lead to several adverse health effects. Farmers are likely to be exposed to pesticides through dermal exposure as a result of mixing, loading, and spraying. Organophosphate pesticides (OPs) are widely used in most of the agricultural areas throughout Thailand. OPs are cholinesterase inhibitors and blood cholinesterase activity is used as a biomarker of OP effects. This study aims to determine the association between blood cholinesterase activity and organophosphate pesticide residues on chili farmer’s hands and their adverse health effects. Ninety chili farmers directly involved with pesticide applications (e.g. mixing, loading, spraying) were recruited and were interviewed face to face. Both enzymes, erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (PChE), were tested with the EQM Test-mate Cholinesterase Test System (Model 400). Hand wipe samples were used for collecting residues on both hands and OP residues for chlorpyrifos and profenofos were quantified using gas chromatography equipped with a flame photometric detector (GC-FPD). The average activity (±SD) of AChE and PChE was 2.73 (±0.88) and 1.58 (±0.56) U/mL, respectively. About 80.0% of the participants had detectable OP residues on hands. The median residues of chlorpyrifos and profenofos were found to be 0.02 and 0.03 mg/kg/two hands, respectively. Half of participants reported having some acute health symptoms within 48 hours after applying pesticides. When adjusted for gender, number of years working in chili farming, and frequency of pesticide use, AChE activity (Adjusted OR = 0.03, 95%CI: 0.01-0.13) and detected OP residues on hands (Adjusted OR = 0.15, 95%CI: 0.02-0.95) were significantly associated with having health effects, but no significant association was found in PChE activity (Adjusted OR = 2.09, 95%CI: 0.63-6.99). This study suggests that regular monitoring for blood cholinesterase and effective interventions to reduce pesticide

  12. [The National Serum Bank].

    Science.gov (United States)

    Magos-López, C; Sánchez-Villarreal, F; Gutiérrez, G; Tapia-Conyer, R

    1992-01-01

    A National Serum Bank was established to store sera obtained during the National Seroepidemiological Survey performed in Mexico in 1987. More than 70,000 serum samples were obtained from subjects of either sex 1-99 years of age in each of the 32 states of the country. The current collection of sera includes 28,704 male samples and 40,629 female samples. This paper describes the procedures for handling serum samples, including reception registry, storage and distribution to several laboratories for detection of measles, rubella, poliomyelitis, AIDS, diphtheria, pertussis, tetanus, brucella, salmonella, amoeba, toxoplasma, American trypanosomiasis and cysticercus. Determinations of total cholesterol were also made in order to describe its distribution and to identify the prevalence of hypercholesterolemia.

  13. Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA

    Directory of Open Access Journals (Sweden)

    Mehnaz Pervin

    2014-07-01

    Full Text Available We aimed to investigate the antioxidant and acetylcholinesterase inhibitory activities of the anthocyanin rich extract of grape skin. Grape skin anthocyanin (GSA neutralized free radicals in different test systems, such as 2,-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS and 2,2-diphenyl-1-picrylhydrazyl (DPPH assays, to form complexes with Fe2+ preventing 2,2'-azobis(2-amidinopropane dihydrochloride (AAPH-induced erythrocyte hemolysis and oxidative DNA damage. Moreover, GSA decreased reactive oxygen species (ROS generation in isolated mitochondria thus inhibiting 2',-7'-dichlorofluorescin (DCFH oxidation. In an in vivo study, female BALB/c mice were administered GSA, at 12.5, 25, and 50 mg per kg per day orally for 30 consecutive days. Herein, we demonstrate that GSA administration significantly elevated the level of antioxidant enzymes in mice sera, livers, and brains. Furthermore, GSA inhibited acetylcholinesterase (AChE in the in vitro assay with an IC50 value of 363.61 µg/mL. Therefore, GSA could be an excellent source of antioxidants and its inhibition of cholinesterase is of interest with regard to neurodegenerative disorders such as Alzheimer’s disease.

  14. Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl/butyryl cholinesterase.

    Science.gov (United States)

    Catto, Marco; Berezin, Andrey A; Lo Re, Daniele; Loizou, Georgia; Demetriades, Marina; De Stradis, Angelo; Campagna, Francesco; Koutentis, Panayiotis A; Carotti, Angelo

    2012-12-01

    Alzheimer's disease (AD) onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target. Two new chemical entities, the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (benzotriazinone I) and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one (triazafluoranthenone II), were explored for their multitarget-directed inhibition of beta-amyloid (Aβ) fibrillization and acetyl- (AChE) and/or butyryl- (BChE) cholinesterase, three valuable targets for AD therapy. Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II, respectively, allowed the preparation of a series of compounds that were tested as Aβ(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Aβ self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 μM. Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors. In particular, benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity, the former displaying IC(50) values of 1.4, 1.5 and 1.9 μM on Aβ aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 μM in the Aβ aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Aβ aggregation inhibition, were submitted to a time course kinetic assay followed with thioflavin T (ThT) spectrofluorimetry, circular dichroism (CD) and transmission electron microscopy (TEM). Experimental data indicated that 24 acted at a low concentration ratio (10 μM 24 vs. 50 μM Aβ), stabilizing the unstructured Aβ peptide and inhibiting fibrillogenesis, and that 29

  15. Molecular Cloning of Human Gene(s) Directing the Synthesis of Nervous System Cholinesterases

    Science.gov (United States)

    1987-09-01

    responsible for at least some of the symptoms observed in hyperthyroidism . The location of primary sequences of human ChE showing high homology to bovine...verteLrates both classes exist in the heart. Humans having non- functional BuChE in the serum show no known symptoms of illness (15) and exhibit normal...become a "physiological nuisance" in cases of hyperthyroidism (such as Graves’ ophthalmopathy). In this disorder, there exists an overproduction of the

  16. Cholinesterase (ChE) response and related mortality among birds fed ChE inhibitors

    Science.gov (United States)

    Ludke, J.L.; Hill, E.F.; Dieter, M.P.

    1975-01-01

    Patterns of mortality and inhibition of brain and plasma ChE in birds treated with ChE inhibitors were studied in an attempt to determine the validity of using ChE activity as a monitoring and diagnostic technique. Analysis of brain ChE activity proved to be reliable for diagnosing and monitoring effects of selected ChE inhibitors in birds. Brain ChE inhibition exceeding 20% indicated exposure, and inhibition greater than 50% was sufficient for diagnosing cause of death. Individuals that died from dietary exposure to parathion or carbofuran had brain ChE activities below 55% of normal; although individuals could survive with brain ChE activity lower than 50%. Problems associated with collection, storage, and analysis of tissues for ChE activity are discussed.

  17. Thermostabilisation of human serum butyrylcholinesterase for detection of its inhibitors in water and biological fluids

    Directory of Open Access Journals (Sweden)

    Lakshmanan Jaganathan

    1999-01-01

    Full Text Available The ability of gelatine-trehalose to convert the normally fragile, dry human serum BChE into a thermostable enzyme and its use in the detection of cholinesterase inhibitors in water and biological fluids is described. Gelatine or trehalose alone is unable to protect the dry enzyme against exposure to high temperature, while a combination of gelatine and trehalose were able to protect the enzyme activity against prolonged exposure to temperature as high as +50°C. A method for rapid, simple and inexpensive means of screening for cholinesterase inhibitors such as carbamates and organophosphates in water, vegetables and human blood has been developed.A capacidade da gelatina-trehalose em converter a frágil BChE do soro humano em uma enzima termoestável e seu uso na descoberta de inibidores de colinesterase em água e fluidos biológicos é apresentado. A Gelatina ou trehalose são incapazes de proteger a enzima seca BchE do soro humano contra exposição a elevadas temperaturas, enquanto que uma combinação de gelatina e trehalose são capazes de proteger a atividade de enzima contra exposição prolongada a temperaturas elevadas e da ordem de 50° C. Um método barato, simples e rápido de screening para inibidores de colinesterase tal como carbamatos e organofosfatos em água, verduras e sangue humano foi desenvolvido.

  18. Radioimmunoassay of haloperidol in human serum: correlation of serum haloperidol with serum prolactin

    International Nuclear Information System (INIS)

    Poland, R.E.; Rubin, R.T.

    1981-01-01

    A radioimmunoassay (RIA) for measurement of serum haloperidol is described. Compared to gaschromatography (GC), RIA vaues average 40% higher. However, a simple organic extraction of serum yields statistically equivalent RIA and GC haloperidol determinations. For both men and women combined, there was a positive correlation between dose (mg/kg/day) and steady-state serum haloperidol level (r = +0.86) and between steady-state serum haloperidol and serum prolactin (PRL) concentration

  19. Effect of a mixture of pyridostigmine and atropine on forced expiratory volume (FEV1), and serum cholinesterase activity in normal subjects

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, B F; Gefke, Kaj; Mosbech, H

    1985-01-01

    injection with a decrease to 27 +/- 5% (mean +/- SEM) of the original activity. Forced expiratory volume in the first 1s (FEV1) was measured at fixed time intervals for 90 min. No decrease in FEV1 was observed; on the contrary, there was a small increase. We conclude that atropine effectively antagonizes...

  20. Serum YKL-40

    DEFF Research Database (Denmark)

    Mylin, Anne K; Abildgaard, Niels; Johansen, Julia S

    2015-01-01

    to clinical progression, i.e. skeletal-related events (SREs), in 230 newly diagnosed patients with multiple myeloma receiving intravenous bisphosphonates. Serum concentrations of YKL-40 and biochemical bone markers (CTX-MMP, CTX-I, PINP) were measured at diagnosis. Patients were evaluated every third month...

  1. 79 - 81_Wali - Serum

    African Journals Online (AJOL)

    DR. AMINU

    2013-06-01

    Jun 1, 2013 ... SERUM ANTIOXIDANT VITAMINS LEVELS IN CHILDREN WITH SICKLE. CELL ANAEMIA IN ... play a role in the development of sickle cell anaemic complications. In the current study, ... vaso-occlusive episodes, acute chest syndrome and impaired ... frequency of sickling crises accompanied by tissue or.

  2. Retrospective detection of exposure to organophosphorus anti-cholinesterases: Mass spectrometric analysis of phosphylated human butyrylcholinesterase

    NARCIS (Netherlands)

    Fidder, A.; Hulst, A.G.; Noort, D.; Ruiter, R. de; Schans, M.J. van der; Benschop, H.P.; Langenberg, J.P.

    2002-01-01

    In this paper a novel and general procedure is presented for detection of organophosphate-inhibited human butyrylcholinesterase (HuBuChE), which is based on electrospray tandem mass spectrometric analysis of phosphylated nonapeptides obtained after pepsin digestion of the enzyme. The utility of this

  3. Cholinesterase response in the rhabdomyosarcoma tumor and small intestine of the BALB/c mice and the radioprotective actions of exogenous ATP after lethal dose of neutron radiation

    International Nuclear Information System (INIS)

    Szeinfeld, D.; De Villiers, N.

    1993-01-01

    The rhabdomyosarcoma tumors were subjected to different doses of 2.0, 3.8 and 7.0 Gy from a neutron beam facility p(66 MeV)/Be. Elevated levels of cholinesterase activity are observed in which there is a correlation between the different doses of neutron radiation and the augmentation response of this enzyme. The increase of cholinesterase activity after 7 Gy neutron irradiation as a feature of involvement in the homeostatic mechanism maintaining the proper choline/acetylcholine ratio in the cell is also observed at 1 and 24 h in both tissues, rhabdomyosarcoma and small intestine. The activity of the enzyme after neutron irradiation with prior administration of ATP showed smaller increases when compared with increase observed after neutron irradiation alone. Moreover in the present work the protective mechanism of ATP in the response of cholinesterase activity is marked differential between both, normal and tumoral tissue and correlated inversely with the administered of the following concentrations of exogenous ATP (8, 25, 80, 250, and 700 mg/kg body weight) prior to exposure to 7 Gy neutron radiation. These results reflect the radioprotective ability of exogenous ATP to exert a number of metabolic adaptations as a defense mechanism in which the cell exposed to neutron radiation could remain viable because the injury is potentially repairable. (orig.) [de

  4. Studies on the molecular dissection of human cholinesterase variants and their genomic origins. Final report, 1 June 1994-30 May 1996

    Energy Technology Data Exchange (ETDEWEB)

    Soreq, H.

    1996-06-01

    To evaluate the capacity of overexpressed recombinant human cholinesterases or mutated variants thereof to confer protection against anti-cholinesterase toxicity, we employed transiently transgenic Xenopus laevis tadpoles and stably transgenic mice. Normal and mutant variants of butyrylcholinesterase (BuChE) revealed partially overlapping binding sites for several inhibitors and demonstrated the involvement of the oxyanion hole in BuChE catalysis. In the developing tadpoles the isoform of AChE, which terminates with the 3`-exon 6, was efficiently accumulated in neuromuscular junctions and conferred resistance to the organophosphate paraoxon. In transgenic mice, exon 6-terminated AChE, under control of its authentic promoter, accumulated in CNS synapses and conferred resistance to paraoxon and several cholinergic agonists, but caused progressive deterioration in both neuromotor and cognitive functioning. Finally, in a human patient carrying the atypical`1 (D7OG) gene for BuChE, we observed adverse responses to prophylactic doses of the carbamate pyridostigmine and from this and in vitro studies predicted a generalized genetic predisposition to anti-cholinesterase therapies, including that approved for the treatment of Alzheimer`s disease.

  5. Cholinesterases and neurotoxicity as highly sensitive biomarkers for an organophosphate insecticide in a freshwater gastropod (Chilina gibbosa) with low sensitivity carboxylesterases.

    Science.gov (United States)

    Bianco, Karina; Yusseppone, María Soledad; Otero, Sofía; Luquet, Carlos; Ríos de Molina, María Del Carmen; Kristoff, Gisela

    2013-11-15

    In the Upper Valley of Río Negro and Río Neuquén in Argentina, agriculture represents the second most important economic activity. Azinphos-methyl has been found in water from this region throughout the year at a maximum concentration of 22.48 μg L(-1) during the application period. Toxicological studies on local non-target species have been performed mostly on vertebrates, while mollusks, which could be more sensitive, have not been studied so far. This work aims to characterize cholinesterase (ChE) and carboxilesterase (CE) activities of Chilina gibbosa, a freshwater gastropod native to southern Argentina and Chile. These enzymes, together with neurotoxicity signals, are evaluated herein after as sensitive biomarkers of exposure to azinphos-methyl at environmentally relevant concentrations. Effects of azinphos-methyl on antioxidant defenses: glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST) are also studied in order to complete a set of biomarkers with different sensitivity and specificity, to propose C. gibbosa as a sentinel species. The highest specific activity was obtained with acetylthiocholine as substrate, followed by propionylthiocholine (83% in comparison to acetylthiocholine) and butyrylthiocholine (19%).The lowest Km and the highest efficiency for ChE were obtained with acetylthiocholine. Regarding CEs activities, a higher efficiency was obtained with p-nitrophenyl butyrate than with p-nitrophenyl acetate. Eserine produced significant inhibition of ChE activity (81% with 0.001 mM and 98% with 1mM) while iso-OMPA did not produce any significant effect on ChE. Our results show that C. gibbosa ChE is very sensitive to azinphos-methyl (CI50 0.02 μg L(-1)) while CEs are inhibited at higher concentrations (CI50 1,000 μg L(-1)). CEs have been reported to be more sensitive to OPs than ChEs in most of the aquatic invertebrates protecting the organisms from neurotoxic effects. In contrast, C. gibbosa, has Ch

  6. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease.

    Science.gov (United States)

    Bautista-Aguilera, Oscar M; Esteban, Gerard; Bolea, Irene; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Soriano, Elena; Unzeta, Mercedes; Marco-Contelles, José

    2014-03-21

    The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. Biochemical toxicology studies of methomyl and its kinetic reaction with cholinesterase in rats

    International Nuclear Information System (INIS)

    Tawfik, S.M.; Abdel-Hamid, F.M.

    2001-01-01

    The effect of the pesticide methomyl on acetylcholinesterase activities in brain and blood of male rats in vivo and the kinetics involved in their reaction in vitro were studied. Also, its effect on peroxidase action of catalase in vivo was studied using 14C - formate. The results showed that methomyl is a competitive inhibitor for acetylcholinesterase and the concentration levels that caused 50% inhibition of the enzyme activity were 2.1 x 10-2 M and 1.9 x 10-4 for brain and blood- Ache, respectively. The inhibition of acetylcholinesterase activity decreased to 67.5 % at the time of appearance of toxicity symptoms. The radioactivity eliminated in both the expired air and in urine was reduced

  8. Serum Creatinine: Not So Simple!

    OpenAIRE

    DELANAYE, Pierre; Cavalier, Etienne; Pottel, Hans

    2017-01-01

    Measuring serum creatinine is cheap and commonly done in daily practice. However, interpretation of serum creatinine results is not always easy. In this review, we will briefly remind the physiological limitations of serum creatinine due notably to its tubular secretion and the influence of muscular mass or protein intake on its concentration. We mainly focus on the analytical limitations of serum creatinine, insisting on important concept such as reference intervals, standardization (and IDM...

  9. Cholinesterase activities and behavioral changes in Hypsiboas pulchellus (Anura: Hylidae) tadpoles exposed to glufosinate ammonium herbicide.

    Science.gov (United States)

    Peltzer, Paola M; Junges, Celina M; Attademo, Andrés M; Bassó, Agustín; Grenón, Paula; Lajmanovich, Rafael C

    2013-09-01

    In this study, amphibian tadpoles of Hypsiboas pulchellus were exposed to herbicide Liberty®, which contains glufosinate ammonium (GLA), for 48 h to the following concentrations: 0 (control), 3.55, 4.74, 6.32, 8.43, 11.25, 15, 20, 26.6, and 35.5 mg GLA L(-1). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, as well as swimming capabilities (swimming speed and mean distance) were measured in tadpoles whose concentrations displayed survival rates > 85 %. Our results reveal that sublethal concentrations of GLA significantly inhibited both AChE and BChE activities in tadpoles with respect to the control, showing a concentration-dependent inhibitory effect. The highest inhibition percentages of AChE (50.86%) and BChE (53.02%) were registered in tadpoles exposed to 15 mg GLA L(-1). At this concentration, a significant increase of the swimming speed and mean distance were found in exposed tadpoles with respect to the control, as well as a negative and significant correlation between swimming speed and BChE activity, thus suggesting that this enzyme inhibition is related to an increase in swimming speed. Therefore, exposure of tadpoles to GLA in the wild at concentrations similar to those tested here may have adverse consequences at population level because neurotransmission and swimming performance are essential for tadpole performance and survival.

  10. The Human Serum Metabolome

    Science.gov (United States)

    Psychogios, Nikolaos; Hau, David D.; Peng, Jun; Guo, An Chi; Mandal, Rupasri; Bouatra, Souhaila; Sinelnikov, Igor; Krishnamurthy, Ramanarayan; Eisner, Roman; Gautam, Bijaya; Young, Nelson; Xia, Jianguo; Knox, Craig; Dong, Edison; Huang, Paul; Hollander, Zsuzsanna; Pedersen, Theresa L.; Smith, Steven R.; Bamforth, Fiona; Greiner, Russ; McManus, Bruce; Newman, John W.; Goodfriend, Theodore; Wishart, David S.

    2011-01-01

    Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca. PMID:21359215

  11. Effect of bilirubin on the spectrophotometric and radionuclide assay for serum angiotensin-converting enzyme

    International Nuclear Information System (INIS)

    Saxe, A.W.; Hollinger, M.A.; Essam, T.

