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1

Diverse inhibitory actions of quaternary ammonium cholinesterase inhibitors on Torpedo nicotinic ACh receptors transplanted to Xenopus oocytes  

PubMed Central

Background and purpose: This work was aimed at comparing and analysing the effects and mechanisms of action of the quaternary ammonium cholinesterase inhibitors (QChEIs) BW284c51, decamethonium and edrophonium, on nicotinic ACh receptor (nAChR) function. Experimental approach: nAChRs purified from Torpedo electroplax were transplanted to oocytes and currents elicited by ACh (IACh) either alone or in presence of these QChEIs were recorded. Key results: None of the QChEIs, by itself, elicited changes in membrane conductance; however, when co-applied with ACh, all of them decreased IACh in a concentration-dependent way. The mechanisms of nAChR inhibition were different for these QChEIs. BW284c51 blockade was non-competitive and voltage-dependent, although it also affected the nH of the dose-response curve. By contrast, decamethonium and edrophonium inhibition, at –60 mV, was apparently competitive and did not modify either desensitisation or nH. Decamethonium effects were voltage-independent and washed out slowly after its removal; by contrast, edrophonium blockade had strong voltage dependence and its effects disappeared quickly after its withdrawal. Analysis of the voltage-dependent blockade indicated that BW284c51 bound to a shallow site into the channel pore, whereas edrophonium bound to a deeper locus. Accordingly, additive inhibitory effects on IACh were found among any pairs of these QChEIs. Conclusions and implications: The tested QChEIs bound to the nAChR at several and different loci, which might account for their complex inhibitory behaviour, acting both as allosteric effectors and, in the case of BW284c51 and edrophonium, as open channel blockers.

Olivera-Bravo, Silvia; Ivorra, Isabel; Morales, Andres

2007-01-01

2

New potential AChE inhibitor candidates.  

PubMed

We have theoretically studied new potential candidates of acetylcholinesterase (AChE) inhibitors designed from cardanol, a non-isoprenoid phenolic lipid of cashew Anacardium occidentale nut-shell liquid. The electronic structure calculations of fifteen molecule derivatives from cardanol were performed using B3LYP level with 6-31G, 6-31G(d), and 6-311+G(2d,p) basis functions. For this study we used the following groups: methyl, acetyl, N,N-dimethylcarbamoyl, N,N-dimethylamine, N,N-diethylamine, piperidine, pyrrolidine, and N,N-methylbenzylamine. Among the proposed compounds we identified that the structures with substitution by N,N-dimethycarbamoyl, N,N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine, and represent possible AChE inhibitors against Alzheimer disease. PMID:19446931

de Paula, A A N; Martins, J B L; dos Santos, M L; Nascente, L de C; Romeiro, L A S; Areas, T F M A; Vieira, K S T; Gambôa, N F; Castro, N G; Gargano, R

2009-09-01

3

Mice heterozygous for AChE are more sensitive to AChE inhibitors but do not respond to BuChE inhibition.  

PubMed

An impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients. PMID:23147415

Mohr, Franziska; Zimmermann, Martina; Klein, Jochen

2013-04-01

4

Pharmacological profile of PMS777, a new AChE inhibitor with PAF antagonistic activity.  

PubMed

The key pathophysiological mechanisms in Alzheimer's disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1-100 microM) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with [3H]PAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC50=2.48+/-0.12 microM; butyrylcholinesterase: IC50=4.47+/-0.15 microM). Ex vivo, PMS777 (5, 10, 20 or 40 mg/kg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mg/kg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped dose-response relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimer's disease. PMID:16426477

Li, Juan; Huang, Hong; Miezan Ezoulin, Jean-Marc; Gao, Xiao-Ling; Massicot, France; Dong, Chang-Zhi; Heymans, Françoise; Chen, Hong-Zhuan

2007-02-01

5

Reaction site-driven regioselective synthesis of AChE inhibitors.  

PubMed

The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE. Finally, a detailed computational modelling of the click reaction was conducted to further understand the origin of this TGS selectivity. PMID:24216754

Oueis, Emilia; Santoni, Gianluca; Ronco, Cyril; Syzgantseva, Olga; Tognetti, Vincent; Joubert, Laurent; Romieu, Anthony; Weik, Martin; Jean, Ludovic; Sabot, Cyrille; Nachon, Florian; Renard, Pierre-Yves

2014-01-01

6

Dual-site binding of bivalent 4-aminopyridine- and 4-aminoquinoline-based AChE inhibitors: contribution of the hydrophobic alkylene tether to monomer and dimer affinities  

Microsoft Academic Search

Three series of 4-aminopyridine-and 4-aminoquinoline based symmetrical bivalent acetylcholinesterase (AChE) inhibitors were prepared and compared to previously synthesized dimers of 9-amino-1,2,3,4-tetrahydroacridine (tacrine). In each case significant, tether length-dependent increases in AChE inhibition potency and selectivity (up to 3000-fold) were observed relative to the corresponding monomer, indicating dual-site binding of these inhibitors to AChE. Assay of the corresponding alkylated monomers revealed

Yi Fan Han; Crystal P.-L Li; Ella Chow; Hong Wang; Yuan-Ping Pang; Paul R Carlier

1999-01-01

7

Novel bis-(?)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property  

SciTech Connect

The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(?)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC{sub 50} values of 9.63 ?M (for ZLA) and 8.64 ?M (for ZLB), and prevent AChE-induced amyloid-? (A?) aggregation with IC{sub 50} values of 49.1 ?M (for ZLA) and 55.3 ?M (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit A? aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. -- Highlights: ? Two novel bis-(?)-nor-meptazinol derivatives are designed and synthesized. ? ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency. ? They are potential leads for disease-modifying treatment of Alzheimer's disease.

Zheng, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China) [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Li, Juan [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Qiu, Zhuibai [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Xia, Zheng [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Li, Wei [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Yu, Lining; Chen, Hailin; Chen, Jianxing [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China)] [NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032 (China); Chen, Yan; Hu, Zhuqin; Zhou, Wei; Shao, Biyun; Cui, Yongyao [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China); Xie, Qiong, E-mail: xiejoanxq@gmail.com [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China)] [Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 200032 (China); Chen, Hongzhuan, E-mail: yaoli@shsmu.edu.cn [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)] [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025 (China)

2012-10-01

8

Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.  

PubMed

We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone. PMID:16772524

Long, Cheng; Chen, Mei-Fang; Sarwinski, Susan J; Chen, Po-Yi; Si, Minliang; Hoffer, Barry J; Evans, M Steven; Lee, Tony J F

2006-07-01

9

Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells.  

PubMed

Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and ?,?-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10??M. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells. PMID:24302971

Wang, Yan; Pan, Wen-Liang; Liang, Wei-Cheng; Law, Wai-Kit; Tsz-Ming Ip, Denis; Ng, Tzi-Bun; Miu-Yee Waye, Mary; Chi-Cheong Wan, David

2013-01-01

10

1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-? aggregation crossing the blood-brain barrier.  

PubMed

Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ? fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC??=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction. PMID:23643737

Prinz, Michaela; Parlar, Sülünay; Bayraktar, Gül?ah; Alptüzün, Vildan; Erciyas, Ercin; Fallarero, Adyary; Karlsson, Daniela; Vuorela, Pia; Burek, Malgorzata; Förster, Carola; Turunc, Ezgi; Armagan, Guliz; Yalcin, Ayfer; Schiller, Carola; Leuner, Kristina; Krug, Manuel; Sotriffer, Christoph A; Holzgrabe, Ulrike

2013-07-16

11

N-methyl-citalopram: A quaternary selective serotonin reuptake inhibitor.  

PubMed

We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [(3)H]citalopram and uptake studies with [(3)H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10(-7)M as well as [(3)H]ketanserin binding to rat brain membranes at 10(-5)M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs. PMID:20696140

Bismuth-Evenzal, Yona; Roz, Netta; Gurwitz, David; Rehavi, Moshe

2010-11-15

12

Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE).  

PubMed

A series of bis-quaternary pyridinium derivatives 3a-3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE. PMID:24721830

Karade, Hitendra N; Valiveti, Aditya Kapil; Acharya, Jyotiranjan; Kaushik, Mahabir Parshad

2014-05-01

13

Toxicity and Efficacy of the Acetylcholinesterase (AChe) Inhibitor Donepezil in Childhood Brain Tumor Survivors: A Pilot Study  

PubMed Central

Background Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction. Procedure A single institution open-label pilot study was conducted in childhood BT survivors: ? 1 year from cancer treatment; and who received > 23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug. Results From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9–11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (p<=0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (p= 0.007), and the Number/Letter task (p= 0.018). Conclusions Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

Castellino, Sharon M.; Tooze, Janet A.; Flowers, Lynn; Hill, Debbie F.; McMullen, Kevin P.; Shaw, Edward G.; Parsons, Susan K.

2012-01-01

14

Determination of a novel carbamate AChE inhibitor meserine in mouse plasma, brain and rat plasma by LC-MS/MS: Application to pharmacokinetic study after intravenous and subcutaneous administration.  

PubMed

In this paper a simple and sensitive method for determination of a novel phenylcarbamate AChE inhibitor, meserine, in mouse plasma, brain and rat plasma was evaluated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Separation was achieved on an Alltech Alltima-C18 column (150mm×2.1mm, 3?m, Deerfield, IL, USA) with isocratic elution at a flow rate of 0.35ml/min. Detection was performed under the multiple reaction monitoring (MRM) mode using an electrospray ionization (ESI) in the positive ion mode. The protein precipitation and liquid-liquid extraction methods were used for the pretreatment of plasma and brain homogenates, respectively. The calibration curves of meserine showed good linearity over the concentration range of 0.5-1000ng/ml for mouse and rat plasma and 0.5-500ng/ml for mouse brain. The intra- and inter-day precision were less than 9.34% and the accuracy was from 95.34% to 107.78% for QC samples. The validated method was successfully applied to a preclinical pharmacokinetic study of meserine in mice and rats after intravenous and subcutaneous administration. The results showed that this novel drug could easily cross the blood-brain barrier to reach the site of drug action. Meserine was rapidly absorbed with a high subcutaneous absolute bioavailability (>90%). PMID:24747147

Xie, Ying; Jiang, Pan; Ge, Xinxing; Wang, Hao; Shao, Biyun; Xie, Qiong; Qiu, Zhuibai; Chen, Hongzhuan

2014-08-01

15

3D MI-DRAGON: new model for the reconstruction of US FDA drug- target network and theoretical-experimental studies of inhibitors of rasagiline derivatives for AChE.  