    1986-01-01

    The effect of bilirubin on serum angiotensin-converting enzyme (ACE) activity was studied with spectrophotometric and radionuclide assays. In the spectrophotometric assay addition of bilirubin to normal serum from dog, mouse, and human produced a dose-related inhibition of ACE activity. A 50% decrease in human ACE activity was produced by the addition of approximately 250 mg/L in vitro. Serum from icteric patients with elevated bilirubin was also associated with a reduction in ACE activity in the spectrophotometric assay. A 50% decrease in ACE activity in these samples was associated with a serum bilirubin of approximately 220 mg/L. In the radionuclide assay, however, addition of bilirubin to normal human serum failed to reduce measured ACE activity. The use of a radionuclide assay for serum ACE in clinical samples offers the advantage of less interference from serum bilirubin

  12. Overcoming the inhibitory effect of serum on lipofection by increasing the charge ratio of cationic liposome to DNA.

    Science.gov (United States)

    Yang, J P; Huang, L

    1997-09-01

    Since cationic liposome was first developed as a lipofection reagent, a drawback has been noted in that the efficiency of lipofection decreases dramatically after addition of serum to the lipofection medium. This drawback hampers the application of cationic liposome for systematic delivery of genes. In the present studies, we found that the effect of serum on DC-chol liposome-mediated lipofection is dependent on the charge ratio of liposome to DNA. Serum inhibited lipofection activity of the lipoplex at low charge ratios, whereas it enhanced the lipofection activity at high charge ratios. This phenomenon was observed using DOTAP/DOPE but not lipofectamine. Measurement of cellular association of DNA showed that serum could reduce the binding of lipoplex to cells at all tested charge ratios, i.e. 0-10.6. Removal of negatively charged proteins from serum by DEAE Sephacel column abolished the inhibitory effect of serum on lipofection. The fraction contained only negatively charged serum proteins which strongly inhibited lipofection at low charge ratios but not at higher charge ratios. Furthermore, preincubation of serum with positively charged polylysine, which neutralized negatively charged serum proteins, eliminated the inhibitory effect of serum on lipofection. In summary, inactivation of cationic liposome by serum is due to negatively charged serum proteins and it can be overcome by increasing charge ratio of cationic liposome-DNA lipoplexes or by neutralizing the serum with polylysine.

  13. Radioimmunological determination of reverse triiodo thyronine in unextracted serum and serum dialysates

    International Nuclear Information System (INIS)

    Laurberg, P.; Weeke, J.

    1977-01-01

    A sensitive radioimmunoassay for measurements of 3,3,5-triiodothyronine (reverse T3,rT3) in small amounts of unextracted serum is described. The interference of rT3 binding proteins in serum was precluded by addition of 8-anilinol-naphthalene sulphonic acid (ANS). The cross reaction of T4 with the rT3 anti-serum varied with the concentration of T4 in the samples. At 50 per cent inhibition of I 125 rT3 binding, the T4 cross reaction was 0.075% (mol/mol). All values were corrected for T4 cross reaction. By the present method total rT3 averaged 0.37 nmol/l in thirty-two normal subjects. Higher values (0.81-1.98 nmol/l) were obtained in seventeen thyrotoxic patients, while the rT3 was very low (<=0.046 nmol/l) in ten patients with severe primary hypothyroidism. A modification of the total rT3 assay was used for measurements of rT3 in serum dialysates (free rT3). The sensitivity was 0.46 pmol/l. This sensitivity did not allow detection of free rT3 in all normal subjects. (Auth.)

  14. Ulcerative Colitis and Crohn’s Disease Are Associated with Decreased Serum Selenium Concentrations and Increased Cardiovascular Risk

    Directory of Open Access Journals (Sweden)

    Teresa Castro Aguilar-Tablada

    2016-12-01

    Full Text Available The incidence of inflammatory bowel disease (IBD and associated oxidative stress is increasing. The antioxidant mineral selenium (Se was measured in serum samples from 106 IBD patients (53 with ulcerative colitis (UC and 53 with Crohn’s disease (CD and from 30 healthy controls. Serum Se concentrations were significantly lower in UC and CD patients than in healthy controls (p < 0.001 and significantly lower in CD patients than in UC patients (p = 0.006. Se concentrations in patients were significantly influenced by sex, body mass index (BMI, the inflammatory biomarker α-1-antitrypsin, surgery, medical treatment, the severity, extent, and form of the disease and the length of time since onset (p < 0.05. Se concentrations in IBD patients were positively and linearly correlated with nutritional (protein, albumin, prealbumin, cholinesterase and total cholesterol and iron status-related (hemoglobin, Fe and hematocrit parameters (p < 0.05. A greater impairment of serum Se and cardiovascular status was observed in CD than in UC patients. An adequate nutritional Se status is important in IBD patients to minimize the cardiovascular risk associated with increased inflammation biomarkers, especially in undernourished CD patients, and is also related to an improved nutritional and body iron status.

  15. Effects of Two-Year Treatment with the Cholinesterase Inhibitor Rivastigmine on Behavioural Symptoms in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Michael Rösler

    1999-01-01

    Full Text Available Alzheimer’s disease (AD is accompanied by prominent behavioural disturbances. They cause significant distress for both caregivers and patients and can play a major role in the decision to institutionalise AD patients. Recent evidence suggests that cholinergic deficiencies not only contribute to the memory and cognitive abnormalities of AD but are also responsible for some behavioural abnormalities seen over the course of the disease. In this study we assessed the ability of rivastigmine, a pseudo-irreversible cholinesterase inhibitor, to improve behavioural and psychopathologic symptoms in AD. The analysis included 34 patients present in the Germanarm of the international study B303 who received and completed long-term treatment with rivastigmine in the open-label study B305. Assessments of behaviour and psychopathological symptoms were performed using the behavioural component of the Clinicians Interview Based Impression of Change Plus (CIBIC-Plus. Results show that long-term treatment with rivastigmine can slow the progression of behavioural and psychopathological symptoms of AD. Behavioural symptoms showing stabilisation included aggressiveness, activity disturbances, hallucinations and paranoid features. Results also suggest that patients treated earlier with rivastigmine may attain a greater benefit compared with patients whose treatment is delayed 6 months. Further studies examining the effects of rivastigmine on behavioural disturbances in AD are therefore warranted.

  16. Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with β-amyloid aggregation.

    Science.gov (United States)

    Brogi, Simone; Butini, Stefania; Maramai, Samuele; Colombo, Raffaella; Verga, Laura; Lanni, Cristina; De Lorenzi, Ersilia; Lamponi, Stefania; Andreassi, Marco; Bartolini, Manuela; Andrisano, Vincenza; Novellino, Ettore; Campiani, Giuseppe; Brindisi, Margherita; Gemma, Sandra

    2014-07-01

    We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. We determined the inhibitory potency of 2a-c on Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Our prototypical pluripotent analogue 2a interferes with Aβ oligomerization process thus reducing Aβ oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues. © 2014 John Wiley & Sons Ltd.

  17. Does the cholinesterase inhibitor, donepezil, benefit both declarative and non-declarative processes in mild to moderate Alzheimer's disease?

    Science.gov (United States)

    Winstein, Carolee J; Bentzen, Kirk R; Boyd, Lara; Schneider, Lon S

    2007-07-01

    Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.

  18. Free serum thyroxine

    International Nuclear Information System (INIS)

    Degrossi, O.J.; Altschuler, Noe; Cabrejas, M.L. de; Pinkas, Mirta; Garcia del Rio, Hernan

    1982-01-01

    The use of radiommunoassay (RIA) tehcniques has increased the diagnosis of thyroid functional alterations. A solid phase RIA method for free thyroxine (FT4) measurement was tested. Serum FT4, Total T4, T3 and TSH were determined by radioimmunoassay in 179 subjects. One hundred twenty two patients were normal (8 to 75 years old); FT4 was 1.42 +- 0.03 ng/100 ml (avg. value and std. error). In 27 cases of thyrotoxicosis the values were 4.66 +- 0.48 ng/100 ml and in 15 cases of hypothyroidism 0.50 +- 0.06 ng/100 ml (statistics probability [es

  19. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning.

    Science.gov (United States)

    Masson, Patrick; Nachon, Florian

    2017-08-01

    Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre- and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

  20. [The activity of blood cholinesterase in rats exposed to dimethypo after drug intervention].

    Science.gov (United States)

    Wan, Weiguo; Xu, Mailing; Zou, Hejian; Lu, Ailing; Shen, Xinyu; Chen, Yuming

    2002-12-01

    To investigate the activity of ChE in rats poisoned by dimehypo and then treated with pralidoxime methylchloride or unithiol. Rats were divided into control group (dimehypo); intervention groups [dimehypo plus pralidoxime methylchloride or dimehypo plus unithiol (sodium dimercaptopropanesulphonate)]. Rats were dosed with 4 different doses of dimehypo: 1/16, 1/8, 1/4 and 1/2 of LD50 respectively(the LD50 of dimehypo is 342 mg/kg). After being poisoned with dimehypo orally, rats were immediately injected intramuscularly with pralidoxime methylchloride or unithiol. The activity of ChE in blood was detected before and 1/2, 1, 2, 4 and 24 h after poisoning in dimehypo and intervention groups. The ChE activity of four dose subgroups at 1 h after poisoning were (1.04 +/- 0.21), (0.84 +/- 0.12), (0.71 +/- 0.12), (0.66 +/- 0.07) U/ml respectively; the ChE activity of pralidoxime methylchloride intervention groups were (1.01 +/- 0.18), (1.17 +/- 0.11), (1.01 +/- 0.04), (1.03 +/- 0.12) U/ml respectively; and the ChE activity of unithiol intervention groups were (1.15 +/- 0.15), (1.26 +/- 0.27), (1.08 +/- 0.08), (1.04 +/- 0.12) U/ml respectively. The inhibited ChE in blood was recovered by either treatment with pyraldoxime methylchloride or unithiol. These two drugs had similar effects of recovering the activity of ChE(P > 0.05), but at higher doses(1/4 and 1/2 of LD50) the effects of both were not so good. Pralidoxime methylchloride and unithiol could partly recover the activity of ChE inhibited by dimehypo.

  1. Serum Creatinine: Not So Simple!

    Science.gov (United States)

    Delanaye, Pierre; Cavalier, Etienne; Pottel, Hans

    2017-01-01

    Measuring serum creatinine is cheap and commonly done in daily practice. However, interpretation of serum creatinine results is not always easy. In this review, we will briefly remind the physiological limitations of serum creatinine due notably to its tubular secretion and the influence of muscular mass or protein intake on its concentration. We mainly focus on the analytical limitations of serum creatinine, insisting on important concept such as reference intervals, standardization (and IDMS traceability), analytical interferences, analytical coefficient of variation (CV), biological CV and critical difference. Because the relationship between serum creatinine and glomerular filtration rate is hyperbolic, all these CVs will impact not only the precision of serum creatinine but still more the precision of different creatinine-based equations, especially in low or normal-low creatinine levels (or high or normal-high glomerular filtration rate range). © 2017 S. Karger AG, Basel.

  2. Superior serum half life of albumin tagged TNF ligands

    International Nuclear Information System (INIS)

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-01-01

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  3. Radioimmunoassay of cholylglycine in serum

    International Nuclear Information System (INIS)

    Wakushima, Tadashi; Yamanishi, Yasuhito; Hirayama, Chisato

    1979-01-01

    Serum levels of cholylglycines (CG) were determined by radioimmunoassay and that of total bile acids (TBA) by enzymatic method. In normal subjects, serum levels of CG, TBA and CG/TBA ratio were 0.6 +- 0.4 μM, 7 +- 2 μM, and 0.08 +- 0.06, respectively. They were increased markedly in acute hepatitis and moderately in chronic hepatitis and cirrhosis. Thus, measurement of serum CG as compared with serum TBA appears to be a sensitive liver test. (author)

  4. On the influence of alkali metal- and alkaline earth metal chlorides on the rate on inhibition of cholinesterases by organic phosphorus inhibitors

    International Nuclear Information System (INIS)

    Brestkin, A.P.; Shataeva, G.A.

    1975-01-01

    Influence of LiCl, NaCl, KCl, RbCl, CsCl, MgCl 2 , CaCl 2 , CrCl 2 , BaCl 2 on bimolecular constant (K 2 ) of the interaction rate of acetylcholinesterazo (ACE) and butylcholinesterazo (BuCE) with phosphororganic inhibitors was studied. K 2 value with increasing of the electrolite concentration for the interaction of ACE and BuCE with charged inhibitor is significantly decreased and significantly increased in case of interaction with neutral inhibitor

  5. TRANSFERABLE RESIDUES FROM DOG FUR AND PLASMA CHOLINESTERASE INHIBITION IN DOGS TREATED WITH A FLEA CONTROL DIP CONTAINING CHLORPYRIFOS. (R825170)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  6. Synthesis, analysis, cholinesterase-inhibiting activity and molecular modelling studies of 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxy-carbonyl)amino]benzoates and their quaternary ammonium salts

    Czech Academy of Sciences Publication Activity Database

    Padrtova, T.; Marvanová, P.; Odehnalová, K.; Kubínová, R.; Parravicini, V.; Garro, A.; Enriz, R. D.; Humpa, O.; Oravec, Michal; Mokrý, P.

    2017-01-01

    Roč. 22, č. 12 (2017), č. článku 2048. ISSN 1420-3049 R&D Projects: GA MŠk(CZ) LM2015061; GA MŠk(CZ) LO1415; GA MŠk(CZ) EF16_013/0001609 Institutional support: RVO:86652079 Keywords : Acetylcholinesterase * Arylcarbonyloxyaminopropanols * Butyrylcholinesterase * Quaternary ammonium salts * Tertiary amines Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 2.861, year: 2016

  7. Valores de referencia de la actividad de la colinesterasa eritrocitaria según las técnicas de Michel y EQM® en población laboral de Antioquia, Colombia Reference values for erythrocyte cholinesterase activity in the working population of Antioquia, Colombia, according to the Michel and EQM techniques

    Directory of Open Access Journals (Sweden)

    Jaime Carmona-Fonseca

    2003-11-01

    Antioquia: (1 the Aburrá Valley (1 540 m above sea level and (2 the near east of the department (2 150 m above sea level. We excluded workers who were using cholinesterase-inhibiting substances in their work or at home, those who had a disease that altered their cholinesterase levels, and those who said they were not in good health. We measured the erythrocyte cholinesterase activity using two methods: (1 the Michel method and (2 the EQM method (EQM Research, Cincinnati, Ohio, United States of America. We carried out the measurements with 827 people, 415 from the Aburrá Valley and 412 from the near east region. We compared proportions using the chi-square test and Fisher's exact test. We utilized the Student's t test for independent samples to compare two averages. To simultaneously compare three or more averages, analysis of variance was used, followed by the Newman-Keuls multiple-range test. When the variables were not normally distributed or when the variances were not homogeneous, Kruskal-Wallis nonparametric analysis of variance was used to compare the medians. Three computer software programs were used in the statistical analysis: SPSS 9.0, SGPlus 7.1, and Epi Info 6.04. In all the statistical tests the level of significance was set at P < 0.05. RESULTS: The average erythrocyte cholinesterase activity value that we found for the studied population by using the Michel method was 0.857 delta pH/hour (95% confidence interval (CI: 0.849 to 0.866, and the average value found through the EQM method was 35.21 U/g hemoglobin (95% CI: 34.82 to 35.60. With the Michel method: (1 the enzymatic activity differed significantly between the two regions, according to the Newman-Keuls test; (2 within each region, the enzymatic activity was significantly higher among males than among females, according to the Newman-Keuls test; and (3 in none of the region-sex strata was there a statistically significant influence of age on the enzymatic activity. Using the EQM method, there were no

  8. Relationship between serum total magnesium and serum potassium ...

    African Journals Online (AJOL)

    Relationship between serum total magnesium and serum potassium in emergency surgical patients in a tertiary hospital in Ghana. Robert Djagbletey, Brenda Phillips, Frank Boni, Christian Owoo, Ebenezer Owusu-Darkwa, Papa Kobina Gyakye deGraft-Johnson, Alfred E. Yawson ...

  9. Butyryl-cholinesterase is related to muscle mass and strength. A new biomarker to identify elderly subjects at risk of sarcopenia.

    Science.gov (United States)

    Cacciatore, Francesco; Della-Morte, David; Basile, Claudia; Curcio, Francesco; Liguori, Ilaria; Roselli, Mario; Gargiulo, Gaetano; Galizia, Gianluigi; Bonaduce, Domenico; Abete, Pasquale

    2015-01-01

    To determine the relationship between Butyryl-cholinesterase (α-glycoprotein synthesized in the liver, b-CHE) and muscle mass and strength. Muscle mass by bioimpedentiometer and muscle strength by grip strength were evaluated in 337 elderly subjects (mean age: 76.2 ± 6.7 years) admitted to comprehensive geriatric assessment. b-CHE levels were lower in sarcopenic than in nonsarcopenic elderly subjects (p elderly subjects. Thus, b-CHE may be considered to be a fair biomarker for identifying elderly subjects at risk of sarcopenia.

  10. State-wide hospital clinical laboratory plan for measuring cholinesterase activity for individuals suspected of exposure to nerve agent chemical weapons.

    Science.gov (United States)

    Wu, Alan H B; Smith, Andrew; McComb, Robert; Bowers, George N; Makowski, Gregory S; McKay, Charles A; Vena, Jason; McDonagh, John; Hopfer, Sidney; Sena, Salvatore F; Malkus, Herbert; Forte, Elaine; Kelly, Katherine

    2008-02-01

    Hospital laboratories currently lack the capacity to provide emergency determination of cholinesterase activity. We have developed a hospital-based 3-tiered system to test plasma for butyrylcholinesterase (BChE) activity and whole blood for red cell acetylcholinesterase (AChE) activity using available technology and personnel. Interagency communications, toxidrome definition, and patient triage will be coordinated by the Connecticut Department of Public Health and the Poison Control Center. Initial BChE data documents good precision between institutions (coefficient of variation chemical terrorism or large scale HazMat events.

  11. Freeze-drying of HI-6-loaded recombinant human serum albumin nanoparticles for improved storage stability.

    Science.gov (United States)

    Dadparvar, Miriam; Wagner, Sylvia; Wien, Sascha; Worek, Franz; von Briesen, Hagen; Kreuter, Jörg

    2014-10-01

    Severe intoxications with organophosphates require the immediate administration of atropine in combination with acetyl cholinesterase (AChE) reactivators such as HI-6. Although this therapy regimen enables the treatment of peripheral symptoms, the blood-brain barrier (BBB) restricts the access of the hydrophilic antidotes to the central nervous system which could lead to a fatal respiratory arrest. Therefore, HI-6-loaded albumin nanoparticles were previously developed to enhance the transport across this barrier and were able to reactivate organophosphate-(OP)-inhibited AChE in an in vitro BBB model. Since HI-6 is known to be moisture-sensitive, the feasibility of freeze-drying of the HI-6-loaded nanoparticles was investigated in the present study using different cryo- and lyoprotectants at different concentrations. Trehalose and sucrose (3%, w/v)-containing formulations were superior to mannitol concerning the physicochemical parameters of the nanoparticles whereas trehalose-containing samples were subject of a prolonged storage stability study at temperatures between -20°C and +40°C for predetermined time intervals. Shelf-life computations of the freeze-dried HI-6 nanoparticle formulations revealed a shelf-life time of 18 months when stored at -20°C. The formulations' efficacy was proven in vitro by reactivation of OP-inhibited AChE after transport over a porcine brain capillary endothelial cell layer model. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Reduced expression of exocytotic proteins caused by anti-cholinesterase pesticides in Brachionus calyciflorus (Rotifera: Monogononta

    Directory of Open Access Journals (Sweden)

    IA Pérez-Legaspi

    Full Text Available AbstractThe organophosphate and carbamate pesticides methyl-parathion and carbaryl have a common action mechanism: they inhibit acetylcholinesterase enzyme by blocking the transmission of nerve impulses. However, they can alter the expression of exocytotic membrane proteins (SNARE, by modifying release of neurotransmitters and other substances. This study evaluated the adverse effects of the pesticides methyl-parathion and carbaryl on expression of SNARE proteins: Syntaxin-1, Syntaxin-4 and SNAP-23 in freshwater rotifer Brachionus calyciflorus. Protein expression of these three proteins was analyzed before and after exposure to these two pesticides by Western Blot. The expression of Syntaxin-1, Syntaxin-4 and SNAP-23 proteins in B. calyciflorussignificantly decreases with increasing concentration of either pesticides. This suggests that organophosphates and carbamates have adverse effects on expression of membrane proteins of exocytosis by altering the recognition, docking and fusion of presynaptic and vesicular membranes involved in exocytosis of neurotransmitters. Our results demonstrate that the neurotoxic effect of anticholinesterase pesticides influences the interaction of syntaxins and SNAP-25 and the proper assembly of the SNARE complex.

  13. Chemical composition, antioxidant properties and anti-cholinesterase activity of Cordia gilletii (Boraginaceae) leaves essential oil.