PubMed

The number of neurodegenerative diseases has been increasing in recent years. Many of the drug candidates to be used in the treatment of neurodegenerative diseases present specific 3D structural features. An important protein in this sense is the acetylcholinesterase (AChE), which is the target of many Alzheimer's dementia drugs. Consequently, the prediction of Drug-Protein Interactions (DPIs/nDPIs) between new drug candidates and specific 3D structure and targets is of major importance. To this end, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out a rational DPIs prediction. Unfortunately, many previous QSAR models developed to predict DPIs take into consideration only 2D structural information and codify the activity against only one target. To solve this problem we can develop some 3D multi-target QSAR (3D mt-QSAR) models. In this study, using the 3D MI-DRAGON technique, we have introduced a new predictor for DPIs based on two different well-known software. We have used the MARCH-INSIDE (MI) and DRAGON software to calculate 3D structural parameters for drugs and targets respectively. Both classes of 3D parameters were used as input to train Artificial Neuronal Network (ANN) algorithms using as benchmark dataset the complex network (CN) made up of all DPIs between US FDA approved drugs and their targets. The entire dataset was downloaded from the DrugBank database. The best 3D mt-QSAR predictor found was an ANN of Multi-Layer Perceptron-type (MLP) with profile MLP 37:37-24-1:1. This MLP classifies correctly 274 out of 321 DPIs (Sensitivity = 85.35%) and 1041 out of 1190 nDPIs (Specificity = 87.48%), corresponding to training Accuracy = 87.03%. We have validated the model with external predicting series with Sensitivity = 84.16% (542/644 DPIs; Specificity = 87.51% (2039/2330 nDPIs) and Accuracy = 86.78%. The new CNs of DPIs reconstructed from US FDA can be used to explore large DPI databases in order to discover both new drugs and/or targets. We have carried out some theoretical-experimental studies to illustrate the practical use of 3D MI-DRAGON. First, we have reported the prediction and pharmacological assay of 22 different rasagiline derivatives with possible AChE inhibitory activity. In this work, we have reviewed different computational studies on Drug- Protein models. First, we have reviewed 10 studies on DP computational models. Next, we have reviewed 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find Drug-Protein QSAR models. Last, we have developped a 3D multi-target QSAR (3D mt-QSAR) models for the prediction of the activity of new compounds against different targets or the discovery of new targets. PMID:23030618

Prado-Prado, Francisco; García-Mera, Xerardo; Escobar, Manuel; Alonso, Nerea; Caamaño, Olga; Yañez, Matilde; González-Díaz, Humberto

2012-01-01

16

Presynaptic nicotinic ACh receptors  

Microsoft Academic Search

Nicotinic ACh (nACh) receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties. However, despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined. This has led to increased interest in presynaptic nACh receptors that act to modulate the release of transmitter from presynaptic terminals.

Susan Wonnacott

1997-01-01

17

Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels  

PubMed Central

The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K+) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially lead to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC50 potencies ranging from 0.26 to 22 ?M. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC50 value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo.

Xia, Menghang; Shahane, Sampada; Huang, Ruili; Titus, Steven A.; Shum, Enoch; Zhao, Yong; Southall, Noel; Zheng, Wei; Witt, Kristine L.; Tice, Raymond R.; Austin, Christopher P.

2011-01-01

18

Centrally acting oximes in reactivation of tabun-phosphoramidated AChE.  

PubMed

Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM. PMID:22960624

Kovarik, Zrinka; Ma?ek, Nikolina; Sit, Rakesh K; Radi?, Zoran; Fokin, Valery V; Barry Sharpless, K; Taylor, Palmer

2013-03-25

19

Centrally Acting Oximes in Reactivation of Tabun-Phosphoramidated AChE  

PubMed Central

Organophosphates (OP) inhibit acetylcholinesterase (AChE, E.C.3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM.

Kovarik, Zrinka; Macek, Nikolina; Sit, Rakesh K.; Radic, Zoran; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer

2012-01-01

20

In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile.  

PubMed

Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC(50) of NDGA on AChE was 46.2 ?M. However, NDGA showed very poor central nervous system (CNS) activity and blood-brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD. PMID:23229229

Remya, Chandran; Dileep, Kalarickal Vijayan; Tintu, Ignatius; Variyar, Elessery Jayadevi; Sadasivan, Chittalakkottu

2013-03-01

21

Design and synthesis of imidazole and triazole derivatives as Lp-PLA? inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.  

PubMed

New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo. PMID:23385210

Wang, Kai; Xu, Wenwei; Liu, Yang; Zhang, Wei; Wang, Wenyi; Shen, Jianhua; Wang, Yiping

2013-03-01

22

Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors  

NASA Astrophysics Data System (ADS)

Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.

Zhou, Ming; Morais-Cabral, João H.; Mann, Sabine; MacKinnon, Roderick

2001-06-01

23

In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes.  

PubMed

Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings. PMID:24065055

Gupta, Bhanushree; Sharma, Rahul; Singh, Namrata; Kuca, Kamil; Acharya, J R; Ghosh, Kallol K

2014-02-01

24

A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease  

Microsoft Academic Search

Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a

Narihiro Toda; Keiko Tago; Shinji Marumoto; Kazuko Takami; Mayuko Ori; Naho Yamada; Kazuo Koyama; Shunji Naruto; Kazumi Abe; Reina Yamazaki; Takao Hara; Atsushi Aoyagi; Yasuyuki Abe; Tsugio Kaneko; Hiroshi Kogen

2003-01-01

25

Myeloperoxidase-mediated oxidation of organophosphorus pesticides as a pre-step in their determination by AChE based bioanalytical methods  

Microsoft Academic Search

In order to improve the sensitivity of assays for inhibitors of the enzyme acetylcholine esterase (AChE), an effective method\\u000a was developed for the conversion of the organophosphate pesticides (OPs) diazinon, malathion, chlorpyrifos, azinphos-methyl\\u000a and phorate into more toxic inhibitors. This was accomplished by converting them from the thio form into their oxo form using\\u000a the enzyme myeloperoxidase. The oxo forms,

Tamara Lazarevi? Pašti; Tatjana Momi?; Antonije Onjia; Ljubodrag Vujisi?; Vesna Vasi?

2010-01-01

26

Microcystin-LR acute exposure increases AChE activity via transcriptional ache activation in zebrafish (Danio rerio) brain.  

PubMed

Microcystins (MCs) constitute a family of cyanobacterial toxins, with more than 80 variants. These toxins are able to induce hepatotoxicity in several organisms mainly through the inhibition of protein phosphatases PP1 and PP2A and oxidative stress generation. Since recent evidence shows that MCs can either accumulate in brain or alter behavior patterns of fish species, in this study we tested the in vitro and in vivo effects of MC-LR at different concentrations on acetylcholinesterase (AChE) activity in zebrafish brain. In vivo studies showed that 100 ?g/L MC-LR led to a significant increase in the AChE activity (27%) when zebrafish were exposed to the toxin dissolved in water, but did not cause any significant changes when injected intraperitoneally. In addition, semiquantitative RT-PCR analysis demonstrated that 100 ?g/L MC-LR exposure also increased ache mRNA levels in zebrafish brain. The in vitro assays did not reveal any significant changes in AChE activity. These findings provide the first evidence that brain AChE is another potential target for MCs and suggest that the observed increases in AChE enzymatic activity and in ache transcript levels after MC-LR exposure depend, at least partially, on branchial uptake or ingestion. PMID:21946396

Kist, Luiza Wilges; Rosemberg, Denis Broock; Pereira, Talita Carneiro Brandão; de Azevedo, Mariana Barbieri; Richetti, Stefânia Konrad; de Castro Leão, Janaína; Yunes, João Sarkis; Bonan, Carla Denise; Bogo, Maurício Reis

2012-03-01

27

Quaternary Studies  

NSDL National Science Digital Library

First, the Irish Quaternary Association (IQUA) website publicizes its aim "to promote Quaternary studies in Ireland through its publications, and the organization of field meetings and conferences" (1). Visitors can learn about the importance of quaternary studies as well as find out the latest news and upcoming meetings. At the second website, the University of Wisconsin-Madison describes the current and recent studies dealing with "basic and applied problems in glacial geology, surficial geology, palynology, sedimentology, geologic mapping, hydrogeology, soils, and environmental geology "(2). The website offers abstracts of publications of members of the Department of Geology and Geophysics and the Wisconsin Geological and Natural History Survey along with descriptions of the lab, a shaded relief map of the Wisconsin area, and amusing glacial songs. Next, the Godwin Institute of Quaternary Research (GIQR) presents the University of Cambridge's history in quaternary research and the seven current research groups and four recent research projects (3 ). The website furnishes news from the research groups, a gallery of historical images of the East Anglia excursion, and summaries of the Institute's reference collections. Fourth, the International Union for Quaternary Research (INQUA) discusses quaternary scientists' investigations "to interpret the changing world of the glacial ages and their impact on our planet's surface environments" (4). Researchers can find out about INQUA-funded projects, meetings, and scientific commissions. Next, the Quaternary Research Association explains that it "exists to promote understanding of the Quaternary Period by publishing field guides, technical guides, and an international journal as well as holding field meetings and speaker meetings" (5). Students and researchers can discover employment, research, grant, meetings, and educational opportunities. Sixth, the University of Wales presents its investigations in the Remote Sensing Laboratory, Palaeoecology Laboratory, and the Luminescence Laboratory (6 ). Users can find concise descriptions of individual researchers' successes, abstracts of published papers, and links to conference information. The seventh website illustrates the Alaska Quaternary Center's commitment "to the promotion of interdisciplinary research and the enhancement of interdisciplinary instruction in Quaternary sciences" (7). Users can view images of the field work and learn how to obtain quaternary data from the Geographic Information Network of Alaska (GINA). Lastly, Rutgers University promotes its Graduate Certificate in Quaternary Studies where students take part in geology, geography, meteorology, and other disciplines interested in the last couple of million years of Earth's history (8). Students and educators can find information on the researchers involved with the program and the necessary course work.

28

Quaternary investigation  

SciTech Connect

The primary purpose of the Quaternary investigation is to provide information on the location and age of Quaternary deposits for use in evaluating the presence or absence of neotectonic deformation or paleoliquefaction features within the Savannah River Site (SRS) region. The investigation will provide a basis for evaluating the potential for capable faults and associated deformation in the SRS vicinity. Particular attention will be paid to the Pen Branch fault.

Stieve, A.

1991-05-15

29

Structural requirements for effective oximes--evaluation of kinetic in vitro data with phosphylated human AChE and structurally different oximes.  

PubMed

Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge. PMID:22827894

Worek, Franz; Wille, Timo; Koller, Marianne; Thiermann, Horst

2013-03-25

30

Back-scattering interferometry: an ultrasensitive method for the unperturbed detection of acetylcholinesterase-inhibitor interactions.  

PubMed

A series of inhibitors of acetylcholinesterase (AChE) have been screened by back-scattering interferometry (BSI). Enzyme levels as low as 100?pM (22,000?molecules of AChE) can be detected. This method can be used to screen for mixed AChE inhibitors, agents that have shown high efficacy against Alzheimer's disease, by detecting dual-binding interactions. E = enzyme, I = inhibitor, S = substrate. PMID:23037915

Haddad, Gabrielle L; Young, Sherri C; Heindel, Ned D; Bornhop, Darryl J; Flowers, Robert A

2012-10-29

31

Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.  

PubMed

Quaternary alkaloids are the major alkaloids isolated from Tinospora species. A previous study pointed to the necessary presence of quaternary nitrogens for strong acetylcholinesterase (AChE) inhibitory activity in such alkaloids. Repeated column chromatography of the vine of Tinospora crispa extract led to the isolation of one new protoberberine alkaloid, 4,13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium (1), along with six known alkaloids-dihydrodiscretamine (2), columbamine (3), magnoflorine (4), N-formylannonaine (5), N-formylnornuciferine (6), and N-trans-feruloyltyramine (7). The seven compounds were isolated and structurally elucidated by spectroscopic analysis. Two known alkaloids, namely, dihydrodiscretamine and columbamine are reported for the first time for this plant. The compounds were tested for AChE inhibitory activity using Ellman's method. In the AChE inhibition assay, only columbamine (3) showed strong activity with IC50 48.1 µM. The structure-activity relationships derived from these results suggest that the quaternary nitrogen in the skeleton has some effect, but that a high degree of methoxylation is more important for acetylcholinesterase inhibition. PMID:24448061

Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter

2014-01-01

32

Effect of pharmaceuticals exposure on acetylcholinesterase (AchE) activity and on the expression of AchE gene in the monogonont rotifer, Brachionus koreanus.  