    Science.gov (United States)

    Bonesi, Marco; Okusa, Philippe N; Tundis, Rosa; Loizzo, Monica R; Menichini, Federica; Stévigny, Caroline; Duez, Pierre; Menichini, Francesco

    2011-02-01

    This study aimed to investigate for the first time the chemical composition, the antioxidant properties and the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity of the essential oil from the leaves of Cordia gilletii De Wild (Boraginaceae). The essential oil, characterized by 23 constituents (90.1% of the total oil), was constituted by terpene derivatives (25.6%) and non-terpene derivatives (64.5%), among which aldehydes, fatty acids and alkanes were present with the percentage of 16.5%, 18.8% and 23.1%, respectively. The antioxidant activity of C. gilletii essential oil was screened by two in vitro tests: DPPH and beta-carotene bleaching test. The essential oil revealed antioxidant activity with an IC50 value of 75.0 and 129.9 microg/mL on DPPH radical and beta-carotene decoloration tests, respectively. Moreover, C. gilletii inhibited AChE enzyme with an IC50 value of 105.6 microg/mL.

  14. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

    Directory of Open Access Journals (Sweden)

    Bautista-Aguilera OM

    2014-10-01

    Full Text Available Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC], Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO (IQOG, CSIC, Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs as multipotent cholinesterase (ChE and monoamine oxidase (MAO inhibitors for the potential treatment of Alzheimer’s disease (AD is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE, and butyrylcholinesterase (BuChE enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE. Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for h

  15. DETERMINATION OF SERUM ALBUMIN WITH ...

    African Journals Online (AJOL)

    The reaction of tribromoarsenazo(TB-ASA) with serum albumin in the presence of emulgent OP was studied by spectrophotometry. In a Britton-Robinson buffer solution at pH 2.9, tribromoarsenazo and bovine serum albumin can immediately form a red compound in the presence of emulgent OP with a maximum absorption ...

  16. Inhibition, recovery and oxime-induced reactivation of muscle esterases following chlorpyrifos exposure in the earthworm Lumbricus terrestris

    International Nuclear Information System (INIS)

    Collange, B.; Wheelock, C.E.; Rault, M.; Mazzia, C.; Capowiez, Y.; Sanchez-Hernandez, J.C.

    2010-01-01

    Assessment of wildlife exposure to organophosphorus (OP) pesticides generally involves the measurement of cholinesterase (ChE) inhibition, and complementary biomarkers (or related endpoints) are rarely included. Herein, we investigated the time course inhibition and recovery of ChE and carboxylesterase (CE) activities in the earthworm Lumbricus terrestris exposed to chlorpyrifos, and the ability of oximes to reactivate the phosphorylated ChE activity. Results indicated that these esterase activities are a suitable multibiomarker scheme for monitoring OP exposure due to their high sensitivity to OP inhibition and slow recovery to full activity levels following pesticide exposure. Moreover, oximes reactivated the inhibited ChE activity of the earthworms exposed to 12 and 48 mg kg -1 chlorpyrifos during the first week following pesticide exposure. This methodology is useful for providing evidence for OP-mediated ChE inhibition in individuals with a short history of OP exposure (≤1 week); resulting a valuable approach for assessing multiple OP exposure episodes in the field. - Esterase inhibition combined with oxime reactivation methods is a suitable approach for monitoring organophosphate contamination

  17. Inhibition, recovery and oxime-induced reactivation of muscle esterases following chlorpyrifos exposure in the earthworm Lumbricus terrestris

    Energy Technology Data Exchange (ETDEWEB)

    Collange, B. [Universite d' Avignon et des Pays de Vaucluse, UMR 406 Abeilles et Environnement, Site AGROPARC, F-84914, Avignon Cede 09 (France); Wheelock, C.E. [Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77, Stockholm (Sweden); Rault, M.; Mazzia, C. [Universite d' Avignon et des Pays de Vaucluse, UMR 406 Abeilles et Environnement, Site AGROPARC, F-84914, Avignon Cede 09 (France); Capowiez, Y. [INRA, Unite PSH, Site AGROPARC, F-84914 Avignon Cedex 09 (France); Sanchez-Hernandez, J.C., E-mail: juancarlos.sanchez@uclm.e [Laboratory of Ecotoxicology, Faculty of Environmental Science, University of Castilla-La Mancha, Avda. Carlos III s/n, 45071, Toledo (Spain)

    2010-06-15

    Assessment of wildlife exposure to organophosphorus (OP) pesticides generally involves the measurement of cholinesterase (ChE) inhibition, and complementary biomarkers (or related endpoints) are rarely included. Herein, we investigated the time course inhibition and recovery of ChE and carboxylesterase (CE) activities in the earthworm Lumbricus terrestris exposed to chlorpyrifos, and the ability of oximes to reactivate the phosphorylated ChE activity. Results indicated that these esterase activities are a suitable multibiomarker scheme for monitoring OP exposure due to their high sensitivity to OP inhibition and slow recovery to full activity levels following pesticide exposure. Moreover, oximes reactivated the inhibited ChE activity of the earthworms exposed to 12 and 48 mg kg{sup -1} chlorpyrifos during the first week following pesticide exposure. This methodology is useful for providing evidence for OP-mediated ChE inhibition in individuals with a short history of OP exposure (<=1 week); resulting a valuable approach for assessing multiple OP exposure episodes in the field. - Esterase inhibition combined with oxime reactivation methods is a suitable approach for monitoring organophosphate contamination

  18. Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases*

    Science.gov (United States)

    Radić, Zoran; Sit, Rakesh K.; Kovarik, Zrinka; Berend, Suzana; Garcia, Edzna; Zhang, Limin; Amitai, Gabriel; Green, Carol; Radić, Božica; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer

    2012-01-01

    We present a systematic structural optimization of uncharged but ionizable N-substituted 2-hydroxyiminoacetamido alkylamine reactivators of phosphylated human acetylcholinesterase (hAChE) intended to catalyze the hydrolysis of organophosphate (OP)-inhibited hAChE in the CNS. Starting with the initial lead oxime RS41A identified in our earlier study and extending to the azepine analog RS194B, reactivation rates for OP-hAChE conjugates formed by sarin, cyclosarin, VX, paraoxon, and tabun are enhanced severalfold in vitro. To analyze the mechanism of intrinsic reactivation of the OP-AChE conjugate and penetration of the blood-brain barrier, the pH dependence of the oxime and amine ionizing groups of the compounds and their nucleophilic potential were examined by UV-visible spectroscopy, 1H NMR, and oximolysis rates for acetylthiocholine and phosphoester hydrolysis. Oximolysis rates were compared in solution and on AChE conjugates and analyzed in terms of the ionization states for reactivation of the OP-conjugated AChE. In addition, toxicity and pharmacokinetic studies in mice show significantly improved CNS penetration and retention for RS194B when compared with RS41A. The enhanced intrinsic reactivity against the OP-AChE target combined with favorable pharmacokinetic properties resulted in great improvement of antidotal properties of RS194B compared with RS41A and the standard peripherally active oxime, 2-pyridinealdoxime methiodide. Improvement was particularly noticeable when pretreatment of mice with RS194B before OP exposure was combined with RS194B reactivation therapy after the OP insult. PMID:22343626

  19. Studies on the direct radioimmunological determination of triiodothyronine in serum

    International Nuclear Information System (INIS)

    Meinhold, H.; Wenzel, K.W.

    1974-01-01

    The production of highly specific antisera for T 3 and the development of a sensitive radioimmunological procedure for the direct measurement of T 3 in serum is described. Anti-T 3 sera were produced by immunizing rabbits with conjugates of T 3 and bovine albumin, human albumin, and ovalbumin. The various antisera produced showed very little variance in quality and could be used for the direct radioimmunological determination of serum-T 3 with final dilutions between 1:60,000 and 1:300,000. Binding of T 3 to thyroid-hormone-binding serum proteins was inhibited by 8-anilinonaphthalene-1-sulfonic acid. This compound showed better inhibition properties than merthiolate and sodium salicylate. The separation of free and bound hormone was performed by the double antibody technique. The separation by dextran-coated charcoal and ion-exchange resin leads to a decrease of the antibody-bound activity. The validation of the method used was tested by serial dilutions of sera, recovery experiments, and by comparing the serum-T 3 values measured in ethanol extracts with those values obtained by the direct measurement in unextracted serum. The lower limit of detection was approximately 0.18 nmol/l serum. The variation coefficient for the intraassay reproducibility was between 4.3 and 6.1%, for the interassay reproducibility between 7.7 and 13.9%. Measured mean T 3 concentrations for various thyroid states were as follows: Normals: 1.77 nmol/l (1.15 μg/l), normal females on contraceptives: 2.03 nmol/l (1.32 μg/l), pregnants: 2.73 nmol/l (1.78 μg/l), hyperthyroidism: 6.30 nmol/l (4.10 μg/l), T 3 -toxicosis: 3.69 nmol/l (2.40 μg/l). In hypothyroidism T 3 ranged from [de

  20. Effect of Xylitol on Candida albicans resistance in serum (in vitro study

    Directory of Open Access Journals (Sweden)

    Ria Puspitawati

    2013-07-01

    Full Text Available Xylitol is reported to inhibit the growth of C. albicans. Objectives: Investigating serum factor role in inhibiting the growth of C. albicans and the effect of 1%, 5%, 10% xylitol on C. albicans resistance in serum in vitro. Methods: Identification of C. albicans (oral swab of candidiasis patient was conducted using CHROMAgar, confirmed by germ tube test. The cultures were serially diluted, inoculated in Saburoud Dextrose Broth (SDB contained 0% (control, 1%, 5%, or 10% xylitol, and kept for 3 or 7 days. These inoculations were then exposed to either active or inactive serum (Fetal Bovine Serum heated in 65ºC for 30 minutes for 2 hours in 37ºC. The colony forming unit (CFU of C. albicans in Saburoud Dextrose Agar (SDA were counted after 2 days. C. albicans ATCC 10231 strain was used as a comparison. One-way ANOVA with 0.05 was used. Results: After 3 days cultured in media with or without xylitol, the CFU of C. albicans exposed to active serum were significantly lower than those exposed to inactive serum (p=0.032. Although not statistically significant (p=0.689, increased concentration of xylitol lead to increased resistance of C. albicans in active serum. Only 7 day exposure of 10% xylitol resulted in significantly higher growth of C. albicans (p=0.034. No significant difference of C. albicans CFU in active or inactive serum (p=0.404. Conclusion: Serum factor has role in inhibiting C. albicans growth in vitro. Exposure of 1%, 5%, or 10% xylitol for 3 or 7 days has no significant effect on C. albicans resistance in serum.DOI: 10.14693/jdi.v16i2.98

  1. Serum-induced G0/G1 transition in chemically transformed 3T3 cells

    International Nuclear Information System (INIS)

    Gray, H.E.; Buchou, T.; Mester, J.

    1987-01-01

    Quiescent, chemically transformed (benzo-a-pyrene) BALB/c 3T3 cells (BP A31) enter the cell division cycle when exposed to complete medium containing 10% fetal calf serum (FCS); the number of cells recruited is a function of the duration of serum exposure. The recruitment of cells by short (<4 h) serum pulses is not inhibited by simultaneous exposure to cycloheximide (CH), and therefore the initial commitment does not require protein synthesis. The cells enter S phase with a constant delay following the removal of CH, even if CH exposure has been continued for as long as 20 h after the end of the serum pulse. The cell recruitment by serum pulses was inhibited by 5,6-dichloro-1-β-D-ribofuranosyl-benzimidazole (DRB), an inhibitor of cytoplasmic mRNA accumulation. These data suggest that serum exposure produces a stable memory that is necessary and sufficient for the eventual progression through G1 to S phase that occurs when protein synthesis is resumed after the removal of CH; this memory probably consists of mRNA species that are induced by serum and that are stable in the absence of protein synthesis. Unexpectedly, pretreatment of quiescent BP A31 cells with CH (8-24 h) dramatically increased the fraction of the total cell population that is recruited by a serum pulse of fixed duration

  2. Circulating angiostatin serum level in patients with systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Zofia Gerlicz-Kowalczuk

    2017-12-01

    Full Text Available Introduction : Systemic sclerosis (SSc is achronic connective tissue disease characterized by microangiopathy with inadequate angiogenesis. Angiostatin (AS is a potent antiangiogenic factor specifically inhibiting proliferation and inducing apoptosis of vascular endothelial cells. Aim : To evaluate the level of angiostatin in the serum of patients with SSc. Material and methods : Serum levels of AS were measured in 20 SSc patients and 12 healthy controls. Results : A statistically significant difference in the serum levels of AS in SSc patients was observed compared to the control group (636.51 vs. 869.20 ng/ml; p = 0.012. Significant correlations between limited and disseminated SSc (lSSc/dSSc were not found, however, a difference between lSSc and the control group was demonstrated (620.00 vs. 869.20 ng/ml; p = 0.011. The serum level of AS was not associated positively with organ changes caused by SSc. However, a statistically significant lower serum level of AS was observed in patients with SSc and no esophageal (p = 0.008 or pulmonary changes (p = 0.007 compared to the control group. Conclusions : Our results reveal significant differences in AS level in SSc patients compared to the healthy controls, and suggest that a low level of AS may occur as a result of impaired angiogenesis.

  3. Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase.

    Science.gov (United States)

    Tham, Elaine; Liu, Jianhua; Innis, Sheila; Thompson, David; Gaylinn, Bruce D; Bogarin, Roberto; Haim, Alon; Thorner, Michael O; Chanoine, Jean-Pierre

    2009-05-01

    Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean +/- SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 +/- 0.2 vs. 10.2 +/- 1.9 ng.ml(-1).90 min(-1), P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 +/- 1.9 vs. 8.6 +/- 1.2 ng.ml(-1).90 min(-1), P = 0.005). In a second group of subjects (n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 +/- 0.5 vs. 4.5 +/- 0.6 microg/ml, P = 0.029) and cholinesterase activity (705 +/- 33 vs. 1,013 +/- 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy

  4. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  5. New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds

    Directory of Open Access Journals (Sweden)

    Maja Katalinić

    2017-07-01

    Full Text Available For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP-inhibited acetylcholinesterase (AChE and butyrylcholinesterase (BChE. In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3, derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease. Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range.

  6. Inhibitory serum factor of lymphoproliferative response to allogeneic cells in pregnancy

    Directory of Open Access Journals (Sweden)

    Silvia Daher

    Full Text Available INTRODUCTION: An inhibitory serum factor of mixed lymphocyte culture (MLC has been associated with successful pregnancy after lymphocyte transfusion in women with unexplained recurrent spontaneous abortions (RSA. OBJECTIVE: Investigate whether the inhibitory serum factor of MLC is essential for a successful pregnancy. METHOD: Sera from 33 healthy pregnant women and from 40 women with RSA were assessed by a one-way MLC in which the woman's lymphocytes were stimulated with her partner's lymphocytes or with third party lymphocytes. RESULTS: An inhibitory serum effect (inhibition > 50% as compared to normal serum was detected in 45% of the pregnant women who had at least 1 previous parity, in 8% of the primigravidea, in 29% of those with one abortion and in 58% of those with more than one abortion. CONCLUSION: MLC inhibitory serum factor does not seem to be an essential factor for pregnancy development. Therefore, it should not be considered as a parameter for the assessment of RSA patients.

  7. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

    DEFF Research Database (Denmark)

    Payne, Ruth O; Silk, Sarah E; Elias, Sean C

    2017-01-01

    serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been...

  8. Serum Adipocytokines (Visfatin and Resistin: New Biomarkers of Breast Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Sanaa A. El-Benhawy

    2015-10-01

    Full Text Available Background: Recent epidemiological studies demonstrate that obesity is associated with an increased risk for breast cancer in women. Increased estrogen levels are suggested as one possible explanation, but this does not fully explain the relationship between obesity and breast cancer. One alternative explanation is secretion by adipocytes of metabolites, hormones and cytokines, collectively known as adipocytokines, which regulate physiological and pathological processes. Among these adipokines are visfatin and resistin. This study investigates whether visfatin or resistin in serum of breast cancer patients can be used as potential diagnostic and prognostic tools for breast cancer, taking into account clinicopathological features and anthropometric parameters. Methods: Blood samples were collected from 70 breast cancer patients (35 obese and 35 non-obese and 20 healthy females matched for age and body mass index as the control group. Serum visfatin levels were measured by enzyme linked immunosorbent assay and serum resistin levels were measured by radioimmunoassay. Inflammatory status was assessed by measuring C-reactive protein levels by an automated turbidimetric analyzer. Results: We observed highly elevated serum resistin and visfatin levels in breast cancer patients compared to controls, independent of body mass index. Serum resistin and visfatin levels were likely to be associated with increased breast cancer risk and correlated with the inflammatory marker C-reactive protein. Conclusion: Targeting resistin and visfatin inhibition can be an effective therapeutic strategy in breast cancer by downregulating the inflammatory microenvironment in breast tissue. Serum visfatin promises to be a novel biomarker of diagnostic and prognostic value. Larger prospective studies are required to confirm our findings.

  9. Serum-Free Media and the Immunoregulatory Properties of Mesenchymal Stem Cells In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    Mei Wu

    2014-02-01

    Full Text Available Background: Mesenchymal stem cells are capable of self-renewal and multi-lineage differentiation. They are used extensively to treat several diseases. Traditionally, mesenchymal stem cells are cultured in serum-containing media, typically supplemented with fetal bovine serum (FBS. However, the variability of FBS is likely to skew experimental results. Although serum-free media used to expand mesenchymal stem cells has facilitated remarkable achievements, immunomodulation of these cells in under serum-free conditions is poorly understood. We hypothesized that mesenchymal stem cells expanded in serum-free media will retain powerful immunoregulatory functions in vitro and in vivo. Design and Methods: Immunosuppressive activity and the immunomodulatory cytokines produced by mesenchymal stem cells in serum-free media were characterized in vitro. Immunomodulation by serum-free mesenchymal stem cell expansion in monocrotaline-induced pulmonary hypertension was explored in vivo. Results: Similar to cells in serum-containing media, mesenchymal stem cells expanded in serum-free media inhibited proliferation and apoptosis of CD4+T cells. They also exhibited strong immunosuppressive activities and secreted high levels of immunomodulatory cytokines such as PGE2, IDO1, COX2, IL-6, and IL-1β, but not HGF. On the other hand, growth of mesenchymal stem cells in serum-free media attenuated pulmonary vascular remodeling and inhibited mRNA expression of proinflammatory cytokines TNF-α, IFN-γ, IL-6, IL-1β, and IL-18. Conclusions: Mesenchymal stem cells in serum-free media maintained powerful immunomodulatory function in vitro and in vivo; serum-free media may replace serum-containing media for basic research and clinical applications.

  10. Probing cocaine-antibody interactions in buffer and human serum.

    Directory of Open Access Journals (Sweden)

    Muthu Ramakrishnan

    Full Text Available Despite progress in cocaine immunotherapy, the kinetic and thermodynamic properties of antibodies which bind to cocaine and its metabolites are not well understood. It is also not clear how the interactions between them differ in a complex matrix such as the serum present in the human body. In the present study, we have used microscale thermophoresis (MST, isothermal titration calorimetry (ITC, and surface plasmon resonance (SPR we have evaluated the affinity properties of a representative mouse monoclonal (mAb08 as well as those of polyclonal antibodies purified from vaccinated mouse and human patient serum.MST analysis of fluorescently tagged mAb08 binding to cocaine reveals an approximately 15 fold decrease in its equilibrium dissociation constant in 20-50% human serum compared with that in saline buffer. A similar trend was also found using enriched polyclonal antibodies purified from vaccinated mice and patient serum, for which we have used fluorescently tagged bovine serum albumin conjugated to succinyl norcocaine (BSA-SNC. This conjugate closely mimics both cocaine and the hapten used to raise these antibodies. The ITC data also revealed that cocaine has a moderate affinity of about 2 µM to 20% human serum and very little interaction with human serum albumin or nonspecific human IgG at that concentration range. In a SPR inhibition experiment, the binding of mAb08 to immobilized BSA-SNC was inhibited by cocaine and benzoylecgonine in a highly competitive manner, whereas the purified polyclonal antibodies from vaccinated humans and mice, revealed preferential selectivity to pharmacologically active cocaine but not to the inactive metabolite benzoylecgonine. We have also developed a simple binding model to simulate the challenges associated with cocaine immunotherapy using the variable quantitative and kinetic properties of the antibodies.High sensitivity calorimetric determination of antibody binding to cocaine and its metabolites provide

  11. Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

    Science.gov (United States)

    Więckowska, Anna; Kołaczkowski, Marcin; Bucki, Adam; Godyń, Justyna; Marcinkowska, Monika; Więckowski, Krzysztof; Zaręba, Paula; Siwek, Agata; Kazek, Grzegorz; Głuch-Lutwin, Monika; Mierzejewski, Paweł; Bienkowski, Przemysław; Sienkiewicz-Jarosz, Halina; Knez, Damijan; Wichur, Tomasz; Gobec, Stanislav; Malawska, Barbara

    2016-11-29

    As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT 6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT 6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT 6 receptor (K b  = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC 50 hAChE  = 12 nM, IC 50 hBuChE  = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. RBC acetyl cholinesterase: A poor man′s early diagnostic biomarker for familial alzheimer′s and Parkinson′s disease dementia

    Directory of Open Access Journals (Sweden)

    Himmatrao Saluba Bawaskar

    2015-01-01

    Full Text Available Objective: Analysis of red blood cell acetyl cholinesterase (AChE in a familial Alzheimer′s diseases (AD Parkinson′s disease dementia (PDD and their first generation. Setting: General hospital, Mahad district, Raigad. Patients and Methods: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. Result: Median red blood cell (RBC cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non-fluent aphasia 1. Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004 and significantly lowered among familial AD patients (P = 0.010, relatives of patients (P = 0.010. Interpretations: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective.