PubMed

Pharmaceuticals are widely used in human and veterinary medicine. However, they are emerging as a significant contaminant in aquatic environments through wastewater. Due to the persistent and accumulated properties of pharmaceuticals via the food web, their potential harmful effects on aquatic animals are a great concern. In this study, we investigated the effects of six pharmaceuticals: acetaminophen, ATP; atenolol, ATN; carbamazepine, CBZ; oxytetracycline, OTC; sulfamethoxazole, SMX; and trimethoprim, TMP on acetylcholinesterase (AChE; EC 3.1.1.7) activity and its transcript expression with chlorpyrifos (as a positive control) in the monogonont rotifer, Brachionus koreanus. ATP, CBZ, and TMP exposure also remarkably inhibited Bk-AChE activity at 100 ?g/L (24 h) and 1000 ?g/L (12 h and 24 h). ATP, CBZ, and TMP exposure showed a significant decrease in the Bk-AChE mRNA level in a concentration-dependent manner. However, in the case of OTC and SMX, a slight decrease in Bk-AChE mRNA expression was found but only at the highest concentration. The time-course experiments showed that ATP positively induced Bk-AChE mRNA 12 h after exposure at both 100 and 1000 ?g/L, while the Bk-AChE mRNA expression was significantly downregulated over 6 to 24 h after exposure to 1000 ?g/L of CBZ, OTC, SMX, and TMP. Our findings suggest that Bk-AChE would be a useful biomarker for risk assessment of pharmaceutical compounds as an early signal of their toxicity in aquatic environments. Particularly, ATP, CBZ, and TMP may have a toxic cholinergic effect on rotifer B. koreanus by inhibiting AChE activity. PMID:24028855

Rhee, Jae-Sung; Kim, Bo-Mi; Jeong, Chang-Bum; Park, Heum Gi; Leung, Kenneth Mei Yee; Lee, Young-Mi; Lee, Jae-Seong

2013-11-01

33

Induction of soluble AChE expression via alternative splicing by chemical stress in Drosophila melanogaster.  

PubMed

Various molecular forms of acetylcholinesterase (AChE) have been characterized in insects. Post-translational modification is known to be a major mechanism for the molecular diversity of insect AChE. However, multiple forms of Drosophila melanogaster AChE (DmAChE) were recently suggested to be generated via alternative splicing (Kim and Lee, 2013). To confirm alternative splicing as the mechanism for generating the soluble form of DmAChE, we generated a transgenic fly strain carrying the cDNA of DmAChE gene (Dm_ace) that predominantly expressed a single transcript variant encoding the membrane-anchored dimer. 3' RACE (rapid amplification of cDNA ends) and western blotting were performed to compare Dm_ace transcript variants and DmAChE forms between wild-type and transgenic strains. Various Dm_ace transcripts and DmAChE molecular forms were observed in wild-type flies, whereas the transgenic fly predominantly expressed Dm_ace transcript variant encoding the membrane-anchored dimer. This supports alternative splicing as the major determinant in the generation of multiple forms of DmAChE. In addition, treatment with DDVP as a chemical stress induced the expression of the Dm_ace splice variant without the glycosylphosphatidylinositol anchor site in a dose-dependent manner and, accordingly, the soluble form of DmAChE in wild-type flies. In contrast, little soluble DmAChE was expressed in the transgenic fly upon exposure to DDVP. DDVP bioassays revealed that transgenic flies, which were unable to express a sufficient amount of soluble monomeric DmAChE, were more sensitive to DDVP compared to wild-type flies, suggesting that the soluble monomer may exert non-neuronal functions, such as chemical defense against xenobiotics. PMID:24637386

Kim, Young Ho; Kwon, Deok Ho; Ahn, Hyo Min; Koh, Young Ho; Lee, Si Hyeock

2014-05-01

34

Expression of acetylcholine (ACh) and ACh-synthesizing activity in Archaea.  

PubMed

Acetylcholine (ACh) is known generally as the neurotransmitter in the mammalian central and peripheral cholinergic nervous systems. However, ACh is also widely expressed in non-neuronal animal tissues and in plants, fungi and bacteria, where it is likely involved in the transport of water, electrolytes and nutrients, and in modulating various other cell functions. We have investigated the expression of ACh and ACh-synthesizing activity in various strains of Archaea, which are situated between Bacteria and Eucarya in the universal phylogenetic tree. Using a sensitive and specific radioimmunoassay, differing levels of ACh were detected in the Hyperthermophiles Thermococcus kodakaraensis KOD1, Sulfolobus tokodaii strain 7 and Pyrobaculum calidifontis VA1; the Methanogens Methanothermobacter thermautotrophicus deltaH and Methanosarcina barkeri; and the Halophiles Halobacterium sp. NRC-1 and Haloferax volcanii. T. kodakaraensis KOD1 expressed the highest levels of ACh among the Archaea tested; moreover, the substance expressed was verified to be ACh using high-performance liquid chromatography with electrochemical detection. Varying degrees of ACh-synthesizing activity were also identified in all of the strains, and the activity of bromoACh-sensitive choline acetyltransferase, an enzyme responsible for ACh synthesis in the nervous system, was detected in T. kodakaraensis KOD1. Our findings demonstrate that ACh and ACh-synthesizing activity are both expressed in evolutionally old Archaea. In the context of the recent discovery of non-neuronal ACh in bacteria, fungi, plants and animals, these findings support the notion that ACh has been expressed in organisms from the origin of life on the earth, functioning as a local mediator as well as a neurotransmitter. PMID:15936779

Yamada, Tomoya; Fujii, Takeshi; Kanai, Tamotsu; Amo, Taku; Imanaka, Tadayuki; Nishimasu, Hiroshi; Wakagi, Takayoshi; Shoun, Hirofumi; Kamekura, Masahiro; Kamagata, Yoichi; Kato, Takeshi; Kawashima, Koichiro

2005-09-01

35

Design, synthesis and structure–Activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease  

Microsoft Academic Search

We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by

Narihiro Toda; Keiko Tago; Shinji Marumoto; Kazuko Takami; Mayuko Ori; Naho Yamada; Kazuo Koyama; Shunji Naruto; Kazumi Abe; Reina Yamazaki; Takao Hara; Atsushi Aoyagi; Yasuyuki Abe; Tsugio Kaneko; Hiroshi Kogen

2003-01-01

36

AChBP-targeted ?-conotoxin correlates distinct binding orientations with nAChR subtype selectivity  

PubMed Central

Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel ?-conotoxin (?-TxIA) in the venom of Conus textile. ?-TxIA bound with high affinity to AChBPs from different species and selectively targeted the ?3?2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases.

Dutertre, Sebastien; Ulens, Chris; Buttner, Regina; Fish, Alexander; van Elk, Rene; Kendel, Yvonne; Hopping, Gene; Alewood, Paul F; Schroeder, Christina; Nicke, Annette; Smit, August B; Sixma, Titia K; Lewis, Richard J

2007-01-01

37

Acetylcholinesterase Inhibitors on the Spinal Cord.  

National Technical Information Service (NTIS)

This report describes studies on organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) in the mammalian spinal cord in which the mechanism and site of action of the OPs on synaptic transmission were studied with selective agonists and antagonist...

J. E. Warnick

1991-01-01

38

Characteristics of ACh-induced hyperpolarization and relaxation in rabbit jugular vein  

PubMed Central

BACKGROUND AND PURPOSE The roles played by endothelium-derived NO and prostacyclin and by endothelial cell hyperpolarization in ACh-induced relaxation have been well characterized in arteries. However, the mechanisms underlying ACh-induced relaxation in veins remain to be fully clarified. EXPERIMENTAL APPROACH ACh-induced smooth muscle cell (SMC) hyperpolarization and relaxation were measured in endothelium-intact and -denuded preparations of rabbit jugular vein. KEY RESULTS In endothelium-intact preparations, ACh (?10?8 M) marginally increased the intracellular concentration of Ca2+ ([Ca2+]i) in endothelial cells but did not alter the SMC membrane potential. However, ACh (10?10–10?8 M) induced a concentration-dependent relaxation during the contraction induced by PGF2? and this relaxation was blocked by the NO synthase inhibitor N?-nitro-l-arginine. ACh (10?8–10?6 M) concentration-dependently increased endothelial [Ca2+]i and induced SMC hyperpolarization and relaxation. These SMC responses were blocked in the combined presence of apamin [blocker of small-conductance Ca2+-activated K+ (SKCa, KCa2.3) channel], TRAM 34 [blocker of intermediate-conductance Ca2+-activated K+ (IKCa, KCa3.1) channel] and margatoxin [blocker of subfamily of voltage-gated K+ (KV) channel, KV1]. CONCLUSIONS AND IMPLICATIONS In rabbit jugular vein, NO plays a primary role in endothelium-dependent relaxation at very low concentrations of ACh (10?10–10?8 M). At higher concentrations, ACh (10?8?3 × 10?6 M) induces SMC hyperpolarization through activation of endothelial IKCa, KV1 and (possibly) SKCa channels and produces relaxation. These results imply that ACh regulates rabbit jugular vein tonus through activation of two endothelium-dependent regulatory mechanisms.

Itoh, Takeo; Maekawa, Takashi; Shibayama, Yasushi

2012-01-01

39

mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells  

PubMed Central

Background Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist. Methods Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses. Results Decreased E-cadherin expression and increased vimentin and ?-SMA expression induced by TGF-?1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-?1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-?1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP. Conclusions Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.

2014-01-01

40

Can hydroxylamine be a more potent nucleophile for the reactivation of tabun-inhibited AChE than prototype oxime drugs? An answer derived from quantum chemical and steered molecular dynamics studies.  

PubMed

Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ?1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (?(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective ?-? interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log?P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme. PMID:24964273

Lo, Rabindranath; Ganguly, Bishwajit

2014-07-29

41

n/Ach Among Agricultural and Business Entrepreneurs of Delhi  

ERIC Educational Resources Information Center

Given the wide acceptance of n/Ach in current research as a critical non-economic variable affecting entrepreneurship, the present study tests Atkinson's hypothesis of n/Ach--that individuals with high n/Ach are more susceptible to changes in economic opportunities than their counterparts with low n/Ach. (SE)

Singh, Narayan Prasad

1970-01-01

42

Altered GPI modification of insect AChE improves tolerance to organophosphate insecticides.  

PubMed

The olive fruit fly Bactrocera oleae is the most destructive and intractable pest of olives. The management of B. oleae has been based on the use of organophosphate (OP) insecticides, a practice that induced resistance. OP-resistance in the olive fly was previously shown to be associated with two mutations in the acetylcholinesterase (AChE) enzyme that, apparently, hinder the entrance of the OP into the active site. The search for additional mutations in the ace gene that encodes AChE revealed a short deletion of three glutamines (?3Q) from a stretch of five glutamines, in the C-terminal peptide that is normally cleaved and substituted by a GPI anchor. We verified that AChEs from B. oleae and other Dipterans are actually GPI-anchored, although this is not predicted by the "big-PI" algorithm. The ?3Q mutation shortens the unusually long hydrophilic spacer that follows the predicted GPI attachment site and may thus improve the efficiency of GPI anchor addition. We expressed the wild type B. oleae AChE, the natural mutant ?3Q and a constructed mutant lacking all 5 consecutive glutamines (?5Q) in COS cells and compared their kinetic properties. All constructs presented identical K(m) and k(cat) values, in agreement with the fact that the mutations did not affect the catalytic domain of the enzyme. In contrast, the mutants produced higher AChE activity, suggesting that a higher proportion of the precursor protein becomes GPI-anchored. An increase in the number of GPI-anchored molecules in the synaptic cleft may reduce the sensitivity to insecticides. PMID:21112395

Kakani, Evdoxia G; Bon, Suzanne; Massoulié, Jean; Mathiopoulos, Kostas D

2011-03-01

43

Flexibility versus "rigidity" of the functional architecture of AChE active center  

PubMed Central

Functional architecture of the AChE active center appears to be characterized by both structural “rigidity”, necessary to stabilize the catalytic triad as well as by flexibility in accommodating the different, high affinity AChE ligands. These seemingly conflicting structural properties of the active center are demonstrated through combination of structural methods with kinetic studies of the enzyme and its mutant derivatives with plethora of structurally diverse ligands and in particular with series of stereoselective covalent and noncovalent AChE ligands. Thus, steric perturbation of the acyl pocket precipitates in a pronounced stereoselectivity toward methylphosphonates by disrupting the stabilizing environment of the catalytic histidine rather than through steric exclusion demonstrating the functional importance of the “rigid” environment of the catalytic machinery. The acyl pocket, the cation-binding subsite (Trp86) and the peripheral anionic subsite were also found to be directly involved in HuAChE stereoselectivity toward charged chiral phosphonates, operating through differential positioning of the ligand cationic moiety within the active center. Residue Trp86 is also a part of the “hydrophobic patch” which seems flexible enough to accommodate the structurally diverse ligands like tacrine, galanthamine and the two diastereomers of huperzine A. Also, we have recently discovered further aspects of the role of both the unique structure and the flexibility of the “hydrophobic patch” in determining the reactivity and stereoselectivity of HuAChE toward certain carbamates including analogs of physostigmine. In these cases the ligands are accommodated mostly through hydrophobic interactions and their stereoselectivity delineates precisely the steric limits of the pocket. Hence, the HuAChE stereoselectivity provides a sensitive tool in the in depth exploration of the functional architecture of the active center. These studies suggest that the combination of “rigidity” and flexibility within the HuAChE gorge are an essential element of its molecular design.