  13. Antioxidant flavonoids bind human serum albumin

    Science.gov (United States)

    Kanakis, C. D.; Tarantilis, P. A.; Polissiou, M. G.; Diamantoglou, S.; Tajmir-Riahi, H. A.

    2006-10-01

    Human serum albumin (HSA) is a principal extracellular protein with a high concentration in blood plasma and carrier for many drugs to different molecular targets. Flavonoids are powerful antioxidants and prevent DNA damage. The antioxidative protections are related to their binding modes to DNA duplex and complexation with free radicals in vivo. However, flavonoids are known to inhibit the activities of several enzymes such as calcium phospholipid-dependent protein kinase, tyrosine protein kinase from rat lung, phosphorylase kinase, phosphatidylinositol 3-kinase and DNA topoisomerases that exhibit the importance of flavonoid-protein interaction. This study was designed to examine the interaction of human serum albumin (HSA) with quercetin (que), kaempferol (kae) and delphinidin (del) in aqueous solution at physiological conditions, using constant protein concentration of 0.25 mM (final) and various drug contents of 1 μM-1 mM. FTIR and UV-vis spectroscopic methods were used to determine the polyphenolic binding mode, the binding constant and the effects of flavonoid complexation on protein secondary structure. The spectroscopic results showed that flavonoids are located along the polypeptide chains through H-bonding interactions with overall affinity constant of Kque = 1.4 × 10 4 M -1, Kkae = 2.6 × 10 5 M -1 and Kdel = 4.71 × 10 5 M -1. The protein secondary structure showed no alterations at low pigment concentration (1 μM), whereas at high flavonoid content (1 mM), major reduction of α-helix from 55% (free HSA) to 42-46% and increase of β-sheet from 15% (free HSA) to 17-19% and β-anti from 7% (free HSA) to 10-20% occurred in the flavonoid-HSA adducts. The major reduction of HSA α-helix is indicative of a partial protein unfolding upon flavonoid interaction.

  14. In Vitro Ability of Currently Available Oximes to Reactivate Organophosphate Pesticide-Inhibited Human Acetylcholinesterase and Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Kamil Musilek

    2011-03-01

    Full Text Available We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6 to reactivate human acetylcholinesterase (AChE, inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos. We also tested reactivation of human butyrylcholinesterase (BChE with the aim of finding a potent oxime, suitable to serve as a “pseudocatalytic” bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos and leptophos-oxon were quite easily reactivatable by all tested reactivators. In the case of methamidophos-inhibited AChE, the lower oxime concentration (10−5 M had higher reactivation ability than the 10−4 M concentration. Therefore, we evaluated the reactivation ability of obidoxime in a concentration range of 10−3–10−7 M. The reactivation of methamidophos-inhibited AChE with different obidoxime concentrations resulted in a bell shaped curve with maximum reactivation at 10−5 M. In the case of BChE, no reactivator exceeded 15% reactivation ability and therefore none of the oximes can be recommended as a candidate for “pseudocatalytic” bioscavengers with BChE.

  15. [Design, synthesis and evaluation of bis-nicotine derivatives as inhibitors of cholinesterases and beta-amyloid aggregation].

    Science.gov (United States)

    Luo, Wen; Zhao, Yong-mei; Tian, Run-guo; Su, Ya-bin; Hong, Chen

    2013-11-01

    A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).

  16. In vitro demonstration of anti-lipogenic activity in serum from obese rats

    International Nuclear Information System (INIS)

    Harris, R.B.S.; Martin, R.J.

    1986-01-01

    Studies with parabiosed rats provide evidence for a humoral factor, originating in obese animals, that specifically inhibits adipose lipogenesis. A bioassay was developed that allows serum from obese rats to be tested for this factor in vitro. Adipocytes are isolated from epididymal fat of 250g Sprague-Dawley rats. The cells are preincubated at 37 0 C for 1 or 12 hrs, in TC199 media containing 1.1 mg/ml glucose, 0.1 M Hepes and 2% serum. Following preincubation, the cells are washed 3 times and resuspended in serum-free media. Aliquots of cells are tested for metabolic activity in a subsequent 2 hour radiolabelled incubation in serum-free media with the addition of 0.5 μCi/ml U- 14 C-glucose. Basal, insulin (100 μU/ml) and norepinephrine (0.1 μg/ml) stimulated rates of glucose oxidation and conversion to triglyceride fatty acids are measured. Using serum from ad libitum fed rats as control, preincubation with serum from obese rats (20 days at 2 x normal intake) depressed basal and insulin stimulated glucose oxidation, and basal fatty acid synthesis. Serum from obese parabiotic rats and parabiotic partners of obese rats depressed basal fatty acid synthesis. This assay allows us to test serum for anti-lipogenic activity and may be used to identify the factor responsible for this activity in obese animals

  17. Lecithin intake and serum cholesterol.

    NARCIS (Netherlands)

    Knuiman, J.T.; Beynen, A.C.; Katan, M.B.

    1989-01-01

    To find out whether the consumption of lecithin has a more beneficial effect on serum cholesterol than does the consumption of equivalent amounts of polyunsaturated oils, we scrutinized 24 studies on the effect of supplementary lecithin intakes ranging from 1 to 54 mg/d. Most of the studies lacked

  18. Serum transferrin receptor in polycythemia.

    Science.gov (United States)

    Manteiga, R; Remacha, A F; Sardà, M P; Ubeda, J

    1998-10-01

    We measured serum transferrin receptor (sTfR) levels in 22 patients with polycythemia vera and in 26 cases of secondary polycythemia. In our study, raised sTfR levels in both polycythemia groups were related to iron deficiency.

  19. Serum zinc level in thalassemia

    International Nuclear Information System (INIS)

    Keikhaei, B.; Badavi, M.; Pedram, M.; Zandian, K.

    2010-01-01

    To compare serum zinc level between Thalassemia Major (TM) patients and normal population at Shafa Hospital in South West of Iran. A total of 25 male and 36 female of TM patients were enrolled in this study. Out of 61 patients thirty were treated by deferroxamine (DFO) and 31 were on the combination of DFO and deferiprone (DEF) protocol therapy. Sixty normal subjects of the matching age and gender were recruited as controls. From each patient and control group 2 ml of blood was taken in fasting condition. Cell blood count and serum zinc were carried out for both thalassemia patients and normal subjects. The mean age of patients and control group was 15+- 5 years. Mean serum zinc level was 68.97+- 21.12 mu g/dl, 78.10-28.50 mu g/dl, and 80.16+- 26.54 mu g/dl in the TM with DFO, TM with DFO + DEF combination protocol and control group respectively. There was no significant correlation between patients and control group. However 50 percent of TM with DFO, 38.7 percent of TM with DFO + DEF and 32.8 percent of control group had hypozincemia. Nearly 40 to 50 percent of TM patients and one third of normal subjects are suffering from hypozincemia. This study shows that low level of serum zinc is a health problem in both thalassemia patients and normal population in South West of Iran. (author)

  20. Photoexcited riboflavin induces oxidative damage to human serum albumin

    Science.gov (United States)

    Hirakawa, Kazutaka; Yoshioka, Takuto

    2015-08-01

    Photoexcited riboflavin induced damage of human serum albumin (HSA), a water soluble protein, resulting in the diminishment of fluorescence from the tryptophan residue. Because riboflavin hardly photosensitized singlet oxygen generation and sodium azide, a singlet oxygen quencher, did not inhibit protein damage, electron transfer-mediated oxidation of HSA was speculated. Fluorescence lifetime of riboflavin was not affected by HSA, suggesting that the excited triplet state of riboflavin is responsible for protein damage through electron transfer. In addition, the preventive effect of xanthone derivatives, triplet quenchers, on photosensitized protein damage could be evaluated using this photosensitized reaction system of riboflavin and HSA.

  1. Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography

    International Nuclear Information System (INIS)

    Sakaguchi, K.; Chai, S.Y.; Jackson, B.; Johnston, C.I.; Mendelsohn, F.A.

    1988-01-01

    Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [ 125 I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors

  2. The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.

    Science.gov (United States)

    Benchekroun, Mohamed; Romero, Alejandro; Egea, Javier; León, Rafael; Michalska, Patrycja; Buendía, Izaskun; Jimeno, María Luisa; Jun, Daniel; Janockova, Jana; Sepsova, Vendula; Soukup, Ondrej; Bautista-Aguilera, Oscar M; Refouvelet, Bernard; Ouari, Olivier; Marco-Contelles, José; Ismaili, Lhassane

    2016-11-10

    Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.

  3. Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions.

    Science.gov (United States)

    Hallikainen, Maarit; Simonen, Piia; Gylling, Helena

    2014-04-27

    absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved. Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117].

  4. Increased serum potassium affects renal outcomes

    DEFF Research Database (Denmark)

    Miao, Y; Dobre, D; Heerspink, H J Lambers

    2011-01-01

    To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy.......To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy....

  5. Preoperative assessment of congestive liver dysfunction using technetium-99m galactosyl human Serum albumin liver scintigraphy in patients with severe valvular heart disease

    International Nuclear Information System (INIS)

    Nishi, Hiroyuki; Matsumiya, Goro; Takano, Hiroshi; Ichikawa, Hajime; Miyagawa, Shigeru; Sawa, Yoshiki; Takahashi, Toshiki

    2007-01-01

    Severe valvular heart disease is often complicated by congestive liver dysfunction, which greatly compromises the operative results. We evaluated congestive liver dysfunction by a novel approach using technetium-99m galactosyl human serum albumin ( 99m Tc-GSA) with liver scintigraphy. Between 1998 and 2004, we performed scintigraphy accompanied by 99m Tc-GSA in 28 patients who had valvular heart disease with moderate-to-severe tricuspid regurgitation and who showed symptoms of right heart failure. Based on the results, we calculated a receptor index (LHL15) and an index of blood clearance (HH15) and assessed the correlation between these factors and postoperative liver dysfunction, defined as the maximum serum total bilirubin level (max T-bil) as >2.0 mg/dl. Nineteen patients, including four who died in hospital, had postoperative liver dysfunction. The level of HH15 was significantly higher and the level of cholinesterase was significantly lower (P 99m Tc-GSA is a clinically useful predictor of postoperative liver dysfunction in patients with severe valvular disease. (author)

  6. Serum aspirin esterase is strongly associated with glucose and lipids in healthy subjects: different association patterns in subjects with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Kotani Kazuhiko

    2010-07-01

    Full Text Available Abstract Background Aspirin esterase (AE activity can account for part of aspirin pharmacokinetics in the circulation, possibly being associated with the impairment of aspirin effectiveness as an inhibitor of platelet aggregation. Aims The study was aimed at investigating the correlations of serum AE activity with cholinesterase (ChE and metabolic variables in healthy subjects in comparison to subjects with type 2 diabetes mellitus (T2DM. Methods In cardiovascular disease-free T2DM subjects and healthy controls, the AE activity levels and/or the correlation patterns between AE and the other variables were analyzed. Results Neither AE nor ChE activities were higher in the subjects with T2DM. Serum AE activity strongly correlated with ChE as well as glucose/lipids variables such as total cholesterol and triglyceride in healthy subjects, while the correlations between AE and glucose/lipids variables were not present in T2DM subjects. Conclusions These data may reflect the pathophysiological changes between healthy and T2DM subjects. Our data may thus provide the basis for future studies to unravel the mechanisms.

  7. De novo amplification within a silent human cholinesterase gene in a family subjected to prolonged exposure to organophosphorus insecticides

    International Nuclear Information System (INIS)

    Prody, C.A.; Dreyfus, P.; Soreq, H.; Zamir, R.; Zakut, H.

    1989-01-01

    A 100-fold DNA amplification in the CHE gene, coding for serum butyrylcholinesterase (BtChoEase), was found in a farmer expressing silent CHE phenotype. Individuals homozygous for this gene display a defective serum BtChoEase and are particularly vulnerable to poisoning by agricultural organophosphorus insecticides, to which all members of this family had long been exposed. DNA blot hybridization with regional BtChoEase cDNA probes suggested that the amplification was most intense in regions encoding central sequences within BtChoEase cDNA, whereas distal sequences were amplified to a much lower extent. This is in agreement with the onion skin model, based on amplification of genes in cultured cells and primary tumors. The amplification was absent in the grandparents but present at the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to the long arm of chromosome 3, close to the site where the authors previously mapped the CHE gene. Altogether, these observations suggest that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning was indicated to be physiologically necessary. These findings demonstrate a de novo amplification in apparently healthy individuals within an autosomal gene producing a target protein to an inhibitor

  8. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  9. Differential solubility of curcuminoids in serum and albumin solutions: implications for analytical and therapeutic applications

    Directory of Open Access Journals (Sweden)

    Quitschke Wolfgang W

    2008-11-01

    Full Text Available Abstract Background Commercially available curcumin preparations contain a mixture of related polyphenols, collectively referred to as curcuminoids. These encompass the primary component curcumin along with its co-purified derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids have numerous biological activities, including inhibition of cancer related cell proliferation and reduction of amyloid plaque formation associated with Alzheimer disease. Unfortunately, the solubility of curcuminoids in aqueous solutions is exceedingly low. This restricts their systemic availability in orally administered formulations and limits their therapeutic potential. Results Methods are described that achieve high concentrations of soluble curcuminoids in serum. Solid curcuminoids were either mixed directly with serum, or they were predissolved in dimethyl sulfoxide and added as aliquots to serum. Both methods resulted in high levels of curcuminoid-solubility in mammalian sera from different species. However, adding aliquots of dimethyl sulfoxide-dissolved curcuminoids to serum proved to be more efficient, producing soluble curcuminoid concentrations of at least 3 mM in human serum. The methods also resulted in the differential solubility of individual curcuminoids in serum. The addition of dimethyl sulfoxide-dissolved curcuminoids to serum preferentially solubilized curcumin, whereas adding solid curcuminoids predominantly solubilized bisdemethoxycurcumin. Either method of solubilization was equally effective in inhibiting dose-dependent HeLa cell proliferation in culture. The maximum concentration of curcuminoids achieved in serum was at least 100-fold higher than that required for inhibiting cell proliferation in culture and 1000-fold higher than the concentration that has been reported to prevent amyloid plaque formation associated with Alzheimer disease. Curcuminoids were also highly soluble in solutions of purified albumin, a major component of

  10. Species-specific patterns of swimming escape performance and cholinesterase activity in a guild of aquatic insects exposed to endosulfan

    International Nuclear Information System (INIS)

    Trekels, Hendrik; Van de Meutter, Frank; Stoks, Robby

    2012-01-01

    Next to imposing direct lethal effects, pollutants may also indirectly impose mortality by making prey organisms more vulnerable to predation. We report that four water boatmen species differed strongly in direct endosulfan-imposed mortality, and only the species that suffered highest mortality, Sigara iactans, also showed a reduction in escape swimming speed. While head AChE activity was inhibited in all four species, body ChE was only inhibited in S. iactans where it covaried with escape swimming speed, indicating a mechanistic link between body ChE and swimming speed. Our study underscores the need for risk assessment to consider sublethal pollutant effects, which may considerably affect survival rates under natural conditions, also when testing concentrations of a pesticide that cause direct mortality. Such sublethal effects may generate discrepancies between laboratory and field studies and should be considered when designing safety factors for toxicants where the risk assessment is solely based on LC50 values. - Highlights: ► Endosulfan, even at lethal levels, did not affect swimming propensity when attacked. ► Endosulfan reduced escape swimming in one out of four tested corixid species. ► Lower body ChE levels were associated with a slower escape speed in one species. ► Head AChE activity was more sensitive to endosulfan than body ChE. ► Endosulfan had strongly different effects on the closely related species. - Endosulfan only detectably reduced escape swimming speed in one of the four studied water boatmen species and this was associated with an inhibition of body ChE.

  11. Ascorbic acid interference in the measurement of serum biochemical parameters: in vivo and in vitro studies.

    Science.gov (United States)

    Martinello, Flávia; da Silva, Edson Luiz

    2006-04-01

    To investigate the negative interference of ascorbic acid in serum biochemical tests in relation to the dose of vitamin C intake and to the time of blood collection. Healthy volunteers (n = 18) consumed daily doses of vitamin C (0.25-4.0 g) for 1 week and serum parameters were assayed prior to the experiment and on the eighth day of consumption. Blood samples were collected 4, 12 and 24 h after vitamin C intake. Serum levels of ascorbic acid increased significantly after vitamin C ingestion inhibiting urate and total bilirubin tests 4 and 12 h after intake (P cholesterol tests. Addition of ascorbic acid to serum inhibited the urate test to a similar extent to that observed after vitamin C intake. However, after ingesting vitamin C, the interference for the bilirubin test was greater than that of the in vitro interference. Commonly taken doses of supplementary vitamin C interfered negatively with the serum urate test based on the Trinder method, and with bilirubin metabolism.

  12. Serum Antibody Biomarkers for ASD

    Science.gov (United States)

    2015-10-01

    typically developing control. US, unaffected sibling control. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a...typically developing (TD) children (e.g., Warren et al., 1990; Singh, 2009). The goal of this study is to identify a serum antibody biomarker for ASD using...50% less IgG1 antibody in ASD boys vs . TD boys (p=0.0096). The level of ASD1 binding to the AM group was the same as to the ASD boys. These data

  13. In-vitro Antioxidant, Cytotoxic, Cholinesterase Inhibitory Activities and Anti-Genotoxic Effects of Hypericum retusum Aucher Flowers, Fruits and Seeds Methanol Extracts in Human Mononuclear Leukocytes.

    Science.gov (United States)

    Keskin, Cumali; Aktepe, Necmettin; Yükselten, Yunus; Sunguroglu, Asuman; Boğa, Mehmet

    2017-01-01

    The present study investigates the antioxidant, anticancer, anticholinesterase, anti-genotoxic activities and phenolic contents of flower, fruit and seed methanol extracts of Hypericum retusum AUCHER. The amounts of protocatechuic acid, catechin, caffeic acid and syringic acid in methanol extracts were determined by HPLC. Total phenolic content of H. retusum seed extract was found more than fruit and flower extracts. The DPPH free radical scavenging activity of flower and seed methanol extracts showed close activity versus BHT as control. Among three extracts of H. retusum only flower methanol extract was exhibited considerable cytotoxic activities against to HeLa and NRK-52E cell lines. Moreover, seed methanol extract showed both acetyl and butyrl-cholinesterase inhibitory activity. The highest anti-genotoxic effects were seen 25 and 50 μg/mL concentrations. In this study, the extracts showed a strong antioxidant and anti-genotoxic effect. The seed extract was more efficient- than extracts of fruit and flowers. Our results suggest that the antioxidant and anti-genotoxic effects of extracts depend on their phenolic contents. Further studies should evaluate the in-vitro and in-vivo the benefits of H. retusum seed methanol extracts.

  14. Cholinesterase inhibitor use is associated with increased plasma levels of anti-Aβ 1-42 antibodies in Alzheimer's disease patients.

    Science.gov (United States)

    Conti, Elisa; Galimberti, Gloria; Tremolizzo, Lucio; Masetto, Alessandro; Cereda, Diletta; Zanchi, Clara; Piazza, Fabrizio; Casati, Marco; Isella, Valeria; Appollonio, Ildebrando; Ferrarese, Carlo

    2010-12-17

    Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well as on behavioural and psychological symptoms of dementia and activities of daily living. The efficacy of AChEI may be ascribed not only to the activation of cholinergic transmission, but also to other mechanisms, among which a putative regulation of the immune response has already been hypothesized. In the present study, we evaluated, in a cross-sectional sample of 66AD patients and 48 healthy controls, the putative influence of AChEI on anti-Abeta 1-42 antibody plasma levels by ELISA assay. AD patients receiving AChEI therapy showed increased plasma levels of anti-Abeta 1-42 antibodies respect to untreated AD patients and antibodies levels similar to those of healthy controls, both before and after normalization by total IgG values. Our results support a potential role of AChEI in the modulation of the immune response against Abeta. We suggest that a strategy aimed at increasing the endogenous response against this peptide might represent an interesting therapeutic target to be further investigated. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  15. Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.

    Science.gov (United States)

    Farina, Roberta; Pisani, Leonardo; Catto, Marco; Nicolotti, Orazio; Gadaleta, Domenico; Denora, Nunzio; Soto-Otero, Ramon; Mendez-Alvarez, Estefania; Passos, Carolina S; Muncipinto, Giovanni; Altomare, Cosimo D; Nurisso, Alessandra; Carrupt, Pierre-Alain; Carotti, Angelo

    2015-07-23

    The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.

  16. Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1-42 Aggregation Inhibitors for Alzheimer's Disease Therapy.

    Science.gov (United States)

    Dgachi, Youssef; Ismaili, Lhassane; Knez, Damijan; Benchekroun, Mohamed; Martin, Hélène; Szałaj, Natalia; Wehle, Sarah; Bautista-Aguilera, Oscar M; Luzet, Vincent; Bonnet, Alexandre; Malawska, Barbara; Gobec, Stanislav; Chioua, Mourad; Decker, Michael; Chabchoub, Fakher; Marco-Contelles, José

    2016-06-20

    Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Resistance to inhibitors of cholinesterase (Ric-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps34 activity.

    Directory of Open Access Journals (Sweden)

    Cedric Boularan

    Full Text Available Resistance to inhibitors of cholinesterase (Ric-8A is a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13, which is implicated in cell signaling and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes. Ric-8A, Gαi subunits, and their regulators are localized at the midbody prior to abscission and linked to the final stages of cell division. Here, we identify a molecular mechanism by which Ric-8A affects cytokinesis and abscission by controlling Vps34 activity. We showed that Ric-8A protein expression is post-transcriptionally controlled during the cell cycle reaching its maximum levels at mitosis. A FRET biosensor created to measure conformational changes in Ric-8A by FLIM (Fluorescence Lifetime Imaging Microscopy revealed that Ric-8A was in a close-state during mitosis and particularly so at cytokinesis. Lowering Ric-8A expression delayed the abscission time of dividing cells, which correlated with increased intercellular bridge length and multinucleation. During cytokinesis, Ric-8A co-localized with Vps34 at the midbody along with Gαi and LGN, where these proteins functioned to regulate Vps34 phosphatidylinositol 3-kinase activity.

  18. Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property.

    Science.gov (United States)

    Liu, Zhikun; Fang, Lei; Zhang, Huan; Gou, Shaohua; Chen, Li

    2017-04-15

    Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K 3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H 2 O 2 /Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K 3-2 , can be considered as potential therapeutic agents for Alzheimer's disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Evaluation of Antioxidant, Cholinesterase Inhibitory and Antimicrobial Properties of Mentha longifolia subsp. noeana and Its Secondary Metabolites

    Directory of Open Access Journals (Sweden)

    Abdulselam Ertaş

    2015-01-01

    Full Text Available The aim of the present study was to determine the chemical structures of the isolated compounds, the essential oil and fatty acid compositions of Mentha longifolia subsp. noeana with their biological activities. Ursolic acid (1, u vaol (2, stigmast-5-ene-3 b -yl formate (3, stigmast-5-en-3-one (4, b -sitosterol (5, bis(2-ethylhexyl benzene-1,2-dicarboxylate (6,hexacosyl (E-ferulate (7 and 5-hydroxy-6,7,3',4'-tetramethoxy flavone (8 were obtained from the aerial parts. The compounds (2-4, 6, 7 were isolated for the first time from a Mentha species. Palmitic acid (40.8% was the major component of the non-polar fraction obtained from the petroleum ether extract. Pulegone (32.3% was the main constituent of the essential oil which exhibited strong butyrylcholinesterase inhibitory activity (77.36 ± 0.29%, moderate antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans. The methanol extract showed 80% inhibition of lipid peroxidation, and the acetone extract possessed moderate DPPH free radical scavenging activity (60% inhibition at 100 m g/mL.

  20. Progesterone production requires activation of caspase-3 in preovulatory granulosa cells in a serum starvation model.

    Science.gov (United States)

    An, Li-Sha; Yuan, Xiao-Hua; Hu, Ying; Shi, Zi-Yun; Liu, Xiao-Qin; Qin, Li; Wu, Gui-Qing; Han, Wei; Wang, Ya-Qin; Ma, Xu

    2012-11-01

    Granulosa cells proliferate, differentiate, and undergo apoptosis throughout follicular development. Previous studies have demonstrated that stimulation of progesterone production is accompanied by caspase-3 activation. Moreover, we previously reported that arsenic enhanced caspase-3 activity coupled with progesterone production. Inhibition of caspase-3 activity can significantly inhibit progesterone production induced by arsenic or follicle-stimulating hormone (FSH). Here, we report that serum starvation induces caspase-3 activation coupled with augmentation of progesterone production. Serum starvation also increased the levels of cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory (StAR) protein, both of which may contribute to progesterone synthesis in preovulatory granulosa cells. Inhibition of caspase-3 activity resulted in a decrease in progesterone production. Deactivation of caspase-3 activity by caspase-3 specific inhibitor also resulted in decreases in P450scc and StAR expression, which may partly contribute to the observed decrease in progesterone production. Our study demonstrates for the first time that progesterone production in preovulatory granulosa cells is required for caspase-3 activation in a serum starvation model. Inhibition of caspase-3 activity can result in decreased expression of the steroidogenic proteins P450scc and StAR. Our work provides further details on the relationship between caspase-3 activation and steroidogenesis and indicates that caspase-3 plays a critical role in progesterone production by granulosa cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. A comparison of serum amyloid A (SAA) synthesis with that of the pentraxins: Serum amyloid P (SAP) and C-reactive protein (CRP)

    International Nuclear Information System (INIS)

    Tatsuta, E.; Shirahama, T.; Sipe, J.D.; Skinner, M.

    1986-01-01

    Serum amyloid A (SAA) and serum amyloid P (SAP) were detected in cultures of hepatocytes which had been isolated from normal CBA/J mice by the collagenase perfusion technique. SAP production in 24 h cultures was more resistant than SAA and total protein synthesis to inhibition by actinomycin D, but was more sensitive to inhibition by 48 h. However, the production of SAP was more sensitive to cycloheximide than SAA and total protein throughout the 48 hr incubation period. SAP and SAA levels in the culture media were suppressed by treatment of liver cells with 10 -6 M of colchicine for 48 h. Inhibition of SAP production by colchicine was the same regardless of culture condition, but the effect of colchicine on SAA synthesis varied according to the presence of serum of monokine. These observations also support the concept that the two amyloid proteins are produced under different regulatory mechanisms. When C-reactive protein (CRP) was not detected in the sera of patients with severe chronic liver diseases, the SAA levels were very low. When CRP was detected, SAA values were within the normal range. Thus, in order to produce SAA, liver cells in these patients not only were viable but also maintained their specialized function

  2. Urine and serum fetuin-A levels in patients with urolithiasis.

    Science.gov (United States)

    Arora, Rajat; Abrol, Nitin; Antonisamy, B; Vanitha, S; Chandrasingh, J; Kumar, Santosh; Kekre, Nitin; Devasia, Antony

    2017-01-01

    Fetuin-A is a glycoprotein secreted by liver and has been shown to inhibit extraosseous mineralization. Urolithiasis may be a manifestation in the urinary tract due to fetuin deficiency in urine. The objective of this study was to compare the 24-h urine and serum fetuin-A levels of patients with and without urolithiasis. Serum and 24-h urine fetuin-A levels were measured in 41 patients with bilateral, multiple, or recurrent urinary tract calculi (Group A) and 41 matched controls with no calculi (Group B). Fetuin levels were measured by enzyme linked immunosorbent assay. Serum and urine fetuin-A levels in the two groups were compared. The median (range) 24-h urine fetuin-A value in Group A was 11.9 (1.12-221) mg/day and in Group B was 37.7 (1.28-125) mg/day. This difference was statistically significant (Mann-Whitney test, P = 0.0169). The median (range) serum fetuin-A in Group A was 0.67 (0.05-2.68) g/L and in Group B was 0.99 (0.01-5.5) g/L. The difference between serum values in the two arms was not statistically significant (Mann-Whitney test, P = 0.1817). However, the serum creatinine-adjusted mean log serum fetuin and urine fetuin were significantly different in the two arms ( P = 0.003). The mean ± standard deviation (range) serum creatinine in Group A was 0.98 ± 0.25 (0.56-1.58) mg% and in Group B was 0.83 ± 0.16 (0.58-1.18) mg% (two sample t -test, P = 0.0031). Patients with urolithiasis have lower urine fetuin-A and creatinine-adjusted serum fetuin-A levels.

  3. Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

    Science.gov (United States)

    Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

    Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

  4. Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice

    DEFF Research Database (Denmark)

    Figeac, Florence; Andersen, Ditte C.; Nipper Nielsen, Casper A.

    2018-01-01

    /TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss....... resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E...

  5. Synthesis and anti-angiogenic effect of conjugates between serum albumin and non-steroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Kjær, Birgitte; Struve, Casper; Friis, Tina

    2010-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growth and angiogenesis. Covalent linkage of naproxen to human serum albumin (HSA) has been shown to target it efficiently to the liver and this may potentially be exploited for liver-selective inhibition of angiogenesis. With the aim...... effect on endothelial cells at or above the level of the non-conjugated NSAIDs in an in vitro angiogenesis assay....

  6. Serum lysozyme determinations, April-June 1961

    Energy Technology Data Exchange (ETDEWEB)

    Finch, S C; Lamphere, J P; Jablon, S

    1963-04-18

    Serum lysozyme levels were determined on 670 consecutive subjects seen for regularly scheduled clinic examinations of the Adult Health Study in Hiroshima. Serum lysozyme levels were found to vary significantly with the absolute peripheral granulocyte count, age, sex, and month of study. A high level of correlation also was noted between serum lysozyme and diabetes mellitus. This was at least in part attributable to greater average age in patients with diabetes. Suggestive relationship was established between serum lysozyme levels, respiratory diseases, and tuberculosis. These changes are believed to reflect active inflammation with excessive destruction of granulocytes and parenchymal tissues in those patients with the more acute processes. No relationship was found between serum lysozyme and previous exposure to ionizing radiation. These studies indicate that the serum lysozyme level may be useful in the study of the kinetics of leukopoiesis, the aging process, and in the detection of subtle inflammatory processes. 21 references, 5 tables.

  7. 125I Radioimmunoassay of serum ursodeoxycholyl conjugates

    International Nuclear Information System (INIS)

    Hill, A.; Ross, P.E.; Bouchier, I.A.D.

    1983-01-01

    A radioimmunoassay for serum ursodeoxycholic conjugates using an iodine-125 ligand has been developed. The bile acid was present in normal fasting serum (0.19 +- SD 0.19 μmol/l, n=24) and 2-hour post-prandial serum (0.8 +- SD 0.8 μmol/l, n=16). Gallstone patients undergoing oral ursodeoxycholic acid therapy had significantly higher post-prandial serum levels (21.5 +- SD 14.0 μmol/l, n=15) by radioimmunoassay. Gas liquid chromatography analysis indicated that in normal serum ursodeoxycholic acid was totally conjugated, whereas sera from gallstone patients contained a proportion as the free bile acid (10.2 +- SD 8.1 μmol/l, n=15). Following an oral dose of ursodeoxycholic acid, both unconjugated and conjugated forms of the bile acid appeared in the serum of healthy individuals. (Auth.)

  8. New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.

    Science.gov (United States)

    Bacalhau, Patrícia; San Juan, Amor A; Marques, Carolina S; Peixoto, Daniela; Goth, Albertino; Guarda, Cátia; Silva, Mara; Arantes, Sílvia; Caldeira, A Teresa; Martins, Rosário; Burke, Anthony J

    2016-08-01

    A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5μM for EeAChE and 153.8μM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4μM (EeAChE) and 277.8μM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. GC/MS analysis, antimicrobial and in vitro anti-cholinesterase activities of the essential oil from Buddleja asiatica

    Directory of Open Access Journals (Sweden)

    Farman Ali Khan

    2015-12-01

    Full Text Available Buddleja asiatica essential oil from the leaves by hydrodistillation was subjected to gas chromatography/mass spectrometery analysis which revealed the presence of 17 constituents out of which 14 were identified as: four monoterpenes hydrocarbons, four oxygenated monoterpenes, one hydrocarbon sesquiterpenes and five oxygenated sesquiterpenes. The major constituent being found was 1,8-cineole (38.1% while β-sinensal, 1, 10-seco-1-hydroxy-calamenen-10-one and α-phellandrene were found to be in 11.8%, 10.2% and 5.8%, respectively. The essential oil exhibited 66% strong antibacterial activity against Shigella boydii while in fungicidal assay, it revealed an outstanding 79% inhibition against Aspergillus flavus. The essential oil showed outstanding acetylcholinesterase (IC50 5.2 μM and butyrylcholinesterase inhibitory effect (IC50 27.9 μM as compared to standard drugs respectively.

  10. Radioimmunoassay of thyrotropin concentrated from serum

    International Nuclear Information System (INIS)

    Nisula, B.C.; Louvet, J.P.

    1978-01-01

    A method for concentrating human TSH (hTSH) from serum for use in RIAs is described. The method takes advantage of the affinity of the plant lectin, concanavalin A, for the carbohydrate portion of the hTSH molecule. The hTSH from 2.5 ml serum was adsorbed to concanavalin A covalently linked to sepharose and then radioimmunoassayed using the hTSH antiserum and hTSH for iodination distributed by the National Pituitary Agency. For the RIA standard curve, the hTSH reference preparation was concentrated from a serum wwith undetectable hTSH in order to correct for recovery and to control for nonspecific effects. The percentage of serum hTSH extracted from 2.5 ml serum with the concentration procedure was 76.6 +- 3.4% (mean +- SD). The coefficient of correlation between serum hTSH, determined with the concentration procedure, and serum hTSH determined without was 0.979 (P < 0.001). Over 95% of normal adult men and women had detectable levels of serum hTSH, ranging from < 0.56 to 4.0 μU/ml. The mean of detectable serum hTSH levels in normal adult women (n = 11) was 1.54 +- 1.03 μU/ml (mean +- SD) and in normal men (n = 9) was 2.02 +- 1.15 μU/ml (mean +- SD). Clinically hyperthyroid patients with diffuse and nodular toxic goiters (n = 8) and patients with hypothyroidism secondary to pituitary disease (n = 6), four of whom were taking replacement doses of thyroid hormone, had undetectable serum hTSH levels. Serum hTSH in patients with primary hypothyroidism uniformly exceeded the normal range. This hTSH concentrating procedure enhances the effective sensitivity and, therefore, the clinical utility of the RIA for hTSH in serum

  11. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  12. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  13. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Characterization of Serum Phospholipase A2 Activity in Three Diverse Species of West African Crocodiles

    Directory of Open Access Journals (Sweden)

    Mark Merchant

    2011-01-01

    Full Text Available Secretory phospholipase A2, an enzyme that exhibits substantial immunological activity, was measured in the serum of three species of diverse West African crocodiles. Incubation of different volumes of crocodile serum with bacteria labeled with a fluorescent fatty acid in the sn-2 position of membrane lipids resulted in a volume-dependent liberation of fluorescent probe. Serum from the Nile crocodile (Crocodylus niloticus exhibited slightly higher activity than that of the slender-snouted crocodile (Mecistops cataphractus and the African dwarf crocodile (Osteolaemus tetraspis. Product formation was inhibited by BPB, a specific PLA2 inhibitor, confirming that the activity was a direct result of the presence of serum PLA2. Kinetic analysis showed that C. niloticus serum produced product more rapidly than M. cataphractus or O. tetraspis. Serum from all three species exhibited temperature-dependent PLA2 activities but with slightly different thermal profiles. All three crocodilian species showed high levels of activity against eight different species of bacteria.

  15. Effect of alprostadil combined with conventional therapy on serum markers in patients with acute cerebral infarction

    Directory of Open Access Journals (Sweden)

    Li-Lan Chen

    2016-01-01

    Full Text Available Objective: To study the effect of alprostadil combined with conventional therapy on serum markers in patients with acute cerebral infarction. Methods: Patients with acute cerebral infarction treated in our hospital from May 2012 to August 2014 were enrolled and randomly divided into two groups. Observation group received alprostadil combined with conventional therapy and control group received conventional treatment. Then serum markers of both groups were compared. Results: (1 contents of serum nerve function related molecules: serum NSE and S100β contents of observation group showed a decreasing trend, and BDNF and NGF contents showed an increasing trend; (2 contents of atherosclerosis related enzymes: serum GGT, iNOS and MPO contents of observation group showed a decreasing trend, and PON1 and PON2 contents showed an increasing trend; (3 platelet activation related molecules: serum PPARγ, CD62p, YKL-40, sCD40L and Fibulin-5 contents of observation group all showed a decreasing trend. Conclusions: Alprostadil combined with conventional treatment is helpful to alleviate neuronal damage and inhibit the processes of atherosclerosis and platelet activation; it’s an ideal method for treating acute cerebral infarction.

  16. Effect of inflammatory serum of 14C-glucosamine incorporation into bone marrow granulocytes in vitro

    International Nuclear Information System (INIS)

    Evans, W.H.; Wilson, S.M.; Torres, A.R.; Peterson, E.A.; Mage, M.G.

    1979-01-01

    As a preliminary approach to developing a biochemical assay for detecting humoral regulators of granulocyte maturation in the normal and inglammatory states, studies were carried out on the effects of normal inflammatory sera on the incorporation of 14 C-glucosamine into the glycoproteins of bone marrow granulocytes in vitro. We observed that, relative to normal serum, inflammatory serum had a marked stimulatory effect on 14 C-glucosamine incorporation into these glycoproteins. This property of inflammatory serum reached a maximum at about 8 h after the initiation of inflammation in vivo and preceded the maximum increase in the mitotic activity of granulocyte precursors in the marrow by 18 h. It was also found that normal serum contains both dialyzable and heat-sensitive nondialyzable factors that inhibit 14 C-glucosamine incorporation into bone marrow granulocytes in vitro. Data are presented which indicate that the stimulatory effect of inflammatory serum is most likely due to a nondialyzable factor which is capable of blocking the effect of the inhibitors present in normal serum. (author)

  17. Serum lipids in hypothyroidism: Our experience

    OpenAIRE

    Prakash, Archana; Lal, Ashok Kumar

    2006-01-01

    In order to determine whether the screening of lipid profile is justified in patients with hypothyroidism we estimated serum lipids in cases having different levels of serum TSH. 60 patients of hypothyroidism in the age group of 20 to 60 yrs were studied for thyroid profile over a period of one year. On the basis of serum TSH level the cases were divided into three groups: In the first group TSH concentration was 8.8±2.99 μlU/ml, 95% confidence interval (Cl) 8.8±1.07, whereas serum total chol...

  18. Ultrasonographic diagnosis of fatty liver and relations with body index, serum lipid, and serum triglyceride

    International Nuclear Information System (INIS)

    Jang, Young Deog; Lee, S. H.; Lee, H. K.; Kim, D. H.; Kwon, K. H.; Kim, K. C.