Shafferman, Avigdor; Barak, Dov; Stein, Dana; Kronman, Chanoch; Velan, Baruch; Greig, Nigel H.; Ordentlich, Arie

2008-01-01

44

The Alaska Quaternary Center  

NSDL National Science Digital Library

This website illustrates the Alaska Quaternary Center's (at the University of Alaska, Fairbanks) commitment "to the promotion of interdisciplinary research and the enhancement of interdisciplinary instruction in Quaternary sciences." Users can view images of the field work and learn how to obtain quaternary data from the AQC Quaternary Research Geodatabase.

1969-12-31

45

Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice.  

PubMed

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-? aggregation inhibition. In this study, we further explored its AChE inhibition kinetic features and cognitive amelioration. Bis-Mep was found to be a mixed-type inhibitor on electric eel AChE by enzyme kinetic study. Molecular docking revealed that two "water bridges" located at the two wings of Bis-Mep stabilized its interaction with both catalytic and peripheral anionic sites of AChE. Furthermore, subcutaneous administration of Bis-Mep (10, 100 or 1000 ng/kg) significantly reversed the scopolamine-induced memory deficits in a typical bell-shaped dose-response manner. The maximal cognitive amelioration of Bis-Mep was achieved at 100 ng/kg, comparable with the effect of a reference drug Huperzine A at 1 mg/kg and also the relevant AChE inhibition in brain. These findings suggested that Bis-Mep might be a promising dual-binding AChE inhibitor for potential AD therapeutics. PMID:23262302

Liu, Ting; Xia, Zheng; Zhang, Wei-Wei; Xu, Jian-rong; Ge, Xin-Xing; Li, Juan; Cui, Yongyao; Qiu, Zhui-Bai; Xu, Jun; Xie, Qiong; Wang, Hao; Chen, Hong-Zhuan

2013-03-01

46

Quaternary and Geomorphology.  

ERIC Educational Resources Information Center

Highlights conferences and meetings of organizations involved with quaternary geology and geomorphology, including International Union of Quaternary Research Conference held in Moscow. The impetus of a revision of "The Quaternary of the United States" resulted from this conference. Includes activities/aims of "Friends of the Pleistocene"…

Andrews, J. T.; Graf, W. L.

1983-01-01

47

Failure of Toxogonin to Reactivate Soman-Inhibited Brain AChE in Monkeys and Regeneration of the Enzyme.  

National Technical Information Service (NTIS)

Administration of Toxogonin to monkeys intoxicated with pinacolyl methylphosphonofluoridate (Soman) did not result in significant reactivation (P = 0.05) of inhibited acetylcholinesterase (AChE). 'Aging,' i.e., refractoriness of reactivation due to rapid ...

M. G. Filbert M. A. Lochner J. H. Fleisher

1972-01-01

48

Oximes: inhibitors of human recombinant acetylcholinesterase. A structure-activity relationship (SAR) study.  

PubMed

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J; Kuca, Kamil

2013-01-01

49

Generation of Recombinant Human AChE Op-Scavengers With Extended Circulatory Longevity.  

National Technical Information Service (NTIS)

We demonstrated in the past that chemical conjugation of polyethylene glycol (PEG) moieties to recombinant human acetylcholinesterase (rHuAChE) gives rise to OP bioscavenger species which reside for very long period of time in the circulation of mice, reg...

A. Shafferman C. Kronman A. Ordentlich B. Velan D. Kaplan

2005-01-01

50

Generation of Recombinant Human AChE OP-Scavengers with Extended Circulatory Longevity.  

National Technical Information Service (NTIS)

We demonstrate that chemical conjugation of polyethylene glycol (PEG) moieties to recombinant human acetylcholinesterase (rHuAChE) gives rise to OP bioscavenger species which reside for very long periods of time in the circulation of mice, regardless of t...

A. Shafferman

2006-01-01

51

Different Cholinesterase Inhibitor Effects on CSF Cholinesterases in Alzheimer Patients  

PubMed Central

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.

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

2014-01-01

52

Current acetylcholinesterase-inhibitors: a neuroinformatics perspective.  

PubMed

This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on 'hybrid of pre-existing drugs' has been incorporated. Furthermore, current status of therapeutic applications of AChEinhibitors has also been summarized. PMID:24059296

Shaikh, Sibhghatulla; Verma, Anupriya; Siddiqui, Saimeen; Ahmad, Syed S; Rizvi, Syed M D; Shakil, Shazi; Biswas, Deboshree; Singh, Divya; Siddiqui, Mohmmad H; Shakil, Shahnawaz; Tabrez, Shams; Kamal, Mohammad A

2014-01-01

53

Natural Compounds Endowed with Cholinergic or Anticholinergic Activity. Enhancement of Acetylcholine Release by a Quaternary Derivative of l Hyoscyamine  

Microsoft Academic Search

New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission\\u000a in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to\\u000a enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular\\u000a junction. The effect was unrelated to membrane depolarization, and was not

Caden Souccar; Ana Lucia V. Salamanca; Mirtes M. Tanae; Maria Teresa R. Lima-Landman; Antonio José Lapa

2010-01-01

54

Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced ?-amyloid aggregation inhibitors  

Microsoft Academic Search

A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced ?-amyloid (A?) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high

Huang Tang; Li-Zhen Zhao; Hao-Tao Zhao; Shi-Liang Huang; Shu-Ming Zhong; Jiang-Ke Qin; Zhen-Feng Chen; Zhi-Shu Huang; Hong Liang

2011-01-01

55

Time Evolution of the Quaternary Structure of Escherichia Coli Aspartate Transcarbamoylase Upon Reaction With the Natural Substrates And a Slow Tight Binding Inhibitor  

SciTech Connect

Here, we present a study of the conformational changes of the quaternary structure of Escherichia coli aspartate transcarbamoylase, as monitored by time-resolved small-angle X-ray scattering, upon combining with substrates, substrate analogs, and nucleotide effectors at temperatures between 5 and 22 {sup o}C, obviating the need for ethylene glycol. Time-resolved small-angle X-ray scattering time courses tracking the T {yields} R structural change after mixing with substrates or substrate analogs appeared to be a single phase under some conditions and biphasic under other conditions, which we ascribe to multiple ligation states producing a time course composed of multiple rates. Increasing the concentration of substrates up to a certain point increased the T {yields} R transition rate, with no further increase in rate beyond that point. Most strikingly, after addition of N-phosphonacetyl-l-aspartate to the enzyme, the transition rate was more than 1 order of magnitude slower than with the natural substrates. These results on the homotropic mechanism are consistent with a concerted transition between structural and functional states of either low affinity, low activity or high affinity, high activity for aspartate. Addition of ATP along with the substrates increased the rate of the transition from the T to the R state and also decreased the duration of the R-state steady-state phase. Addition of CTP or the combination of CTP/UTP to the substrates significantly decreased the rate of the T {yields} R transition and caused a shift in the enzyme population towards the T state even at saturating substrate concentrations. These results on the heterotropic mechanism suggest a destabilization of the T state by ATP and a destabilization of the R state by CTP and CTP/UTP, consistent with the T and R state crystallographic structures of aspartate transcarbamoylase in the presence of the heterotropic effectors.

West, J.M.; Xia, J.; Tsuruta, H.; Guo, W.; O'Day, E.M.; Kantrowitz, E.R.

2009-05-26

56

Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection.  

PubMed

Acetylcholinesterase is a member of the ?/? hydrolase protein super family, with a significant role in acetylcholine-mediated neurotransmission. Research in the modulators of AChEs has moved from a potent poison (Sarin, Soman) in war times to the potent medicine (physostigmine) in peaceful times. Natural anti-AChE includes carbamates, glycoalkaloids, anatoxins derived from green algae; synthetic anti-AChE includes highly poisonous organophosphates used as nerve gases and insecticides. Recently, the role of anti-AChE was reassessed from neurotoxins to neuron-protective in the diseases characterized by impaired acetylcholine-mediated neurotransmission like Alzheimer's disease (AD). So, the AChE has been proven to be the most viable therapeutic target for the symptomatic treatment of AD. This review article gives a spectrum of strategies to design AChE inhibitors used in the Alzheimer therapy. PMID:24148993

Singh, Manjinder; Kaur, Maninder; Kukreja, Hitesh; Chugh, Rajan; Silakari, Om; Singh, Dhandeep

2013-12-01

57

Modelling interactions between Loop1 of Fasciculin2 (Fas2) and Torpedo californica acetylcholinesterase ( Tc AChE)  

NASA Astrophysics Data System (ADS)

Four interaction models for the binding of Torpedo californica acetylcholinesterase ( TcAChE) with Loop1 of Fasciculin2 are investigated at the B3LYP/6-311G(d,p) level of theory. The total binding energy of three fragments (P1-P3) which belong to the omega loop Cys67-Cys94 of TcAChE contributes almost 67% of the entire binding, suggesting the domination of this omega loop on the interaction between AChE and Loop1 of Fas2. The energy decomposition illustrates that the interactions mainly consist of electrostatic components. The polar solvent which reduces the binding energies of the studied models implies the significant impact of the solvent on the binding of Fas2 and AChE.

Wang, Jing; Gu, Jiande; Leszczynski, Jerzy

2006-11-01

58

The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors  

Microsoft Academic Search

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (?7, ?4?2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibitor peptide. In primary cultures of rat hippocampal neurons, nefiracetam increased the rate of nicotine-sensitive

Tomoyuki Nishizaki; Tamotsu Nomura; Toshiyuki Matuoka; Takeshi Kondoh; Grigori Enikolopo; Katumi Sumikawa; Shigeo Watabe; Tadashi Shiotani; Mitsunobu Yoshii

2000-01-01

59

Quaternary Research Association  

NSDL National Science Digital Library

The Quaternary Research Association explains that it "exists to promote understanding of the Quaternary Period by publishing field guides, technical guides, and an international journal as well as holding field meetings and speaker meetings." Students and researchers can discover employment, research, grant, meetings, and educational opportunities.

1969-12-31

60

Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.  

PubMed

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM. PMID:23273608

Hu, Yueqing; Zhang, Jun; Chandrashankra, Oormila; Ip, Fanny C F; Ip, Nancy Y

2013-02-01

61

Acetylcholinesterase inhibitors and Gulf War illnesses  

Microsoft Academic Search

Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms

Beatrice Alexandra Golomb

2008-01-01

62

Paired-pulse potentiation of ?7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones  

PubMed Central

Diverse subtypes of nicotinic acetylcholine receptors (nAChRs), including fast-desensitizing ?7-containing receptors, are expressed in the CNS. While nAChRs appear to regulate cognitive processing and synaptic plasticity, little is known to date about how this regulation occurs, particularly in brain regions known to be important for cognition. By combining patch-clamp electrophysiology with local photolysis of caged carbachol to rapidly activate the ?7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones in slices, we describe a novel transient up-regulation of channel function. The nAChRs were activated using a paired-pulse uncaging protocol, where the duration of the UV laser pulses (5–25 ms) and the interval between pulses (200 ms to 30 s) were varied. At relatively long interpulse intervals, we observed a strong (> 75%) decrease in the amplitude of the second response due to desensitization. However, when two pulses were applied at a 200 ms interval, a > 3-fold increase in the amplitude of the second response was observed, a phenomenon referred to here as paired-pulse potentiation. Interestingly, this potentiation appeared to be regulated by [Ca2+]i, and/or Ca2+-dependent processes, as it was significantly enhanced by dialysing cells with either the Ca2+ chelator BAPTA, or with peptide inhibitors of either calcineurin or PKC, and was attenuated by dialysing cells with the CaMKII inhibitor KN-93. No potentiation was observed using caged GABA or glutamate, indicating some specificity for nAChRs. Thus, rat hippocampal ?7-containing nAChRs possess a newly described phenomenon of paired-pulse potentiation that may be involved in regulating synaptic plasticity in the hippocampus.

Klein, Rebecca C; Yakel, Jerrel L

2005-01-01

63

Endosulfan exposure inhibits brain AChE activity and impairs swimming performance in adult zebrafish (Danio rerio).  

PubMed

Endosulfan is a broad spectrum organochlorine pesticide that is still widely in use in many developing countries. Following application, endosulfan can get to watercourses through surface runoff from agricultural fields and disturb the non-target aquatic animals including freshwater fish species. Given that the activity of the enzyme acetylcholinesterase (AChE) is one of the most recurrently used biomarkers of exposure to pesticides and there are controversial results concerning the effects of endosulfan exposure and AChE activity in fish, the aim of the present study was to evaluate the effects of endosulfan in brain AChE activity and its gene expression pattern using adult zebrafish (Danio rerio) as an animal model. Moreover, we have analyzed the effects of endosulfan exposure in different parameters of zebrafish swimming activity and in long-term memory formation. After 96 h of exposition, fish in the 2.4 ?g endosulfan/L group presented a significant decrease in AChE activity (9.44 ± 1.038 ?mol SCh h(-1) mg protein(-1); p=0.0205) when compared to the control group (15.87 ± 1.768 ?mol SCh h(-1) mg protein(-1); p=0.0205) which corresponds to approximately 40%. The down-regulation of brain AChE activity is not directly related with the transcriptional control as demonstrated by the RT-qPCR analysis. Our results reinforce AChE activity inhibition as a pathway of endosulfan-induced toxicity in brain of fish species. In addition, exposure to 2.4 ?g endosulfan/L during 96 h impaired all exploratory parameters evaluated: decreased line crossings (?21%, 273.7 ± 28.12 number of line crossings compared to the control group 344.6 ± 21.30, p=0.0483), traveled distance (?20%, 23.44 ± 2.127 m compared to the control group 29.39 ± 1.585, p=0.0281), mean speed (?25%, 0.03 ± 0.003 m/s compared to the control group 0.04 ± 0.002, p=0.0275) and body turn angle (?21%, 69,940 ± 4871 absolute turn angle compared to the control group 88,010 ± 4560, p=0.0114). These results suggest that endosulfan exposure significantly impairs animals' exploratory performance, and potentially compromises their ecological and interspecific interaction. Our results also showed that the same endosulfan exposure did not compromise animals' performance in the inhibitory avoidance apparatus. These findings provide further evidence of the deleterious effects of endosulfan exposure in the nervous system. PMID:22459995

Pereira, Vanessa Maynart; Bortolotto, Josiane Woutheres; Kist, Luiza Wilges; Azevedo, Mariana Barbieri de; Fritsch, Rachel Seemann; Oliveira, Renata da Luz; Pereira, Talita Carneiro Brandão; Bonan, Carla Denise; Vianna, Monica Ryff; Bogo, Maurício Reis

2012-06-01

64

Don't Blame Bad Weather for Your Aching Back  

MedlinePLUS

... Your Aching Back New study discounts notion that wind, rain influence lower back pain (*this news item ... between back pain and temperature, humidity, air pressure, wind direction or precipitation. Higher wind speeds and gusts ...

65

Gripped by Gout: Avoiding the Ache and Agony  

MedlinePLUS

... please review our exit disclaimer . Subscribe Gripped by Gout Avoiding the Ache and Agony Sudden, painful swelling ... toe is often the first warning sign of gout. It can affect other joints as well. Without ...

66

In Vivo Effects of Deltamethrin Exposure on Activity and Distribution of Molecular Forms of Carp AChE  

Microsoft Academic Search

The in vivo effects of the insecticide deltamethrin (DM) on the activity and molecular forms of acetylcholinesterase (AChE, EC 3.1.1.7) were examined in different organs (brain, blood serum, heart, liver, and skeletal muscle) of carp. The chosen exposure conditions were a DM concentration of 2 ?g\\/liter in the water (12 ± 1°C) for 3 days. All the treated fish survived

T. Szegletes; T. Balint; Z. Szegletes; J. Nemcsok

1995-01-01

67

Quaternary Research Center  

NSDL National Science Digital Library

"The Quaternary Research Center (QRC) fosters interdisciplinary research on the last two million years of the global environment: a time which encompasses massive, abrupt changes of climate, sea level, global biota and ice extent, as well the evolution of humans and the advent of civilization." Divided into six laboratories, the University of Washington's Center studies Cosmogenic Isotopes, Stable Isotopes, Old Quaternary Isotopes, Periglacial environments, quaternary ecology, paleoecology, and remote sensing. Researchers can find a tremendous amount of isotope, carbon dioxide, and chemistry data on the Taylor Dome, a part of the East Antarctic ice sheet. Students and educators can read papers by the center covering topics such as interactions among climate, surface, and tectonics; and glaciations and climate variations in the Pacific Northwest.

68

New Acetylcholinesterase Inhibitors for Alzheimer's Disease  

PubMed Central

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

2012-01-01

69

New acetylcholinesterase inhibitors for Alzheimer's disease.  

PubMed

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds. PMID:22216416

Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

2012-01-01

70

Acetylcholine and an acetylcholinesterase inhibitor neostigmine can aggravate tularemia progress in BALB/c mice  

PubMed Central

The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected.

Pohanka, Miroslav; Pavlis, Oto; Svobodova, Hana; Pikula, Jiri

2012-01-01

71

Acetylcholine and an acetylcholinesterase inhibitor neostigmine can aggravate tularemia progress in BALB/c mice.  

PubMed

The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected. PMID:22783145

Pohanka, Miroslav; Pavlis, Oto; Svobodova, Hana; Pikula, Jiri

2012-03-01

72

Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.  

PubMed

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 ?M, 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 ?M, 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. PMID:24594354

Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

2014-04-01

73

Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.  

PubMed

Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme. PMID:24291005

López-Granero, Caridad; Cardona, Diana; Giménez, Estela; Lozano, Rafael; Barril, José; Aschner, Michael; Sánchez-Santed, Fernando; Cañadas, Fernando

2014-01-01

74

Isocorilagin, a cholinesterase inhibitor from Phyllanthus niruri.  

PubMed

Drugs that have dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) produce better clinical efficacy against Alzheimer's disease (AD) than those that selectively inhibit one enzyme. A dual cholinesterase inhibitory-guided fractionation of Phyllanthus niruri leaves afforded isocorilagin, a bioactive tannin possessing good inhibitory activities against AChE (IC50: 0.49 microM) and BChE (IC50: 4.20 microM). Interestingly, isocorilagin was relatively 2- to 3-fold more potent than galanthamine, the clinically used inhibitor. The kinetic analyses suggested that isocorilagin was a non-competitive inhibitor for AChE and an uncompetitive inhibitor for BChE, with calculated Ki values of 1.49 microM and 2.86 microM, respectively. In silico molecular docking revealed that isocorilagin effectively blocked the substrate entry by forming hydrogen bonding with residues at the entrance of the AChE active site. With BChE, the compound completely docked inside and occupied the active site of the enzyme. This study demonstrated for the first time the potent cholinesterase inhibitory activities of isocorilagin, a promising lead that is worthy of further investigation. PMID:24868872

Koay, Yee-Hui; Basiri, Alireza; Murugaiyah, Vikneswaran; Chan, Kit-Lam

2014-04-01

75

Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine  

Microsoft Academic Search

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range

Rui Wang; Han Yan; Xi-can Tang

2006-01-01

76

Synthesis and Biological Evaluation of a Phosphonate Analog of the Natural Acetyl Cholinesterase Inhibitor Cyclophostin  

PubMed Central

Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than cis isomer against AChE from two sources.

Bandyopadhyay, Saibal; Dutta, Supratik; Spilling, Christopher D.; Dupureur, Cynthia M.; Rath, Nigam P.

2009-01-01

77

Quaternary Alloy Microwave MESFET.  

National Technical Information Service (NTIS)

Liquid phase epitaxial growth techniques have been used to grow quaternary alloys, Ga sub 1-x In sub x P sub 1-y As sub y, on InP substrates, using (100), (111) A and (111) B orientations. Liquidus and solidus data at 660 C have been used to determine dis...

J. W. Harrison S. B. Phatak M. A. Littlejohn G. Kelner H. H. Stadelmaier

1979-01-01

78

Quaternary Faunal Environments  

NSDL National Science Digital Library

Students collect information the environments associated with a list of presently living mammals. Students use FAUNMAP to explore the spatial patterns associated with these living mammals during the late Quaternary. They compare these distributions for living mammals to the distribution patterns for a set of extinct mammals. Students answer a set of questions that provide a basis for a summary report.

Hill, Christopher

79

Mechanisms of flow and ACh-induced dilation in rat soleus arterioles are altered by hindlimb unweighting  

NASA Technical Reports Server (NTRS)

The purpose of this study was to test the hypothesis that endothelium-dependent dilation (flow-induced dilation and ACh-induced dilation) in rat soleus muscle arterioles is impaired by hindlimb unweighting (HLU). Male Sprague-Dawley rats (approximately 300 g) were exposed to HLU or weight-bearing control (Con) conditions for 14 days. Soleus first-order (1A) and second-order (2A) arterioles were isolated, cannulated, and exposed to step increases in luminal flow at constant pressure. Flow-induced dilation was not impaired by HLU in 1A or 2A arterioles. The cyclooxygenase inhibitor indomethacin (Indo; 50 microM) did not alter flow-induced dilation in 1As or 2As. Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine (L-NNA; 300 microM) reduced flow-induced dilation by 65-70% in Con and HLU 1As. In contrast, L-NNA abolished flow-induced dilation in 2As from Con rats but had no effect in HLU 2As. Combined treatment with L-NNA + Indo reduced tone in 1As and 2As from Con rats, but flow-induced dilation in the presence of L-NNA + Indo was not different from responses without inhibitors in either Con or HLU 1As or 2As. HLU also did not impair ACh-induced dilation (10(-9)-10(-4) M) in soleus 2As. L-NNA reduced ACh-induced dilation by approximately 40% in Con 2As but abolished dilation in HLU 2As. Indo did not alter ACh-induced dilation in Con or HLU 2As, whereas combined treatment with L-NNA + Indo abolished ACh-induced dilation in 2As from both groups. We conclude that flow-induced dilation (1As and 2As) was preserved after 2 wk HLU, but HLU decreased the contribution of NOS in mediating flow-induced dilation and increased the contribution of a NOS- and cyclooxygenase-independent mechanism (possibly endothelium-derived hyperpolarizing factor). In soleus 2As, ACh-induced dilation was preserved after 2-wk HLU but the contribution of NOS in mediating ACh-induced dilation was increased.