    1989-01-01

    Hepatic fatty infiltration appears as an area of increased echogenicity. And many factors concerned to fatty infiltration. With 65 cases of fatty liver and 42 cases of normal group, we analyzed fatty liver with grading and attempt to find relations between grade of fatty liver and levels of body index, serum triglyceride, and serum lipid. And compared fatty liver with normal control group. Patients with fatty liver are higher percentage of supra-normal value in body index, serum lipid, and serum triglyceride than normal control group. As fatty infiltration progressed, serum lipid, serum trig-lyceride and body index are also increased. Conclusively ultrasonographic examination of liver with serum triglyceride, serum lipid, and body index are simple method, useful follow-up examination of fatty liver, and preventive routine check-up of chronic liver disease

  19. Bone mineralisation in premature infants cannot be predicted from serum alkaline phosphatase or serum phosphate

    DEFF Research Database (Denmark)

    Faerk, J; Peitersen, Birgit; Petersen, S

    2002-01-01

    BACKGROUND: The bone mineral content of premature infants at term is lower than in mature infants at the same postconceptional age. Serum alkaline phosphatase and serum phosphate are often used as indicators of bone mineralisation. OBJECTIVE: To analyse the association between bone mineral content...... content was measured at term (mean gestational age 41 weeks) by dual energy x ray absorptiometry and corrected for body size. RESULTS: Serum alkaline phosphatase was significantly negatively associated with serum phosphate (p mineral content was not associated with mean serum alkaline...... and serum alkaline phosphatase and serum phosphate. METHODS: Serum alkaline phosphatase and phosphate were measured at weekly intervals during admission in 108 premature infants of gestational age below 32 weeks (mean (SD) gestational age 29 (2) weeks; mean (SD) birth weight 1129 (279) g). Bone mineral...

  20. SARI BUAH MARKISA UNGU MENCEGAH PENINGKATAN MDA SERUM TIKUS DENGAN DIET ATEROGENIK

    Directory of Open Access Journals (Sweden)

    Inggita Kusumastuty

    2014-07-01

    Full Text Available Abstrak Markisa ungu merupakan buah tropis yang mengandung antioksidan antara lain vitamin A, vitamin C, β-karoten, komponen flavonoid dan fiber. Dalam 100 ml sari buah markisa ungu terdapat 1070 µg β-karoten. Pemberian sari buah markisa diduga dapat mencegah peningkatan MDA. Tujuan dari penelitian ini adalah untuk mengetahui pengaruh pemberian sari buah markisa ungu per oral terhadap pencegahan peningkatan kadar MDA serum. Desain penelitian ini adalah Post-test Control Group yang dilakukan pada 30 ekor tikus jantan. Kelompok I adalah tikus yang diberi pakan normal (P0, kelompok II diberi diet aterogenik (P1, kelompok III diberi diet aterogenik dan sari buah markisa ungu 2,3 ml (P2, kelompok IV diberi diet aterogenik dan sari buah markisa ungu 3,3 ml (P3 dan kelompok V diberi diet aterogenik dan sari buah markisa ungu 4,2 ml (P4. Pemberian sari buah markisa ungu dilakukan secara oral melalui sonde setiap hari selama 60 hari. Parameter yang diukur dalam penelitian ini adalah kadar MDA serum dengan spektrofotometer. Hasil penelitian menunjukkan terdapat pengaruh pemberian sari buah markisa ungu terhadap penghambatan  peningkatan kadar MDA serum (ANOVA, p=0.000. Uji Post Hoc Tukey menunjukkan ketiga dosis sari markisa ungu yang diberikan dapat mencegah peningkatan kadar MDA serum tikus wistar. Dosis ketiga yaitu 4,2 ml/ hari yang diberikan selama 60 hari bersamaan dengan diet aterogenik secara statistik dapat mengembalikan tikus pada kondisi normal (post hoc tuckey, p=0,115. Kata kunci : sari buah markisa ungu, kadar MDA serum, diet aterogenik   Abstract Purple passion fruit is the one of tropical fruits which is contain of antioxidans such as vitamin A, vitamin C, β-karoten, flavonoid and fiber. One hundred mililitres of purple passion fruit’s juice contain 1070 µg of β-karoten. Purple passion fruit’s juice has been predicted to  inhibit the increase of MDA. The aim of this study was to find the effects of purple passion fruit

  1. Inhibition by 2-deoxy-D-ribose of DNA synthesis and growth in Raji cells

    International Nuclear Information System (INIS)

    Ulrich, F.

    1988-01-01

    When Raji cells were cultured for 3 days in serum-free medium, addition of 2-deoxy-D-ribose at the start of culture inhibited incorporation of [ 3 H]thymidine and cell division. At deoxyribose concentrations between 1 and 5 mM, viability was 80% or greater after 3 days of culture even though 5 mM deoxyribose inhibited thymidine incorporation 95-99%. Inhibition by deoxyribose could be completely reversed if the culture medium was replaced with fresh medium up to 8 hr after the start of culture. The inhibition was specific for deoxyribose since other monosaccharides had no effect. Inhibition of DNA synthesis did not appear to be due to depletion of essential nutrients in the medium since the percentage inhibition of thymidine incorporation by cells cultured either in suboptimal serum-free media or in media supplemented with 0.025-5% human AB serum was similar. When DNA repair synthesis was measured as hydroxyurea-resistant thymidine incorporation, addition of deoxyribose to Raji cultures caused increased thymidine incorporation. These results, together with data from others,suggest that deoxyribose damages DNA

  2. Induction of calcification by serum depletion in cell culture: a model for focal calcification in aortas related to atherosclerosis

    Directory of Open Access Journals (Sweden)

    Villar Maria T

    2008-01-01

    Full Text Available Abstract Background Since aortic calcification has been shown to initiate in the lower zone of well-thickened plaques (LZP adjacent to the aortic media of rabbits fed supplemental cholesterol diets, a restricted supply of serum to vascular cells could play a role in vascular calcification. This study was designed to use a cell culture model to support this hypothesis. Results Rabbit aortic smooth muscle cells were grown to confluence in a culture media containing 10 % fetal bovine serum (FBS. The confluent cells were then exposed to the media for 2 hrs with or without serum at a Ca × P ion product range of 4.5–9.4 mM2. In contrast to the cells cultured in the presence of FBS, confluent cells in its absence displayed marked mineral-positive alizarin red staining and infrared absorption of mineral phosphate. A kinetic parameter C1/2 was used to designate the concentration of serum or its protein constituents needed to reduce the deposition of Ca and P by half. The C1/2 for FBS and rabbit serum was 0.04–0.07 % The C1/2 value for rabbit serum proteins was 13.5 μg/ml corresponding to the protein concentration in 0.06 % of serum. This C1/2 was markedly smaller than 86.2 μg/ml for bovine serum albumin present in 0.37 % serum (p Conclusion The aortic smooth muscle cell culture model suggests that serum depletion may play a role in the initiation of aortic calcification. The serum exhibits remarkable ability to inhibit cell-mediated calcification.

  3. Association of canine obesity with reduced serum levels of C-reactive protein.

    Science.gov (United States)

    Veiga, Angela P M; Price, Christopher A; de Oliveira, Simone T; Dos Santos, Andréa P; Campos, Rómulo; Barbosa, Patricia R; González, Félix H D

    2008-03-01

    The prevalence of obesity is increasing in dogs as well as in humans. C-reactive protein (CRP) is an important tool for the detection of inflammation and/or early tissue damage and is linked to obesity in humans. The objective of the present study was to determine if serum CRP levels are altered in obese dogs. Fifteen lean (control group) and 16 overweight (obese group) dogs were examined. Blood samples were collected under fasted conditions for serum determination of CRP, glucose, insulin, cholesterol, triglyceride, and fructosamine. Results indicated that obese dogs were insulin resistant because serum insulin and insulin/glucose ratios were higher than in lean dogs (P obese dogs than in controls (P obese group compared with the control group. Based on these results, it can be postulated that CRP production is inhibited by obesity and insulin resistance in dogs.

  4. Further characterization of serum alkaline phosphatase from male and female beagle dogs.

    Science.gov (United States)

    Amacher, D E; Higgins, C V; Schomaker, S J; Clay, R J

    1989-01-01

    Alkaline phosphatase (AP) from the sera of both male and female beagle dogs was partially purified and then analyzed for the presence of AP isoenzymes having intestinal or osseous characteristics as detected by bromotetramisole inhibition or wheat germ lectin agarose electrophoresis, respectively. The sera from both sexes were similar in regard to the presence of AP isoenzymes with intestinal (16 vs. 20%) or osseous (19 vs. 23%) characteristics, but serum AP from the male had a greater sialic acid content and only the male serum contained a detectable constitutive acidic (pI = 3.4) AP isoenzyme. This was similar to a serum AP isoenzyme previously found elevated in the sera of dogs afflicted with hyperadrenocorticalism or of dogs treated with certain corticosteroids.

  5. A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Wattmo C

    2013-03-01

    Full Text Available Carina Wattmo, Elisabeth Paulsson, Lennart Minthon, Elisabet LondosClinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, SwedenBackground: To investigate the long-term effects of cholinesterase inhibitor (ChEI therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS by patients with Alzheimer’s disease (AD.Methods: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL, and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.Results: During the study, 332 patients (38% used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.Conclusions: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.Keywords: cognition, activities of daily living, treatment effect, gender, predictors

  6. Qualitative and quantitative two-dimensional thin-layer chromatography/high performance liquid chromatography/diode-array/electrospray-ionization-time-of-flight mass spectrometry of cholinesterase inhibitors.

    Science.gov (United States)

    Mroczek, Tomasz

    2016-09-10

    Recently launched thin-layer chromatography-mass spectrometry (TLC-MS) interface enabling extraction of compounds directly from TLC plates into MS ion source was unusually extended into two-dimensional thin-layer chromatography/high performance liquid chromatography (2D, TLC/HPLC) system by its a direct connection to a rapid resolution 50×2.1mm, I.D. C18 column compartment followed by detection by diode array (DAD) and electrospray ionisation time-of-flight mass spectrometry (ESI-TOF-MS). In this way, even not separated bands of complicated mixtures of natural compounds could be analysed structurally, only within 1-2min after development of TLC plates. In comparison to typically applied TLC-MS interface, no ion suppression for acidic mobile phases was observed. Also, substantial increase in ESI-TOF-MS sensitivities and quality of spectra, were noticed. It has been utilised in combination with TLC- based bioautographic approaches of acetylcholinesterase (AChE) inhibitors, However, it can be also applied in any other procedures related to bioactivity (e.g. 2,2-Diphenyl-1-picryl-hydrazyl-DPPH screen test for radicals). This system has been also used for determination of half maximal inhibitory concentration (IC50 values) of the active inhibitor-galanthamine, as an example. Moreover, AChE inhibitory potencies of some of purified plant extracts, never studied before, have been quantitatively measured. This is first report of usage such the 2D TLC/HPLC/MS system both for qualitative and quantitative evaluation of cholinesterase inhibitors in biological matrices. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  8. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  9. Serum paraoxonase 1 activity in dogs

    DEFF Research Database (Denmark)

    Rossi, Gabriele; Giordano, Alessia; Pezzia, Francesca

    2013-01-01

    Serum activity of paraoxonase (PON1) decreases during inflammation in many species. Little information is available on paraoxon-based tests and the possible role of PON1 in dogs.......Serum activity of paraoxonase (PON1) decreases during inflammation in many species. Little information is available on paraoxon-based tests and the possible role of PON1 in dogs....

  10. Serum release boosts sweetness intensity in gels

    NARCIS (Netherlands)

    Sala, G.; Stieger, M.A.; Velde, van de F.

    2010-01-01

    This paper describes the effect of serum release on sweetness intensity in mixed whey protein isolate/gellan gum gels. The impact of gellan gum and sugar concentration on microstructure, permeability, serum release and large deformation properties of the gels was determined. With increasing gellan

  11. Serum testosterone concentration in chloroquine- treated rats ...

    African Journals Online (AJOL)

    ONOS

    2010-07-05

    Jul 5, 2010 ... The effects of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) were studied on serum testosterone ... chloroquine are probably mediated via the generation of free radicals. ... Effects of ascorbic acid and alpha-tocopherol on serum testosterone concentration in chloroquine-treated rats. Groups.

  12. Serum bicarbonate and dehydration severity in gastroenteritis

    OpenAIRE

    Narchi, H.

    1998-01-01

    The concentration of bicarbonate was measured in serum samples from 106 children with gastroenteritis and dehydration. A concentration less than 22 mmol/l was more common in children with severe dehydration, but the magnitude of bicarbonate reduction was not significantly different with increasing degrees of dehydration. Doctors should not rely on the serum bicarbonate concentration when assessing fluid deficit.



  13. Determination of serum IgD radioimmunoassay

    International Nuclear Information System (INIS)

    Fayol, V.; Hartmann, D.J.; Sabbagh, I.; Ville, G.

    1986-01-01

    We describe a sensitive liquid phase radioimmunoassay for serum IgD. Extreme values obtained from 85 control patients sera are 0.2 and 121 mg/l with an arithmetic mean of 25 mg/l. In atopic patients (with high serum IgE levels), arithmetic mean is 47 mg/l [fr

  14. Determination of serum IgD radioimmunoassay

    Energy Technology Data Exchange (ETDEWEB)

    Fayol, V.; Hartmann, D.J.; Sabbagh, I.; Ville, G.

    1986-01-01

    We describe a sensitive liquid phase radioimmunoassay for serum IgD. Extreme values obtained from 85 control patients sera are 0.2 and 121 mg/l with an arithmetic mean of 25 mg/l. In atopic patients (with high serum IgE levels), arithmetic mean is 47 mg/l.

  15. Serum lipids in hypothyroidism: Our experience.

    Science.gov (United States)

    Prakash, Archana; Lal, Ashok Kumar

    2006-09-01

    In order to determine whether the screening of lipid profile is justified in patients with hypothyroidism we estimated serum lipids in cases having different levels of serum TSH. 60 patients of hypothyroidism in the age group of 20 to 60 yrs were studied for thyroid profile over a period of one year. On the basis of serum TSH level the cases were divided into three groups: In the first group TSH concentration was 8.8±2.99 μlU/ml, 95% confidence interval (Cl) 8.8±1.07, whereas serum total cholesterol and LDL-chol levels were 196±37.22 and 126±29.17 mg/dl respectively. The statistical analysis of these two groups showed a significant correlation between raised TSH levels and serum total cholesterol and LDL-chol (Phypothyrodism is associated with changes in lipid profile.

  16. Immunoradiometric assay for quantification of serum antibodies to dental plaque antigen in immunized dogs

    International Nuclear Information System (INIS)

    Ahlstedt, S.; Rylander, H.

    1975-01-01

    An immunoradiometric assay (IRMA) was used for quantifying dog serum antibodies to antigens from dental plaque collected from full-grown dogs. The antigens were adsorbed onto the inner surface of plastic tubes and then incubated with dog-anti-plaque serum, 125 I-labelled anti-dog plasma-immunoglobulin was used for quantification of the specific antibodies. Four 10 months old Beagle dogs in excellent gingival health were immunized for 10 weeks with ultrasonicated dog dental plaque. The antibody levels in antisera sampled 6, 8, 10 and 11 weeks after the first antigen injection were 2 to 5 times as high as those recorded before the immunizing period. The variability of the assay as judged from the difference between duplicate samples was found to be 18 percent+-4 (p<0.01) of the mean value and the variability between the same serum ran on different test occasions 13 percent+-7 (p<0.01). The specificity of the antigen-antibody reaction in the immuno assay was tested by inhibition experiments. Preincubation of the antisera with dental plaque antigen significantly inhibited the antigen-antibody reaction in the IRMA, while bovine serum albumin did not. (author)

  17. Immunoradiometric assay for quantification of serum antibodies to dental plaque antigen in immunized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Ahlstedt, S; Rylander, H [Goeteborg Univ. (Sweden)

    1975-01-01

    An immunoradiometric assay (IRMA) was used for quantifying dog serum antibodies to antigens from dental plaque collected from full-grown dogs. The antigens were adsorbed onto the inner surface of plastic tubes and then incubated with dog-anti-plaque serum, /sup 125/I-labelled anti-dog plasma-immunoglobulin was used for quantification of the specific antibodies. Four 10 months old Beagle dogs in excellent gingival health were immunized for 10 weeks with ultrasonicated dog dental plaque. The antibody levels in antisera sampled 6, 8, 10 and 11 weeks after the first antigen injection were 2 to 5 times as high as those recorded before the immunizing period. The variability of the assay as judged from the difference between duplicate samples was found to be 18 percent+-4 (p<0.01) of the mean value and the variability between the same serum ran on different test occasions 13 percent+-7 (p<0.01). The specificity of the antigen-antibody reaction in the immuno assay was tested by inhibition experiments. Preincubation of the antisera with dental plaque antigen significantly inhibited the antigen-antibody reaction in the IRMA, while bovine serum albumin did not.

  18. Brain regional acetylcholinesterase activity and muscarinic acetylcholine receptors in rats after repeated administration of cholinesterase inhibitors and its withdrawal

    International Nuclear Information System (INIS)

    Kobayashi, Haruo; Suzuki, Tadahiko; Sakamoto, Maki; Hashimoto, Wataru; Kashiwada, Keiko; Sato, Itaru; Akahori, Fumiaki; Satoh, Tetsuo

    2007-01-01

    Activity of acetylcholinesterase (AChE) and specific binding of [ 3 H]quinuclidinyl benzilate (QNB), [ 3 H]pirenzepine (PZP) and [ 3 H]AF-DX 384 to muscarinic acetylcholine receptor (mAChR) preparations in the striatum, hippocampus and cortex of rats were determined 1, 6 and 11 days after the last treatment with an organophosphate DDVP, a carbamate propoxur or a muscarinic agonist oxotremorine as a reference for 7 and 14 days. AChE activity was markedly decreased in the three regions 1 day after the treatment with DDVP for 7 and 14 days with a gradual recovery 6 to 11 days, and much less decreased 1, 6 and 11 days after the treatment with propoxur for 7 days but not for 14 days in the hippocampus and cortex. The binding of [ 3 H]-QNB, PZP and AF-DX 384 in the three regions was generally decreased by the treatment with DDVP for 7 and 14 days. Such down-regulations were generally restored 6 or 11 days after the treatment for 7 but not for 14 days. The down-regulation or up-regulation as measured by [ 3 H]-QNB, PZP and AF-DX 384 was observed 1, 6 or 11 days after treatment with propoxur for 7 days and/or 14 days. Repeated treatment with oxotremorine produced similar effects except AChE activity to DDVP. These results suggest that repeated inhibition of AChE activity may usually cause down-regulation of mAChRs with some exception in the hippocampus when a reversible antiChE propoxur is injected

  19. Serum gonadotropins levels in childhood

    International Nuclear Information System (INIS)

    Hertogh, R. De; Vankrieken, L.; Wolter, R.; Vliet, G. Van

    1989-01-01

    The complex changes in serum LH and FSH levels from infancy to adulthood are diversely evaluated by radioimmunoassays or bioassays. The relative lack of sensitivity and specificity of radioimmunoassay, using polyclonal antibodies, could possibly be overcome by new immunoradiometric assays, using specific antibodies to LH and FSH. Significant differences were indeed observed between radioimmunoassays and immunoradiometric assays. During the prepubertal period, LH levels, measured by the immunoradiometric assays, were below the sensitivity of the method in the majority of the samples. LH levels were, however, well detectable when measured with radioimmunoassay, showing the heterogeneity of circulating LH structures. At the onset of puberty, LH levels increased at least 3 to 4 times in both sexes, when measured with immunoradiometric assays, whereas their increase was only 20 to 60% with the radioimmunoassays. FSH levels remained well detectable in the prepubertal period whether measured by immunoradiometric or radioimmunoassays. At pubertal onset, FSH increase in both sexes was more important in the immunoradiometric assays. The results obtained with immunoradiometric assays give a better insight into the quantitative and qualitative function of the gonadotropes during childhood. The almost complete absence of LH during the prepubertal period and the steep increase at the onset of puberty better reflects the reported data obtained with bioassays. The persistance of significant levels of FSH in the prepubertal ages, and the lesser increase at the onset of puberty, when compared with LH, illustrates that the individual regulation of LH and FSH secretion vary over time and is influenced by developmental factors. (author)

  20. Correlation of Serum Magnesium with Serum Parathormone Levels in Patients on Regular Hemodialysis

    Directory of Open Access Journals (Sweden)

    Baradaran Azar

    2006-01-01

    Full Text Available Secondary hyperparathyroidism (SHPT is a common, important, and treatable complication of end-stage renal disease. This study was conducted to investigate the role of serum magnesium (Mg in regulating the secretion of parathyroid hormone (PTH by the parathyroid gland in patients on maintenance hemodialysis (HD. Pre-dialysis serum levels of calcium (Ca, phosphorus (P, Mg, alkaline phosphatase (ALP, intact serum PTH (iPTH, serum 25-hydroxy Vitamin D (25-OH Vit D and plasma bicarbonate (HCO3 were measured. The Urea Reduction Rate as well as duration and dosage of HD treatment were noted. Our study did not show any significant correlation between serum Mg levels and duration of HD treatment, levels of serum ALP, and plasma HCO3, Ca and P. An inverse correlation, albeit insignificant, was found between the serum Mg levels and iPTH (r=-0.30 p=0.079; also, a significant positive correlation was found between serum Mg levels and serum 25-OH Vit D levels (r= 0.40 p= 0.009. Our findings are in agreement with previous data, which suggest that factors other than serum Mg are more important in the regulation of PTH secretion in HD patients. A positive and strong association between serum Mg with 25-OH Vit D needs to be studied in greater detail.