Schrage, William G.; Woodman, Christopher R.; Laughlin, M. Harold

2002-01-01

80

Molecular interaction of human brain acetylcholinesterase with a natural inhibitor huperzine-B: an enzoinformatics approach.  

PubMed

The present study emphasizes the molecular interactions between human brain acetylcholinesterase (AChE) and the natural ligand Huperzine-B and its comparison to 'AChE-Tolserine interactions'. Docking between Huperzine-B and AChE was performed using 'Autodock4.2'. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Huperzine-B within the 'catalytic site' of AChE to permit docking. However, docking of Tolserine to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Huperzine-B. Scope still remains in the determination of the three-dimensional structure of AChE-Huperzine-B complex by X-ray crystallography to validate the described data. Furthermore, this study confirms that Huperzine-B is a more efficient inhibitor of human brain AChE compared to tolserine with reference to Ki and ?G values. PMID:24059299

Alam, Aftab; Shaikh, Sibhghatulla; Ahmad, Syed S; Ansari, Mohammad A; Shakil, Shahnawaz; Rizvi, Syed M D; Shakil, Shazi; Imran, Mohammad; Haneef, Mohammad; Abuzenadah, Adel M; Kamal, Mohammad A

2014-01-01

81

Stereocontrol by quaternary centres: a stereoselective synthesis of (-)-luminacin D.  

PubMed

Very high diastereoselectivity can be achieved by 1,3-chelation-controlled allylation of aldehydes that possess a non-chelating ?-ether substituent, even if the ?-position is a quaternary centre and/or a spiro-epoxide. This reaction was used as a key step in an enantioselective synthesis of the angiogenesis inhibitor luminacin?D. PMID:24519660

Bartlett, Nathan; Gross, Leona; Péron, Florent; Asby, Daniel J; Selby, Matthew D; Tavassoli, Ali; Linclau, Bruno

2014-03-17

82

Formulation of a Product Containing the Multifunctional Corrosion Inhibitor System DNBM.  

National Technical Information Service (NTIS)

Four quaternary ammonium salt inhibitors-DNBM(dichromate, nitrite, borate, and molybdate)-based on the quaternary ammonium chloride phase-change catalyst Adogen 464 were synthesized by double displacement reactions in the laboratory. The DNBM product in k...

L. J. Bailin

1989-01-01

83

Interactions between xylene-linked carbamoyl bis-pyridinium mono-oximes and organophosphates inhibited-AChE: a kinetic study.  

PubMed

Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by oximes is inadequate against various OP nerve agents known till date owing to their diverse structural features. As a consequence, in the past decades widespread research programs have been undertaken independently throughout the world to develop and identify more effective oxime reactivators. The efficacy of oxime reactivators is estimated through different in vitro and in vivo models using AChE from various sources against structurally different OPs. In the present study, reactivation kinetics of OP (paraoxon, DFP, sarin and VX) inhibited AChE by xylene linked carbamoyl bis-pyridinum mono-oximes have been described. It was found that the reactivation potency of tested oximes varied with the inhibitors used as 5l (4-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) was found to be the most effective reactivator against paraoxon. In case of DFP, 5k (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) showed best reactivation while in case of sarin 5e (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,4-phenylenedimethyl)-bis-pyridinium dibromide) exhibited outstanding reactivation ability in comparison to standard oximes (2-PAM, obidoxime and TMB-4) as indicated by its highest value of second order reactivation rate constant (k(r2)) 3.26 mM?¹ min?¹. The enhanced reactivation efficacy of oximes may be attributed to the optimal length of xylene linker which facilitates appropriate positioning of carbamoyl function to the peripheral anionic site (PAS) and extending the oxime moiety to the active site of AChE. PMID:24345352

Sharma, Rahul; Gupta, Bhanushree; Acharya, J; Kaushik, M P; Ghosh, Kallol K

2014-02-28

84

Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors.  

PubMed

Acetylcholinesterase (AChE) inhibitors have been used for the symptomatic treatment of Alzheimer's disease. Eleven whole plants from Panama belonging to the Lycopodiaceae family have been screened for their anticholinesterase inhibitory and antioxidant activities by a thin-layer chromatography (TLC) bioautography method. Of these, only Lycopodium clavatum subsp. clavatum showed strong AChE inhibition. Seven plant extracts showed moderate inhibition, two of them, Huperzia cf chamaeleon and Huperzia reflexa, also possessed an antioxidant activity. This is the first report of anticholinesterase and antioxidant activities in these two native plants. Additionally, alkaloid extracts of the Lycopodiaceae plants were also analysed by TLC and LC-MS to identify the well-known AchE inhibitor, huperzine A. Two plants, H. cf chamaeleon and H. reflexa var. minor, showed the presence of huperzine. PMID:22746970

Calderón, Angela I; Simithy-Williams, Johayra; Sanchez, Rocío; Espinosa, Alex; Valdespino, Iván; Gupta, Mahabir P

2013-03-01

85

The Ache: Genocide Continues in Paraguay. IWGIA Document No. 17.  

ERIC Educational Resources Information Center

In 1972, the Paraguayan Roman Catholic Church protested against the massacre of Indians in Paraguay. This was followed by further protests from Paraguayan intellectuals. These protests led to the removal of Jesus de Pereira, one of the executors of the official Ache policy. Thus, the critics were appeased. Since the beginning of 1973, new protests…

Munzel, Mark

86

Environmentally Contingent Reproductive Strategies in Mayan and Ache Males  

Microsoft Academic Search

This research explores male reproductive parameters, particularly the timing of first reproduction, in two traditional populations. Predictions are drawn from theoretical arguments that have their roots in evolutionary psychology and behavioral ecology, and that interpret variation in reproductive outcomes as environmentally contingent adaptations. In both Ache and Mayan samples, father absence, predicted to act as a stressor that causes precocious

David Waynforth; A. Magdalena Hurtado; Kim Hill

1998-01-01

87

Effect of acetylcholinesterase (AChE) point-of-care testing in OP poisoning on knowledge, attitudes and practices of treating physicians in Sri Lanka  

PubMed Central

Background Toxicology and Emergency medicine textbooks recommend measurement of acetylcholinesterase (AChE) in all symptomatic cases of organophosphorus (OP) poisoning but laboratory facilities are limited in rural Asia. The accuracy of point-of-care (POC) acetylcholinesterase testing has been demonstrated but it remains to be shown whether results would be valued by clinicians. This study aims to assess the effect of seeing AChE POC test results on the knowledge, attitudes and practices of doctors who frequently manage OP poisoning. Methods We surveyed 23 clinicians, who had different levels of exposure to seeing AChE levels in OP poisoned patients, on a) knowledge of OP poisoning and biomarker interpretation, b) attitudes towards AChE in guiding poison management, oxime therapy and discharge decisions, and c) practices of ordering AChE in poisoning scenarios. Results An overall high proportion of doctors valued the test (68-89%). However, we paradoxically found that doctors who were more experienced in seeing AChE results valued the test less. Lower proportions valued the test in guidance of acute poisoning management (50%, p = 0.015) and guidance of oxime therapy (25%, p = 0.008), and it was apparent it would not generally be used to facilitate early discharge. The highest proportion of respondents valued it on admission (p < 0.001). A lack of correlation of test results with the clinical picture, and a perception that the test was a waste of money when compared to clinical observation alone were also comments raised by some of the respondents. Greater experience with seeing AChE test results was associated with increased knowledge (p = 0.034). However, a disproportionate lack of knowledge on interpretation of biomarkers and the pharmacology of oxime therapy (12-50%) was noted, when compared with knowledge on the mechanism of OP poisoning and management (78-90%). Conclusions Our findings suggest an AChE POC test may not be valued by rural doctors. The practical use of AChE in OP poisoning management is complex, and a poor understanding of how to interpret test results may have affected its perceived utility. Future research should evaluate the impact of providing both AChE and training in interpretation on clinicians’ attitudes and practice.

2014-01-01

88

The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors.  

PubMed

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (alpha7, alpha4beta2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibitor peptide. In primary cultures of rat hippocampal neurons, nefiracetam increased the rate of nicotine-sensitive miniature excitatory postsynaptic currents, without affecting the amplitude, and the increase was inhibited by GF109203X. In addition, the drug caused a marked increase in the glutamate release from electrically stimulated guinea pig hippocampal slices, and the effect was abolished by the nicotinic ACh receptor antagonists, alpha-bungarotoxin and mecamylamine. Nefiracetam induced a long-lasting facilitation of synaptic transmission in both the CA1 area and the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by alpha-bungarotoxin and mecamylamine. Such facilitatory action was still found in the hippocampus with selective cholinergic denervation. The results of the present study, thus, suggest that nefiracetam enhances activity of nicotinic ACh receptors by interacting with a PKC pathway, thereby increasing glutamate release from presynaptic terminals, and then leading to a sustained facilitation of hippocampal neurotransmission. This may represent a cellular mechanism underlying the cognition-enhancing action of nefiracetam. The results also provide the possibility that nefiracetam could be developed as a promising therapeutic drug for senile dementia or Alzheimer's disease. PMID:11039729

Nishizaki, T; Nomura, T; Matuoka, T; Kondoh, T; Enikolopov, G; Enikolopo, G; Sumikawa, K; Watabe, S; Shiotani, T; Yoshii, M

2000-08-14

89

Acetylcholinesterase Inhibitors Promote Angiogenesis in Chick Chorioallantoic Membrane and Inhibit Apoptosis of Endothelial Cells  

PubMed Central

Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. Recently, a great attention has been paid to the possible role of vascular changes in the pathogenesis of AD. Reduced microvascular density and degeneration of the endothelium are of structural cerebrovascular changes in AD. Acetylcholinesterase (AChE) inhibitors are widely used for the improvement of AD symptoms. Until now, however, the effects of AChE inhibitors on vascular changes including angiogenesis and endothelial cell apoptosis are not fully understood. In the present work, the effects of three AChE inhibitors (donepezil, rivastigmine, and galantamine) were tested on H2O2-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and on angiogenesis in chicken chorioallantoic membrane model. Incubation of HUVEC with H2O2 led to a significant decrease in cell viability and an increase in the percentage of apoptotic cells. The tested drugs, at concentrations of 1–100??M, significantly inhibited the H2O2-induced toxicity. Also, all donepezil, rivastigmine and galantamine significantly increased the number of vessels in the chorioallantoic membrane when injected into fertilized eggs. In conclusion, AChE inhibitors possess angiogenesis-accelerating properties and have antiapoptotic effects on endothelial cells. These effects of AChE inhibitors may be involved in their beneficial effects on AD.

Mortazavian, Seyed Mohsen; Parsaee, Heydar; Mousavi, Seyed Hadi; Tayarani-Najaran, Zahra; Sadeghnia, Hamid Reza

2013-01-01

90

Acetylcholinesterase inhibitors and Gulf War illnesses.  

PubMed

Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV. PMID:18332428

Golomb, Beatrice Alexandra

2008-03-18

91

Geissoschizine methyl ether, a corynanthean-type indole alkaloid from Uncaria rhynchophylla as a potential acetylcholinesterase inhibitor.  

PubMed

Geissoschizine methyl ether (1), a newly discovered strong acetylcholinesterase (AChE) inhibitor, along with six weakly active alkaloids, vallesiachotamine (2), hisuteine (3), hirsutine (4), isorhynchophylline (5), cisocorynoxeine (6) and corynoxeine (7) have been isolated from Uncaria rhynchophylla. Geissoschizine methyl ether (1) inhibited 50% of AChE activity at concentrations of 3.7?±?0.3?µg?mL(-1) while the IC(50) value of physostigmine as a standard was 0.013?±?0.002?µg?mL(-1). The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE. PMID:21714741

Yang, Zhong-Duo; Duan, Dong-Zhu; Du, Juan; Yang, Ming-Jun; Li, Shuo; Yao, Xiao-Jun

2012-01-01

92

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of ?-Amyloid Aggregation.  