  1. Serum lipoproteins attenuate macrophage activation and Toll-Like Receptor stimulation by bacterial lipoproteins

    Directory of Open Access Journals (Sweden)

    James Richard W

    2010-09-01

    Full Text Available Abstract Background Chlamydia trachomatis was previously shown to express a lipoprotein, the macrophage infectivity potentiator (Mip, exposed at the bacterial surface, and able to stimulate human primary monocytes/macrophages through Toll Like Receptor (TLR2/TLR1/TLR6, and CD14. In PMA-differentiated THP-1 cells the proinflammatory activity of Mip was significantly higher in the absence than in the presence of serum. The present study aims to investigate the ability of different serum factors to attenuate Mip proinflammatory activity in PMA-differentiated THP-1 cells and in primary human differentiated macrophages. The study was also extend to another lipoprotein, the Borrelia burgdorferi outer surface protein (OspA. The proinflammatory activity was studied through Tumor Necrosis Factor alpha (TNF-α and Interleukin (IL-8 release. Finally, TLR1/2 human embryonic kidney-293 (HEK-293 transfected cells were used to test the ability of the serum factors to inhibit Mip and OspA proinflammatory activity. Results In the absence of any serum and in the presence of 10% delipidated FBS, production of Mip-induced TNF-α and IL-8 in PMA-differentiated THP-1 cells were similar whereas they were significantly decreased in the presence of 10% FBS suggesting an inhibiting role of lipids present in FBS. In the presence of 10% human serum, the concentrations of TNF-α and IL-8 were 2 to 5 times lower than in the presence of 10% FBS suggesting the presence of more potent inhibitor(s in human serum than in FBS. Similar results were obtained in primary human differentiated macrophages. Different lipid components of human serum were then tested (total lipoproteins, HDL, LDL, VLDL, triglyceride emulsion, apolipoprotein (apoA-I, B, E2, and E3. The most efficient inhibitors were LDL, VLDL, and apoB that reduced the mean concentration of TNF-α release in Mip-induced macrophages to 24, 20, and 2%, respectively (p Conclusions These results demonstrated the ability of

  2. Radioimmunoassay of serum d-Norgestrel in women following oral and intravaginal administration

    International Nuclear Information System (INIS)

    Stanczyk, F.Z.; Hiroi, M.; Goebelsmann, U.; Brenner, P.F.; Lumkin, M.E.; Mishell, D.R. Jr.

    1975-01-01

    A radioimmunoassay (RIA) method for measuring d-Norgestrel (d-Ng) in serum has been developed utilizing petroleum ether extraction, an antiserum raised against d-Norgestrel-3-(0-carboxymethyl) oxime-epsilon-aminocaproic acid--boxine serum albumin, d-Norgestrel-3-(0-carboxymethyl) imino-[ 125 I]-iodohistamine, and dextran-coated charcoal separation. Control serum blanks were undetectable, 6 pg of d-Ng was measurable in 0.1 ml of serum with a high reliability, and intra- and interassay coefficients of variation were 4.4 and 4.9 percent, respectively. d-Ng added to control serum was quantitatively recovered. This RIA proved to be highly specific for d-Ng, cross-reacting less than 0.01 percent with 1-Ng and some 4 to 8 percent with 5α- and 5β-tetrahydro-d-Ng. Serum d-Ng levels measured in 3 women after ingestion of 75 μg of dl-Ng rose to 1.5 to 2 ng/ml within 1/2 to 2-3 hours after oral intake and fell rapidly thereafter to 0.2 to 0.4 ng/ml within 24 hours. Insertion of Silastic intravaginal rings (IVRs), containing 50 or 100 mg of dl-Ng, into 3 women for periods of 3 weeks resulted in a rapid rise of serum d-Ng after insertion. Serum d-Ng levels were highest 24 to 48 hours after the first insertion of each IVR, reaching peak levels of about 5 and 7 to 11 ng/ml, respectively, and declined gradually during the ensuing 15 to 20 days to some 30 to 40 percent of the peak serum d-Ng concentration. Serum d-Ng levels attained after IVR reinsertion remained relatively constant at 1 to 3 ng/ml during each subsequent cycle in all subjects and fell rapidly after each IVR removal. Serum estradiol and progesterone concentrations, measured about 3 times a week in these patients, indicated that ovulation was consistently inhibited

  3. Serum gastrin level in pregnancy running a normal course

    Energy Technology Data Exchange (ETDEWEB)

    Milev, N; Todorov, G; Pumpalov, A; Ignatov, A [Meditsinska Akademiya, Sofia (Bulgaria). Nauchen Inst. po Rentgenologiya i Radiobiologiya

    1982-01-01

    The serum gastrin level (SGL) is studied in dynamics during each lunar month of pregnancy in order to accumulate data which may serve the purpose of a tentative standard for serum gastrin level in this peculiar physiologic condition. A group of 110 pregnant women with a normal development of pregnancy, as documented by the clinical and paraclinical examination, are covered by the study. Blood samples are taken before meal, and a radioimmunologic method is used for SGL assessment. The number of women analyzed and the mean age by lunar months are shown. The normal value established in nonpregnant women of the same age group is 28+-7 mg/ml, relative to which the average values during the first five i.m. do not show statistically significant differences. During the 6th l.m. SGL increases to 68.5 mg/ml, while after the 7th l.m. values are recorded exceeding 1aa mg/ml with a maximum observed in the 8th and 9th l.m. The mechanisms eventually involved in the occurrence of gastrinemia during the second half of pregnancy are discussed, e.g. 1/mechanical compression of the stomach by the progressively growing uterus, 2/decreased breakdown, inhibition and elimimation of the hormone by the kidneys, and 3/possible correlative dependence between changes in SGL and changes in the level of hormones playing a predominant role in the hormonal status after the fifth month of pregnancy.

  4. QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites.

    Science.gov (United States)

    Correa-Basurto, J; Bello, M; Rosales-Hernández, M C; Hernández-Rodríguez, M; Nicolás-Vázquez, I; Rojo-Domínguez, A; Trujillo-Ferrara, J G; Miranda, René; Flores-Sandoval, C A

    2014-02-25

    A set of 84 known N-aryl-monosubstituted derivatives (42 amides: series 1 and 2, and 42 imides: series 3 an 4, from maleic and succinic anhydrides, respectively) that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesterase (ChEs) was considered for Quantitative structure-activity relationship (QSAR) studies. These QSAR studies employed docking data from both ChEs that were previously submitted to molecular dynamics (MD) simulations. Donepezil and galanthamine stereoisomers were included to analyze their quantum mechanics properties and for validating the docking procedure. Quantum parameters such as frontier orbital energies, dipole moment, molecular volume, atomic charges, bond length and reactivity parameters were measured, as well as partition coefficients, molar refractivity and polarizability were also analyzed. In order to evaluate the obtained equations, four compounds: 1a (4-oxo-4-(phenylamino)butanoic acid), 2a ((2Z)-4-oxo-4-(phenylamino)but-2-enoic acid), 3a (2-phenylcyclopentane-1,3-dione) and 4a (2-phenylcyclopent-4-ene-1,3-dione) were employed as independent data set, using only equations with r(m(test))²>0.5. It was observed that residual values gave low value in almost all series, excepting in series 1 for compounds 3a and 4a, and in series 4 for compounds 1a, 2a and 3a, giving a low value for 4a. Consequently, equations seems to be specific according to the structure of the evaluated compound, that means, series 1 fits better for compound 1a, series 3 or 4 fits better for compounds 3a or 4a. Same behavior was observed in the butyrylcholinesterase (BChE). Therefore, obtained equations in this QSAR study could be employed to calculate the inhibition constant (Ki) value for compounds having a similar structure as N-aryl derivatives described here. The QSAR study showed that bond lengths, molecular electrostatic potential and frontier orbital energies are important in both ChE targets. Docking studies revealed that

  5. Serum homocystein level in patients with scleroderma.

    Science.gov (United States)

    Nazarinia, Mohammadali; Shams, Mesbah; Kamali Sarvestani, Eskandar; Shenavande, Saeede; Khademalhosseini, Maryam; Khademalhosseini, Zeinab

    2013-01-01

    Systemic Sclerosis (SSc) is a systemic connective tissue disease. In this study, we compared the serum Homocystein (Hcy) level between patients with SSc and normal control group. The current study was conducted to determine whether serum Hcy levels are elevated in SSc patients and whether there is any correlation between Hcy levels and RP, Gastro intestinal and lung involvement. Forty one patients who fulfilled the diagnostic criteria for SSc (39 females and 5 males) and Forty four community-based healthy individuals (sex and age matched) were enrolled in to the study. Serum Hcy, vitamin B12, and folate levels were determined. Thirty three patients (70.45%) had GI involvement, twenty two patients (50%) had lung involvement and twenty seven patients (61.36%) had Raynaud's phenomena. Mean serum Hcy level in control group was 22.78 ± 6.018 μmol/L and in case group was 19.43 ± 7.205 μmol/L, shows that the serum Hcy level in control group was significantly higher than patients (P = 0.020). Serum Hcy level is significantly lower in SSc patients than in control group. There is no statistically significant correlation between serum Hcy level and organ involvements.

  6. [Serum glycosaminoglycans in Graves' disease patients].

    Science.gov (United States)

    Winsz-Szczotka, Katarzyna B; Olczyk, Krystyna Z; Koźma, Ewa M; Komosińska-Vassev, Katarzyna B; Wisowski, Grzegorz R; Marcisz, Czesław

    2006-01-01

    The aim of the study was to determine the blood serum sulfated glycosaminoglycans (GAGs) and hyaluronic acid (HA) concentration of Graves' disease patients before treatment and after attainment of the euthyroid state. The study was carried out on the blood serum obtained from 17 patients with newly recognised Graves' disease and from the same patients after attainment of the euthyroid state. Graves' patients had not any clinical symptoms neither of ophthalmopathy nor pretibial myxedema. GAGs were isolated from the blood serum by the multistage extraction and purification using papaine hydrolysis, alkali elimination, as well as cetylpyridium chloride binding. Total amount of GAGs was quantified by the hexuronic acids assay. HA content in obtained GAGs sample was evaluated by the ELISA method. Increased serum concentration of sulfated GAGs in non-treated Graves' disease patients was found. Similarly, serum HA level in untreated patients was significantly elevated. The attainment of euthyroid state was accompanied by the decreased serum sulfated GAGs level and by normalization of serum HA concentration. In conclusion, the results obtained demonstrate that the alterations of GAGs metabolism connected with Graves' disease can lead to systemic changes of the extracellular matrix properties.

  7. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  8. Interferon-γ Inhibits Ebola Virus Infection.

    Science.gov (United States)

    Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

    2015-01-01

    Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  9. Acetylcholinesterase inhibition and locomotor function after motor-sensory cortex impact injury.

    Science.gov (United States)

    Holschneider, Daniel P; Guo, Yumei; Roch, Margareth; Norman, Keith M; Scremin, Oscar U

    2011-09-01

    Traumatic brain injury (TBI) induces transient or persistent dysfunction of gait and balance. Enhancement of cholinergic transmission has been reported to accelerate recovery of cognitive function after TBI, but the effects of this intervention on locomotor activity remain largely unexplored. The hypothesis that enhancement of cholinergic function by inhibition of acetylcholinesterase (AChE) improves locomotion following TBI was tested in Sprague-Dawley male rats after a unilateral controlled cortical impact (CCI) injury of the motor-sensory cortex. Locomotion was tested by time to fall on the constant speed and accelerating Rotarod, placement errors and time to cross while walking through a horizontal ladder, activity monitoring in the home cages, and rearing behavior. Assessments were performed the 1st and 2nd day and the 1st, 2nd, and 3rd week after TBI. The AChE inhibitor physostigmine hemisulfate (PHY) was administered continuously via osmotic minipumps implanted subcutaneously at the rates of 1.6-12.8 μmol/kg/day. All measures of locomotion were impaired by TBI and recovered to initial levels between 1 and 3 weeks post-TBI, with the exception of the maximum speed achievable on the accelerating Rotarod, as well as rearing in the open field. PHY improved performance in the accelerating Rotarod at 1.6 and 3.2 μmol/kg/day (AChE activity 95 and 78% of control, respectively), however, higher doses induced progressive deterioration. No effect or worsening of outcomes was observed at all PHY doses for home cage activity, rearing, and horizontal ladder walking. Potential benefits of cholinesterase inhibition on locomotor function have to be weighed against the evidence of the narrow range of useful doses.

  10. In vitro evaluation of the effect of botanical formulations used in the control of Aedes aegypti L. (Diptera: Culicidae on liver enzymes.

    Directory of Open Access Journals (Sweden)

    Karla Rejane de Andrade Porto

    Full Text Available Abstract: INTRODUCTION: Dengue fever is a viral disease transmitted by the Aedes aegypti Linn. (1792 (Diptera: Culicidae mosquito, which is endemic in several regions of Brazil. Alternative methods for the control of the vector include botanical insecticides, which offer advantages such as lower environmental contamination levels and less likelihood of resistant populations. Thus, in this study, the ability of botanical insecticide formulations to inhibit the activity of the liver enzymes serum cholinesterase and malate dehydrogenase was evaluated. METHODS: Inhibition profiles were assessed using in vitro assays for cholinesterase and malate dehydrogenase activity and quantitated by ultraviolet-visible spectroscopy at 410nm to 340nm. RESULTS Insecticide products formulated from cashew nutshell liquid [A] and ricinoleic acid [B] showed cholinesterase activity levels of 6.26IU/mL and 6.61IU/mL, respectively, while the control level for cholinesterase was 5-12IU/mL. The products did not affect the level of 0.44IU/mL established for malate dehydrogenase, as the levels produced by [A] and [B] were 0.43IU/mL and 0.45IU/mL, respectively. CONCLUSIONS Our findings show that in vitro testing of the formulated products at concentrations lethal to A. aegypti did not affect the activity of cholinesterase and malate dehydrogenase, indicating the safety of these products.

  11. In vitro evaluation of the effect of botanical formulations used in the control of Aedes aegypti L. (Diptera: Culicidae) on liver enzymes.

    Science.gov (United States)

    Porto, Karla Rejane de Andrade; Motti, Priscilla Rezende; Machado, Alexandre Alves; Roel, Antonia Railda

    2016-01-01

    Dengue fever is a viral disease transmitted by the Aedes aegypti Linn. (1792) (Diptera: Culicidae) mosquito, which is endemic in several regions of Brazil. Alternative methods for the control of the vector include botanical insecticides, which offer advantages such as lower environmental contamination levels and less likelihood of resistant populations. Thus, in this study, the ability of botanical insecticide formulations to inhibit the activity of the liver enzymes serum cholinesterase and malate dehydrogenase was evaluated. Inhibition profiles were assessed using in vitro assays for cholinesterase and malate dehydrogenase activity and quantitated by ultraviolet-visible spectroscopy at 410nm to 340nm. Insecticide products formulated from cashew nutshell liquid [A] and ricinoleic acid [B] showed cholinesterase activity levels of 6.26IU/mL and 6.61IU/mL, respectively, while the control level for cholinesterase was 5-12IU/mL. The products did not affect the level of 0.44IU/mL established for malate dehydrogenase, as the levels produced by [A] and [B] were 0.43IU/mL and 0.45IU/mL, respectively. Our findings show that in vitro testing of the formulated products at concentrations lethal to A. aegypti did not affect the activity of cholinesterase and malate dehydrogenase, indicating the safety of these products.

  12. Soluble serum Klotho levels in healthy subjects

    DEFF Research Database (Denmark)

    Pedersen, Lise Mariager; Pedersen, Susanne Møller; Brasen, Claus Lohman

    2013-01-01

    Klotho concentrations were determined in 120 healthy adults aged 19-66years. Blood samples were collected, and stored sera were assayed for Klotho according to age and gender. In addition several other clinical and laboratory characteristics were determined in the cohort and compared to the levels...... genders. Concentrations of serum Klotho were independently associated with estimated glomerular filtration rate (eGFR) and body weight using TRF whereas serum Klotho concentrations were associated with age using the ELISA. CONCLUSION: Comparison of two different immunoassays for serum Klotho indicate...

  13. Modeling Serum Creatinine in Septic ICU Patients

    DEFF Research Database (Denmark)

    De Gaetano, Andrea; Cortese, Giuliana; Pedersen, Morten Gram

    2004-01-01

    Serum creatinine is a metabolite assumed to be constantly produced by the normally functioning muscle mass and is a good measure for monitoring daily renal function in the intensive care unit (ICU). High serum creatinine levels or an abnormal departure from normal pre-disease basal levels....... The present work details the structure of a model describing observed creatinine serum concentration (CSC) variations, depending on the time-varying septic insult to renal function in ICU patients, as well as the estimation of its parameters. CSC determinations were routinely obtained from 12 patients...

  14. Leptin in first trimester pregnancy serum

    DEFF Research Database (Denmark)

    Hedley, Paula; Pihl, Kasper; Krebs, Lone

    2009-01-01

    and its relation to fetal growth disturbances were examined in this study. The study is a case-control study with 36 small-for-gestational-age (SGA) (pregnancies and 108 appropriate-for-gestational-age (AGA) (> or =5th percentile) pregnancies. The groups were matched by maternal age...... maternal BMI. There was no significant difference in maternal serum leptin concentrations between SGA and AGA pregnancies. In conclusion, SGA pregnancies are not associated with a lower maternal serum leptin concentration in first trimester. The maternal serum leptin concentration is largely determined...

  15. Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs.

    Science.gov (United States)

    King, J N; Christinaz, C; Strehlau, G; Hornfeld, J

    2018-06-01

    To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5-1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25-0.5 mg/kg benazepril BID); D (0.25-0.5 mg/kg benazepril and 0.125-0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25-0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5-1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan. © 2018 John Wiley & Sons Ltd.

  16. [Patients with functional hypothalamic amenorrhea are characterized by low serum inhibin B concentrations].

    Science.gov (United States)

    Podfigurna-Stopa, Agnieszka; Luisi, Stefano; Lazzeri, Lucia; Ciani, Valentina; Meczekalski, Błazej; Petraglia, Felice

    2010-05-01

    Functional hypothalamic disturbances may be the cause of secondary amenorrhea and are related to aberration in both the pattern of pulsatility and amplitude in the release of gonadotropin-releasing hormone (GnRH) in hypothalamus. Inhibin B, as an ovarian peptide plays a crucial role in reproduction function throughout regulation of folliculotropin (FSH) pituitary production and inhibiting GnRH secretion during the menstrual cycle. To measure and estimate serum inhibin B concentration in patients with functional hypothalamic amenorrhea. Material and methods. The study included 41 women suffering from functional hypothalamic amenorrhea. Secondary amenorrhea was defined as the lack of menstruation lasting at least 90 days not due to pregnancy, characterized by low serum concentrations of lutropin (LH < 5 mIU/ml)) and typical for functional hypothalamic disturbances anamnestic investigation. The control group consists of 40 healthy women with normal menstrual cycles and Body Mass Index (BMI between 18.5- 24.9 kg/m2). Medical history, examination and laboratory analysis of LH, FSH, estradiol (E), prolactin, testosterone and inhibin B were performed (ELISA--enzyme-linked immunosorbent assay). There are statistically lower serum inhibin B, FSH, LH, estradiol and prolactin concentrations in patients with functional hypothalamic amenorrhea in comparison to healthy women. Positive correlation between serum concentration of inhibin B and estradiol concentration was found in patients with functional hypothalamic amenorrhea. Patients with functional hypothalamic amenorrhea are characterized by statistical significant decrease in serum inhibin B concentration in comparison to the control group.