PubMed

Photochromic cholinesterase inhibitors were obtained from cis-1,2-?-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced ?-amyloid (A?) aggregation assay gave further experimental support to this finding: A?1-40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays. PMID:24628027

Chen, Xinyu; Wehle, Sarah; Kuzmanovic, Natascha; Merget, Benjamin; Holzgrabe, Ulrike; König, Burkhard; Sotriffer, Christoph A; Decker, Michael

2014-05-21

93

Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi  

PubMed Central

The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAChE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE has low sensitivity (IC50 = 200 ?M) toward tacrine, a monovalent catalytic site inhibitor with sub micromolar blocking potency in all previous species tested. Similarly, a series of bis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency toward BmAChE. Molecular homology models suggest the rBmAChE enzyme possesses a W384F orthologous substitution near the catalytic site, where the larger tryptophan side chain obstructs the access of larger ligands to the active site, but functional analysis of this mutation suggests it only partially explains the low sensitivity to tacrine. In addition, BmAChE1 and PpAChE have low nanomolar sensitivity to some experimental carbamate anticholinesterases originally designed for control of the malaria mosquito, Anopheles gambiae. One experimental compound, 2-((2-ethylbutyl)thio)phenyl methylcarbamate, possesses >300-fold selectivity for BmAChE1 and PpAChE over human AChE, and a mouse oral LD50 of >1500 mg/kg, thus providing an excellent new lead for vector control.

Swale, Daniel R.; Tong, Fan; Temeyer, Kevin B.; Li, Andrew; Lam, Polo C-H.; Totrov, Maxim M.; Carlier, Paul R.; Perez de Leon, Adalberto A.; Bloomquist, Jeffrey R.

2013-01-01

94

Bivalent Ligands Derived from Huperzine A as Acetylcholinesterase Inhibitors  

Microsoft Academic Search

The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the \\

H. Haviv; D. M. Wong; I. Silman; J. L. Sussman

2007-01-01

95

Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors.  

PubMed

Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes. PMID:24681070

Aslam, Sana; Zaib, Sumera; Ahmad, Matloob; Gardiner, John M; Ahmad, Aqeel; Hameed, Abdul; Furtmann, Norbert; Gütschow, Michael; Bajorath, Jürgen; Iqbal, Jamshed

2014-05-01

96

Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer's Disease and Type 2 Diabetes Mellitus  

PubMed Central

Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and ?-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer’s and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development.

Kaladhar, Dowluru SVGK; Yarla, Nagendra Sastry; Anusha, N.

2013-01-01

97

Selective cholinesterase inhibitors from Buxus sempervirens L. and their molecular docking studies.  

PubMed

In this work, two alkaloids namely (+)-buxabenzamidienine (1) and (+)-buxamidine (2) were isolated from Buxus sempervirens, using bioassay-guided fractionation and isolation method. Their acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitory activities were studied and the compounds were found to be quite selective inhibitors of AChE. IC50 values of compound 1 for electric eel AChE and horse BChE were 0.787 and 7.68 mM, respectively; while the corresponding IC50 of compound 2 were 1.70 and 549.98 mM, respectively. Theoretical (quantum mechanical, homology modelling and docking) calculations were performed in order to explain their interactions with different AChE (electric eel and human) and BChE (horse and human). The x-ray crystal structures of electric eel AChE, human AChE, human BChE and a model of horse BChE constructed by homology with human BChE were used for docking of compounds 1 and 2. Density functional theory (DFT) calculations of the compounds were performed at the B3LYP/6- 31G** level using the program Spartan™, and their HOMO and LUMO energy levels were calculated. Docking studies exhibited that compound 1 interacts with the acyl-binding pocket of the active site gorge of huAChE, and including several other hydrophobic interactions. PMID:22050684

Orhan, Ilkay E; Khan, Mahmud T H; Erdem, Sinem A; Kartal, Murat; Sener, Bilge

2011-12-01

98

Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody  

PubMed Central

In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft.

Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

2013-01-01

99

[The biological activity of quaternary ammonium salts (QASs)].  

PubMed

Quaternary ammonium salts (QASs), especially those of cationic surfactant character, are applied as antibacterial and antifungal disinfectants. QASs affect lipid-enveloped viruses, including human immunodeficiency virus (HIV) and hepatitis B virus (HBV), but not non-enveloped viruses. These compounds are extensively used in domestic (as ingredients of shampoos, hair conditioners), agricultural (as fungicides, pesticides, insecticides), healthcare (as medications), and industrial applications (as biocides, fabric softeners, corrosion inhibitors). The extensive use of quaternary ammonium disinfectants in recent years has led to the development of resistance in microorganisms to these drugs. Thus Staphylococcus aureus strains contain the plasmid-carrying genes qacA and qacB encoding resistance to quaternary ammonium compounds and acriflavine. The membrane proteins QacA and QacB confer multidrug resistance by exporting the compound by the proton motive force which is generated by the transmembrane electrochemical proton gradient. PMID:20400784

Ob?ak, Ewa; Gamian, Andrzej

2010-01-01

100

Topic in Depth - Quaternary Studies  

NSDL National Science Digital Library

Quaternary Studies examines the geologic period of the Quaternary, the last two million years up to the present day. Glaciers formed and receded; animals evolved and went extinct. Here, visitors can learn all about current research and education initiatives in this field of stratigraphic geology.

2010-09-14

101

Identification of Novel ?4?2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity  

PubMed Central

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.

Yu, Li-Fang; Tuckmantel, Werner; Eaton, J. Brek; Caldarone, Barbara; Fedolak, Allison; Hanania, Taleen; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

2012-01-01

102

Selective and Irreversible Inhibitors of Mosquito Acetylcholinesterases for Controlling Malaria and Other Mosquito-Borne Diseases  

PubMed Central

New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 µM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast (?30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force microscopy, circular dichroism spectroscopy, X-ray crystallography, time-resolved fluorescence spectroscopy, and liquid chromatography triple quadrupole mass spectrometry. These results support our view that the mosquito-specific Cys is a viable target for developing new mosquitocides to control disease vectors and to alleviate resistance problems with reduced toxicity toward non-target species.

Pang, Yuan-Ping; Ekstrom, Fredrik; Polsinelli, Gregory A.; Gao, Yang; Rana, Sandeep; Hua, Duy H.; Andersson, Bjorn; Andersson, Per Ola; Peng, Lei; Singh, Sanjay K.; Mishra, Rajesh K.; Zhu, Kun Yan; Fallon, Ann M.; Ragsdale, David W.; Brimijoin, Stephen

2009-01-01

103

Identification of potential bivalent inhibitors from natural compounds for acetylcholinesterase through in silico screening using multiple pharmacophores.  

PubMed

The symptomatic cure observed in the treatment of Alzheimer's disease (AD) by FDA approved drugs could possibly be due to their specificity against the active site of acetylcholinesterase (AChE) and not by targeting its pathogenicity. The AD pathogenicity involved in AChE protein is mainly due to amyloid beta peptide aggregation, which is triggered specifically by peripheral anionic site (PAS) of AChE. In the present study, a workflow has been developed for the identification and prioritization of potential compounds that could interact not only with the catalytic site but also with the PAS of AChE. To elucidate the essential structural elements of such inhibitors, pharmacophore models were constructed using PHASE, based on a set of fifteen best known AChE inhibitors. All these models on validation were further restricted to the best seven. These were transferred to PHASE database screening platform for screening 89,425 molecules deposited at the "ZINC natural product database". Novel lead molecules retrieved were subsequently subjected to molecular docking and ADME profiling. A set of 12 compounds were identified with high pharmacophore fit values and good predicted biological activity scores. These compounds not only showed higher affinity for catalytic residues, but also for Trp86 and Trp286, which are important, at PAS of AChE. The knowledge gained from this study, could lead to the discovery of potential AChE inhibitors that are highly specific for AD treatment as they are bivalent lead molecules endowed with dual binding ability for both catalytic site and PAS of AChE. PMID:23353586

Lakshmi, V; Kannan, V Santhosh; Boopathy, R

2013-03-01

104

Crystal Structure of Lymnaea stagnalis AChBP Complexed with the Potent nAChR Antagonist DH?E Suggests a Unique Mode of Antagonism  

PubMed Central

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that belong to the Cys-loop receptor superfamily. These receptors are allosteric proteins that exist in different conformational states, including resting (closed), activated (open), and desensitized (closed) states. The acetylcholine binding protein (AChBP) is a structural homologue of the extracellular ligand-binding domain of nAChRs. In previous studies, the degree of the C-loop radial extension of AChBP has been assigned to different conformational states of nAChRs. It has been suggested that a closed C-loop is preferred for the active conformation of nAChRs in complex with agonists whereas an open C-loop reflects an antagonist-bound (closed) state. In this work, we have determined the crystal structure of AChBP from the water snail Lymnaea stagnalis (Ls) in complex with dihydro-?-erythroidine (DH?E), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DH?E to AChBP imposes closure of the C-loop as agonists, but also a shift perpendicular to previously observed C-loop movements. These observations suggest that DH?E may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.

Shahsavar, Azadeh; Kastrup, Jette S.; Nielsen, Elsebet ?.; Kristensen, Jesper L.; Gajhede, Michael; Balle, Thomas

2012-01-01

105

Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade  

Microsoft Academic Search

We show here that donepezil, galanathamine and tacrine, therapeutic acetylcholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-?-erythroidine and methyllycaconitine, antagonists for ?4-nAChR and ?7-nAChR, respectively, antagonized the protective

Yuki Takada-Takatori; Toshiaki Kume; Mitsuhiro Sugimoto; Hiroshi Katsuki; Hachiro Sugimoto; Akinori Akaike

2006-01-01

106

Quantum realization of some quaternary circuits  

Microsoft Academic Search

We present the design of quaternary quantum version of reversible circuits such as Toffoli gate, modified Fredkin gate, mux, demux, encoder-decoder using linear ion realizable quaternary Muthukrishnan-Stroud gates. Our realization of quaternary Toffoli gate is more efficient than the previous realization and other quaternary circuits are realized for the time in literature.

Mahmud Muntakim Khan; Ayan Kumar Biswas; Shuvro Chowdhury; M. Tanzid; K. M. Mohsin; M. Hasan; A. I. Khan

2008-01-01

107

Natural compounds endowed with cholinergic or anticholinergic activity. Enhancement of acetylcholine release by a quaternary derivative of L-hyoscyamine.  