  17. Membrane potential, serum calcium and serum selenium decrease in preeclampsia subjects in Owerri

    Directory of Open Access Journals (Sweden)

    Johnkennedy Nnodim

    2017-08-01

    Full Text Available Background Pre-eclampsia is a serious hypertensive condition of pregnancy associated with high maternal and fetal morbidity and mortality. Women who have had pre-eclampsia have a greater risk of developing hypertension, stroke and ischemic heart disease in later life. The etiology of pre-eclampsia remains unclear. Placental insufficiency plays a key role in the progression of this disease. The aim of this study was to determine membrane potential, serum calcium and serum selenium levels in preeclampsia subjects in Owerri.   Methods A case control study involving 200 primigravida (100 preeclamptic and 100 apparently healthy between the ages of 20 and 32 years attending General Hospital Owerri. Fasting venous blood was collected for the determination of serum selenium and serum calcium while membrane potential was calculated using the Nernst equation. The serum calcium was estimated using Randox Kit and serum selenium by atomic absorption spectrophotometry. The Independent Student t test was used for statistical analysis.   Results The results revealed that membrane potential and serum selenium as well as serum calcium were significantly decreased in preeclampsia when compared with the controls, at p<0.05.   Conclusion Our study demonstrated that the decrease in membrane potential, serum calcium and serum selenium levels may play a critical role in the pathogenesis of pre-eclampsia. There may be a need for increasing the dietary intake of these essential trace metals during pregnancy to prevent pre-eclampsia in Owerri.

  18. Coptis chinensis Polysaccharides Inhibit Advanced Glycation End Product Formation.

    Science.gov (United States)

    Yang, Ye; Li, Yun; Yin, Dengke; Chen, Song; Gao, Xiangdong

    2016-06-01

    Coptis chinensis Franch (Huanglian) is commonly used to treat diabetes in China. In this study, the effects of the C. chinensis Franch polysaccharides (CCP) on advanced glycation end product (AGE) formation in vitro and in streptozotocin-induced diabetic mice were investigated. CCP significantly inhibited all the three periods of nonenzymatic protein glycation in vitro, including Amadori product, dicarbonyl compound, and AGE formation (P < .01). In diabetic mice, the administration of CCP not only improved both bodyweight and serum insulin and decreased fasting blood glucose and glycated serum protein concentrations but also decreased the AGE accumulations and morphological abnormalities in pancreas and liver. The inhibitory effects of CCP on AGE formation afford a potential therapeutic use in the prevention and treatment of diabetes.

  19. Radioisotopic 51Cr-leukocyte adherence inhibition (LAI) assay. I

    International Nuclear Information System (INIS)

    Tsang, P.H.; Tangnavarad, K.; Lesnick, G.; Holland, J.F.; Bekesi, J.G.; Perloff, M.

    1980-01-01

    A simplified radioisotopic leukocyte adherence inhibition assay ( 51 Cr-LAI assay) was used to determine tumor-directed immune responses in patients with cancer of the breast. Essential steps in development of this assay are the standardization of conditions for optimal 51 Cr uptake by peripheral blood lymphocytes (PBL) and the inclusion of autologous or normal AB serum in the incubation media. A dextrose salt mixture (GNK) was found to enhance intracellular uptake of 51 Cr significantly (8-fold) without affecting viability of the cells or without causing selective loss of lymphocyte subpopulations. The presence of 10% autologous or normal AB serum prevented non-specific LAI responses to unrelated tumor antigens. Experimental results are presented and it is seen that this short term (4 h) 51 Cr-LAI assay provides reproducible and specific results analogous to those using tube-LAI assay. The test has the advantages of being accurate, sensitive and free from technical bias. (Auth.)

  20. Maternal serum leptin concentration in gestational diabetes

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    Sedigheh Soheilykhah

    2011-06-01

    Conclusion: Our data showed that serum leptin level was higher in GDM and had a positive correlation with insulin resistance. Our findings suggest that high leptin levels might be a risk factor for GDM and IGT in pregnant women.

  1. Autologous serum therapy in chronic urticaria

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    Sharmila Patil

    2013-01-01

    Full Text Available Autologous serum therapy is a promising therapy for treatment resistant urticaria. This is useful in developing countries as this is economical option. Minimum instruments like centrifuge, syringe and needles are required for the procedure.

  2. METABOLITE CHARACTERIZATION IN SERUM SAMPLES FROM ...

    African Journals Online (AJOL)

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    Metabonomics offers a distinct advantage over other tests as it can be ... Metabolic profiling in heart disease has also been successfully ... resonances of the small metabolites showing fingerprints of serum metabolomic profile (Figure. 3).

  3. Relationship between some serum electrolytes and ...

    African Journals Online (AJOL)

    ADEYEYE

    2014-02-03

    Feb 3, 2014 ... The effect of Trypanosoma brucei infection on changes in concentration of some serum electrolytes and the ... the modulatory responses of the autonomic nervous system ..... Concurrent hyponatremia and hypocalcemia have.

  4. Serum Prolactin in Diagnosis of Epileptic Seizures

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-09-01

    Full Text Available The results of studies in databases and references concerning serum prolactin levels (PRL in patients with suspected seizures were rated for quality and analyzed by members of the Therapeutics Subcommittee of the American Academy of Neurology.

  5. Alteration of serum adropin level in preeclampsia.

    Science.gov (United States)

    Wang, Huihua; Gao, Bo; Wu, Zaigui; Wang, Hanzhi; Dong, Minyue

    2017-04-01

    To clarify the alterations in serum adropin and preptin concentrations in preeclampsia, we determined serum adropin and preptin levels in 29 women with normal pregnancy and 32 women with preeclampsia. We found that maternal age, body mass index and fetal gender were not significantly different between two groups; however, blood pressure, gestational age and neonatal birth weight were significantly different. Serum adropin levels were significantly increased in women with preeclampsia compared with those with normal pregnancy but there were no significant differences in preptin levels. An increase in maternal serum adropin level was found in preeclampsia, and this may be a compensation for pregnancy complicated with preeclampsia. Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

  6. Serum homocysteine levels in cerebrovascular accidents

    OpenAIRE

    Zongte, Zolianthanga; Shaini, L.; Debbarma, Asis; Singh, Th Bhimo; Devi, S. Bilasini; Singh, W. Gyaneshwar

    2008-01-01

    Hyperhomocysteinemia has been considered an independent risk factor in the development of stroke. The present study was undertaken to evaluate serum homocysteine levels in patients with cerebrovascular accidents among the Manipuri population and to compare with the normal cases. Ninety-three cerebrovascular accident cases admitted in the hospital were enrolled for the study and twenty-seven age and sex matched individuals free from cerebrovascular diseases were taken as control group. Serum h...

  7. Cholinesterase activity in blood and pesticide presence in sweat as biomarkers of children`s environmental exposure to crop protection chemicals

    Directory of Open Access Journals (Sweden)

    Lucyna Kapka-Skrzypczak

    2015-09-01

    Full Text Available Introduction. On the contrary to the adult population exposed to pesticides, mostly on occupational basis, rural children are mostly exposed to pesticides deposited in the environment. However, even this constant, distributed in time exposure to low concentrations of pesticides may led to permanent health disorders and limit children’s harmonious development. Objective. The main objective of the study was to evaluate the usefulness of aacetylcholinesterase (AChE and butyrylcholinesterase (BuChE activity determination as a marker of children’s environmental exposure to pesticides. An additional aim was to evaluate the usefulness of sweat patches as a novel, non-invasive method of detection of pesticides in sweat as a measure of pesticide exposure. Materials and method. A total of 108 children living in areas of intense pesticide use, and as a control group, 92 children living in an agro-tourist area were enrolled in the study. The AChE and BuChE activity was assayed colorimetricaly in diluted whole blood or plasma, respectively. In addition, selected pesticides were measured by GC/MS analysis in samples of the subject’s sweat absorbed onto a sorbent. Results. The study demonstrated significantly lower AChE and BuChE activity, respectively, in the diluted whole blood and plasma of children exposed to pesticides, compared to the control group (p<0.001 and p=0.003, respectively. The measured mean level of AChE activity was 241.63 ± 26.76 and 348.0±46.95 mU/µmolHb in the exposed and the control group, respectively, whereas the mean activity of BuChE was 424.1±81.1 and 458.6 ± 86.5 mmol/L/min. In addition, pesticide metabolites were detected in 19 (17.6% sweat samples collected from exposed children. Conclusions. Altogether, the study indicated that cholinesterase activity is a sensitive marker of the children’s environmental exposure to pesticides, whereas sweat patches are useful devices for collecting samples to be analysed for the

  8. Resistance to Inhibitors of Cholinesterase 3 (Ric-3 Expression Promotes Selective Protein Associations with the Human α7-Nicotinic Acetylcholine Receptor Interactome.

    Directory of Open Access Journals (Sweden)

    Matthew J Mulcahy

    Full Text Available The α7-nicotinic acetylcholine receptor (α7-nAChR is a ligand-gated ion channel widely expressed in vertebrates and is associated with numerous physiological functions. As transmembrane ion channels, α7-nAChRs need to be expressed on the surface of the plasma membrane to function. The receptor has been reported to associate with proteins involved with receptor biogenesis, modulation of receptor properties, as well as intracellular signaling cascades and some of these associated proteins may affect surface expression of α7-nAChRs. The putative chaperone resistance to inhibitors of cholinesterase 3 (Ric-3 has been reported to interact with, and enhance the surface expression of, α7-nAChRs. In this study, we identified proteins that associate with α7-nAChRs when Ric-3 is expressed. Using α-bungarotoxin (α-bgtx, we isolated and compared α7-nAChR-associated proteins from two stably transfected, human tumor-derived cell lines: SH-EP1-hα7 expressing human α7-nAChRs and the same cell line further transfected to express Ric-3, SH-EP1-hα7-Ric-3. Mass spectrometric analysis of peptides identified thirty-nine proteins that are associated with α7-nAChRs only when Ric-3 was expressed. Significantly, and consistent with reports of Ric-3 function in the literature, several of the identified proteins are involved in biological processes that may affect nAChR surface expression such as post-translational processing of proteins, protein trafficking, and protein transport. Additionally, proteins affecting the cell cycle, the cytoskeleton, stress responses, as well as cyclic AMP- and inositol triphosphate-dependent signaling cascades were identified. These results illuminate how α-bgtx may be used to isolate and identify α7-nAChRs as well as how the expression of chaperones such as Ric-3 can influence proteins associating with α7-nAChRs. These associating proteins may alter activities of α7-nAChRs to expand their functionally-relevant repertoire as

  9. Regeneration of Red Cell Cholinesterase Activity Following Pralidoxime (2-PAM) Infusion in First 24 h in Organophosphate Poisoned Patients.

    Science.gov (United States)

    Goel, Parul; Gupta, Nidhi; Singh, Surjit; Bhalla, Ashish; Sharma, Navneet; Gill, K D

    2012-01-01

    Oximes such as pralidoxime chloride reactivate acetylcholinesterase. However their role in management of organophosphate poisoning is controversial. The study was carried out to find effectiveness of pralidoxime chloride (2-PAM) in regenerating red cell acetyl cholinesterase in first 24 h following administration of it in dose recommended by WHO. Eight patients with OPP [chlorpyriphos (3), phorate (3), dichlorvos (1) and monocrotophos (1) who fulfilled the criteria for inclusion were investigated. In addition to decontamination and atropine, all these patients were administered 30 mg/kg body wt of 2-PAM as bolus dose followed by 7.5 mg/kg body wt/h with maximum dose being 500 mg/h as continuous infusion till first 24 h. Red cell AChE activity was estimated every 15 min for first 4 h, one hourly for next 4 h and then 2 hourly till 24 h and subsequently without 2-PAM every 12 h till 7 days or discharge or death which ever earlier. In all the patients maximum increase in activity was observed in first 4 h following which rise was very slow despite continued 2-PAM infusion and reaching a steady state in 20 h in all the cases. The increase in red cell AChE activity observed in diethyl group at 24 h of 2-PAM infusion was 154% vs. 81% in dimethyl group. At 7 days the increase in activity was 215% vs. 118% respectively. However on multiple repeated ANOVA, no statistically significant difference was observed between diethyl and dimethyl groups at admission and discharge (P > 0.05). Similarly no significant difference was observed in three groups when patients were categorized according to WHO classification of organophosphates (P > 0.05). The maximum increase in red cell AChE activity occurs in first 4 h of 2-PAM administration followed by a slow increase despite 2-PAM infusion till 24 h.

  10. Serum amyloid P down-regulates CCL-1 expression, and inhibits ...

    African Journals Online (AJOL)

    Goya I, Gutiérrez J, Varona R, Kremer L, Zaballos A,. Márquez G. Identification of CCR8 as the specific receptor for the human beta-chemokine I-309: cloning and molecular characterization of murine CCR8 as the receptor for TCA-3. J Immunol 2014; 160: 1975-1981. 21. Napolitano M, Zingoni A, Bernardini G, Spinetti G, ...

  11. Serum Soluble Corin is Decreased in Stroke.

    Science.gov (United States)

    Peng, Hao; Zhu, Fangfang; Shi, Jijun; Han, Xiujie; Zhou, Dan; Liu, Yan; Zhi, Zhongwen; Zhang, Fuding; Shen, Yun; Ma, Juanjuan; Song, Yulin; Hu, Weidong

    2015-07-01

    Soluble corin was decreased in coronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to examine the association in patients wtith stroke and community-based healthy controls. Four hundred eighty-one patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum soluble corin and some conventional risk factors of stroke were examined. Because circulating corin was reported to be varied between men and women, the association between serum soluble corin and stroke was evaluated in men and women, respectively. Patients with ischemic and hemorrhagic stroke had a significantly lower level of serum soluble corin than healthy controls in men and women (all P values, stroke than men in the highest quartile. Women in the lowest quartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidence interval, 1.76-5.44) and hemorrhagic (OR, 8.54; 95% confidence interval, 2.35-31.02) stroke than women in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin in men and women (all P values for trend, stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke. © 2015 American Heart Association, Inc.

  12. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  13. Effect of Thymol on Serum Antioxidant Capacity of Rats Following Myocardial Hypertrophy

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    Mohabbat Jamhiri

    2017-07-01

    Full Text Available Abstract Background: Oxidative stress plays an important role in the pathogenesis of hypertension- induced cardiac hypertrophy. Plants are a rich source of antioxidant compounds. Thymol is a natural monoterpen phenol which is plentiful in some plants and shows many biological effects. The aim of the present study was to assess the effects of thymol on activity of antioxidant enzyme catalase, malondialdehyde (MDA level and the activity of the inhibition of free radical DPPH (2,2-Diphenyl-1-picryl-hydrazyl, following left ventricular hypertrophy in rats. Materials and Methods: In this experimental study, rats were divided into hypertrophied group without any treatment (H group and rats pretreated with 25 and 50 mg/kg/day of thymol (Thy25+H and Thy50+H groups, respectively. Intact animals were served as control (Ctl. Animal model of left ventricular hypertrophy was induced by abdominal aortic banding. Serum catalase (CAT activity, malondialdehyde (MDA level and the activity of inhibition of free radicals DPPH were determined by the biochemical methods. Results: In Thy25+H and Thy50+H groups, the CAT activity was increased significantly in serum (p<0.01, vs. Ctl. Also, serum level of MDA was decreased significantly compared to the group H in Thy25+H and Thy50+H groups (p<0.05 and p<0.001, respectively. The effect of inhibiting DPPH free radicals was increased significantly in Thy25+H and Thy50+H groups compared to the group H (p<0.001 and p<0.05, respectively. Conclusion: The findings of this study suggest that thymol as an antioxidant causes cardioprotective effects and as well as prevents left ventricular hypertrophy via augmentation of serum antioxidant capacity.

  14. Technetium-99m-Labeled Autologous Serum Albumin: A Personal-Exclusive Source of Serum Component

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    Wang, Yuh-Feng; Chen, Yi-Chun; Li, Dian-Kun; Chuang, Mei-Hua

    2011-01-01

    Technetium-99m human serum albumin (99mTc-HSA) is an important radiopharmaceutical required in nuclear medicine studies. However, the risk of transfusion-transmitted infection remains a major safety concern. Autopreparation of serum component acquired from patient provides a “personal-exclusive” source for radiolabeling. This paper is to evaluate the practicality of on-site elusion and subsequent radiolabeling efficacy for serum albumin. Results showed that the autologous elute contained more...

  15. Thyrotropin - Binding Inhibiting Immunoglobulin (TBII) in Patients with Autoimmune Thyroid Diseases

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    Jang, Dae Sung; Ahn, Byeong Cheol; Sohn, Sang Kyun; Lee, Jae Tae; Lee, Kyu Bo

    1996-01-01

    In order to evaluate the significance of thyrotropin-binding inhibiting immunoglobulin (TBII) in the patients with autoimmune thyroid diseases, the authors investigated 402 cases of Graves' disease and 230 cases of Hashimoto's thyroiditis comparing 30 cases of normal healthy adult at Kyung Pook University Hospital from February 1993 to August 1994. The TBII was tested by radioimmunoassay and assessed on the dynamic change with the disease course, thyroid functional parameters, and other thyroid autoantibodies; antithyroglobulin antibody(ATAb) and antimicrosomal antibody(AMAb) including thyroglobulin. The serum level of TBII was 40.82 ± 21.651(mean ± SD)% in hyperthyroid Graves' disease and 8.89 ± 14.522% in Hashimoto's thyroiditis and both were significant different from normal control of which was 3.21 ± 2.571%. The frequency of abnormally increased TBII level was 92.2% in hyperthyroid Craves' disease, 46.7% in euthyroid Graves' disease or remission state of hyperthyroidism, and 23.9% in Hashimoto's thyroiditis. The serum levels of increased TBII in Graves' disease were positively correlated with RAIU, serum T3, T4, and FT4, but negatively correlated with serum TSH(each p<0.001). The TBII in Graves' disease had significant positive correlation with serum thyroglobulin and AMAb, but no significant correlation with ATAb. In the Hashimoto's thyroiditis, the serum levels of TBII were positively correlated with RAIU, serum T3, TSH and AMAb, but not significantly correlated with serum T4, FT4, thyroglobulin and ATAb. Therefore serum level of TBII seemed to be a useful mean of assessing the degree of hyperthyroidism in Graves' disease and correlated well with thyroidal stimulation. The serum level of TBII in Hashimoto's thyroiditis is meaningful for the degree of both functional abnormality reflecting either hyperfunction or hypofunction and the immunologic abnormality.

  16. Thyrotropin - Binding Inhibiting Immunoglobulin (TBII) in Patients with Autoimmune Thyroid Diseases

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    Jang, Dae Sung; Ahn, Byeong Cheol; Sohn, Sang Kyun; Lee, Jae Tae; Lee, Kyu Bo [Kyungpook National University School of Medicine, Taegu (Korea, Republic of)

    1996-03-15

    In order to evaluate the significance of thyrotropin-binding inhibiting immunoglobulin (TBII) in the patients with autoimmune thyroid diseases, the authors investigated 402 cases of Graves' disease and 230 cases of Hashimoto's thyroiditis comparing 30 cases of normal healthy adult at Kyung Pook University Hospital from February 1993 to August 1994. The TBII was tested by radioimmunoassay and assessed on the dynamic change with the disease course, thyroid functional parameters, and other thyroid autoantibodies; antithyroglobulin antibody(ATAb) and antimicrosomal antibody(AMAb) including thyroglobulin. The serum level of TBII was 40.82 +- 21.651(mean +- SD)% in hyperthyroid Graves' disease and 8.89 +- 14.522% in Hashimoto's thyroiditis and both were significant different from normal control of which was 3.21 +- 2.571%. The frequency of abnormally increased TBII level was 92.2% in hyperthyroid Craves' disease, 46.7% in euthyroid Graves' disease or remission state of hyperthyroidism, and 23.9% in Hashimoto's thyroiditis. The serum levels of increased TBII in Graves' disease were positively correlated with RAIU, serum T3, T4, and FT4, but negatively correlated with serum TSH(each p<0.001). The TBII in Graves' disease had significant posi