PubMed

New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular junction. The effect was unrelated to membrane depolarization, and was not induced by an increase of calcium influx into the nerve terminal. Phen also presented a competitive antimuscarinic activity and blocked noncompetitively the neuromuscular transmission. In this work we re-examined the mechanisms underlying the facilitatory actions of Phen on [(3)H]-ACh release in isolated ganglia of the guinea pig ileal myenteric plexus. Exposure of the preparations to Phen (10-50 microM) increased the release of [(3)H]-ACh by 81 to 68% over the basal. The effect was not affected by the ganglionic nAChR antagonist hexamethonium (1 nM) at a concentration that inhibited the increase of [(3)H]-ACh release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP, 30 microM). Association of Phen (10 microM) with DMPP potentiated the facilitatory effect of Phen. [(3)H]-ACh release was not altered by the muscarinic antagonists atropine (1 nM) or pirenzepine (1 microM). However, both antagonists inhibited the release of [(3)H]-ACh induced by either the muscarinic M1 agonist McN-343 (10 microM) or Phen (20 microM). The facilitatory effect of Phen was not altered by CdCl(2) (50 mM), but it was potentiated in the presence of tetraethylammonium (40 mM). The results indicate that the facilitatory action of Phen appears to be mediated by an increase of the inwardly rectifying potassium channels conductance probably related to the compound antimuscarinic activity. PMID:19688610

Souccar, Caden; Salamanca, Ana Lucia V; Tanae, Mirtes M; Lima-Landman, Maria Teresa R; Lapa, Antonio José

2010-01-01

108

Quaternary GIS Laboratory  

NSDL National Science Digital Library

This is the home page of the Quaternary Geographic Information System (GIS) Laboratory at the Institute of Arctic and Alpine Research (INSTAAR) at the University of Colorado. The laboratory supports quantitative spatial analysis of glacier, climate, coastal, and other environmental relationships at high latitudes. Users can access a collection of climate animations for the State of Alaska which show seasonal variation in monthly temperature and precipitation. There is also a set of high-resolution imagery and terrain models for Barrow, Alaska, an animation of the land bridge between Asia and North America, an atlas of paleoglaciation for the state, and links to a variety of other projects involving climatology, paleoclimatology, and glacial geomorphology in the Sate of Alaska.

109

Quaternary GIS Laboratory  

NSDL National Science Digital Library

This is the home page of the Quaternary Geographic Information System (GIS) Laboratory at the Institute of Arctic and Alpine Research (INSTAAR) at the University of Colorado. The laboratory supports quantitative spatial analysis of glacier, climate, coastal, and other environmental relationships at high latitudes. Users can access a collection of climate animations for the State of Alaska which show seasonal variation in monthly temperature and precipitation. There is also a set of high-resolution imagery and terrain models for Barrow, Alaska, an animation of the land bridge between Asia and North America, an atlas of paleoglaciation for the state, and links to a variety of other projects involving climatology, paleoclimatology, and glacial geomorphology in the Sate of Alaska.

2007-02-27

110

Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees  

PubMed Central

Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24?h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15?min. At a 10?nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1??M concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival.

Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

2013-01-01

111

Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees.  

PubMed

Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24?h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15?min. At a 10?nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1??M concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

Williamson, Sally M; Moffat, Christopher; Gomersall, Martha A E; Saranzewa, Nastja; Connolly, Christopher N; Wright, Geraldine A

2013-01-01

112

Seasonal screening of AChE, GSH and gonad histology, in European sea bass Dicentrarchus labrax L. reared in three different fish farms  

Microsoft Academic Search

The aim of this work was to do a preliminary seasonal screening of ecotoxicological biomarkers in European sea bass Dicentrarchus labrax in three different fish farms, to know if the different location and typology can discriminate them. A set of selected biomarkers of xenobiotic exposure, such as acetylcholinesterase (AChE) activity, Glutathione (GSH) and gonad morphology were investigated seasonally in male

Maria Vittoria Cangialosi; Ilaria Corsi; Stefano Bonacci; Cristiana Sensini; Nicola Cicero; Silvano Focardi; Antonio Mazzola

2012-01-01

113

Synthesis of Quaternary Heterocyclic Salts  

PubMed Central

The microwave synthesis of twenty quaternary ammonium salts is described. The syntheses feature comparable yields to conventional synthetic methods reported in the current literature with reduced reaction times and the absence of solvent or minimal solvent.

Winstead, Angela J.; Nyambura, Grace; Matthews, Rachael; Toney, Deveine; Oyaghire, Stanley

2014-01-01

114

Esterase metabolism of cholinesterase inhibitors using rat liver in vitro.  

PubMed

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; however, the relative potencies of the chemicals across and within species depend in part on chemical-specific metabolic and detoxification processes. Carboxylesterases and A-esterases (paraoxonases, PON) are two enzymatic detoxification pathways that have been widely studied. We used an in vitro system to measure esterase-dependent detoxification of 15 AChE inhibitors. The target enzyme AChE served as a bioassay of inhibitor concentration following incubation with detoxifying tissue. Concentration-inhibition curves were determined for the inhibitor in the presence of buffer (no liver), rat liver plus calcium (to stimulate PONs and thereby measure both PON and carboxylesterase), and rat liver plus EGTA (to inhibit calcium-dependent PONs, measuring carboxylesterase activity). Point estimates (concentrations calculated to produce 20, 50, and 80% inhibition) were compared across conditions and served as a measure of esterase-mediated detoxification. Results with well-known inhibitors (chlorpyrifos oxon, paraoxon, methyl paraoxon, malaoxon) were in agreement with the literature, serving to support the use of this assay. Only a few other inhibitors showed slight or a trend towards detoxification via carboxylesterases or PONs (mevinphos, aldicarb, oxamyl). There was no apparent PON- or carboxylesterase-mediated detoxification of the remaining inhibitors (carbofuran, chlorfenvinphos, dicrotophos, fenamiphos, methamidophos, methomyl, monocrotophos, phosphamidon), suggesting that the influence of esterases on these chemicals is minimal. Thus, generalizations regarding these metabolic pathways may not be appropriate. As with other aspects of AChE inhibitors, their metabolic patterns appear to be chemical-specific. PMID:21237238

Moser, V C; Padilla, S

2011-03-15

115

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-?-Induced Neurotoxicity  

PubMed Central

The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2–7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14–18), and quinolinodonepezils (19–21) are described. Pyridonepezils 15–18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19–21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC50 (hAChE) = 0.25 ± 0.02 ?M]. Pyridonepezils 15–18 and quinolinodonepezils 20–21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC50 (EeAChE) = 0.0167 ± 0.0002 ?M], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by A?1–42. All compounds were effective in preventing the enhancement of AChE activity induced by A?1–42. Compounds 2–7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by A?1–42. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer’s disease.

2013-01-01

116

Increased ratio of rapsyn to ACh receptor stabilizes postsynaptic receptors at the mouse neuromuscular synapse  

PubMed Central

The metabolic turnover of nicotinic ACh receptors (AChR) at the neuromuscular synapse is regulated over a tenfold range by innervation status, muscle electrical activity and neural agrin, but the downstream effector of such changes has not been defined. The AChR-associated protein rapsyn is essential for forming AChR clusters during development. Here, rapsyn was tagged with enhanced green fluorescent protein (EGFP) to begin to probe its influence at the adult synapse. In C2 myotubes, rapsyn–EGFP participated with AChR in agrin-induced AChR cluster formation. When electroporated into the tibialis anterior muscle of young adult mice, rapsyn–EGFP accumulated in discrete subcellular structures, many of which colocalized with Golgi markers, consistent with the idea that rapsyn assembles with AChR in the exocytic pathway. Rapsyn–EGFP also targeted directly to the postsynaptic membrane where it occupied previously vacant rapsyn binding sites, thereby increasing the rapsyn to AChR ratio. At endplates displaying rapsyn–EGFP, the metabolic turnover of AChR (labelled with rhodamine-?-bungarotoxin) was slowed. Thus, the metabolic half-life of receptors at the synapse may be modulated by local changes in the subsynaptic ratio of rapsyn to AChR.

Gervasio, Othon L; Phillips, William D

2005-01-01

117

Structural determinants of selective ?-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP  

PubMed Central

The nicotinic acetylcholine receptor (nAChR) is the prototype member of the superfamily of pentameric ligand-gated ion channels. How the extracellular ligand-binding domain coordinates selective binding of ligand molecules to different subtypes of the receptor is unknown at the structural level. Here, we present the 2.2-Å crystal structure of a homolog of the ligand-binding domain of the nAChR, Aplysia californica AChBP (Ac-AChBP), in complex with ?-conotoxin ImI. This conotoxin is unique in its selectivity toward the neuronal ?3?2 and ?7 nAChR, a feature that is reflected in its selective binding to Ac-AChBP compared with other AChBP homologs. We observe a network of interactions between the residues of the ligand-binding site and the toxin, in which ImI Arg-7 and Trp-10 play a key role. The toxin also forms interactions in the ligand-binding site that were not seen in the complex of Ac-AChBP with PnIA(A10L D14K), a conotoxin variant that lacks binding selectivity to AChBP homologs. In combination with electrophysiological recordings obtained by using the wild-type ?7 nAChR and L247T mutant, we show that conotoxin ImI inhibits ion conduction by stabilizing the receptor in a desensitized conformation. Comparison of the Ac-AChBP–ImI crystal structure with existing AChBP structures offers structural insight into the extent of flexibility of the interface loops and how their movement may couple ligand binding to channel gating in the context of a nAChR.

Ulens, Chris; Hogg, Ronald C.; Celie, Patrick H.; Bertrand, Daniel; Tsetlin, Victor; Smit, August B.; Sixma, Titia K.

2006-01-01

118

PKC and PKA Regulate AChR Dynamics at the Neuromuscular Junction of Living Mice  

PubMed Central

The steady state of the acetylcholine receptor (AChR) density at the neuromuscular junction (NMJ) is critical for efficient and reliable synaptic transmission. However, little is known about signaling molecules involved in regulating the equilibrium between the removal and insertion of AChRs that establishes a stable postsynaptic receptor density over time. In this work, we tested the effect of activities of two serine/threonine kinases, PKC and PKA, on the removal rate of AChRs from and the re-insertion rate of internalized recycled AChRs into synaptic sites of innervated and denervated NMJs of living mice. Using an in vivo time-lapse imaging approach and various pharmacological agents, we showed that PKC and PKA activities have antagonistic effects on the removal and recycling of AChRs. Inhibition of PKC activity or activation of PKA largely prevents the removal of pre-existing AChRs and promotes the recycling of internalized AChRs into the postsynaptic membrane. In contrast, stimulation of PKC or inactivation of PKA significantly accelerates the removal of postsynaptic AChRs and depresses AChR recycling. These results indicate that a balance between PKA and PKC activities may be critical for the maintenance of the postsynaptic receptor density.

Martinez-Pena y Valenzuela, Isabel; Pires-Oliveira, Marcelo; Akaaboune, Mohammed

2013-01-01

119

?7nAchR/NMDAR coupling affects NMDAR function and object recognition  

PubMed Central

The ?7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that ?7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the ?7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the ?7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by ?7nAchR using both electrophysiological and behavioral tests. We have found that activation of ?7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the ?7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that ?7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory.

2013-01-01

120

?7nAchR/NMDAR coupling affects NMDAR function and object recognition.  

PubMed

The ?7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that ?7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the ?7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the ?7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by ?7nAchR using both electrophysiological and behavioral tests. We have found that activation of ?7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the ?7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that ?7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory. PMID:24360204

Li, Shupeng; Nai, Qiang; Lipina, Tatiana V; Roder, John C; Liu, Fang

2013-01-01

121

Seasonal screening of AChE, GSH and gonad histology, in European sea bass Dicentrarchus labrax L. reared in three different fish farms.  

PubMed

The aim of this work was to do a preliminary seasonal screening of ecotoxicological biomarkers in European sea bass Dicentrarchus labrax in three different fish farms, to know if the different location and typology can discriminate them. A set of selected biomarkers of xenobiotic exposure, such as acetylcholinesterase (AChE) activity, Glutathione (GSH) and gonad morphology were investigated seasonally in male European sea bass D. labrax (L.) reared in three different intensive farms: a land-based farm of cement tanks (T), an in-shore sea cages farm (C1) and an off-shore sea cages farm (C2). The results showed that both location and typology can discriminate AChE activity, GSH content and gonad morphology. Further investigation is needed to propose these biomarkers in the protocol of fish farm quality control. PMID:22533608

Cangialosi, Maria Vittoria; Corsi, Ilaria; Bonacci, Stefano; Sensini, Cristiana; Cicero, Nicola; Focardi, Silvano; Mazzola, Antonio

2013-01-01

122

Reporter mutation studies show that nicotinic acetylcholine receptor (nAChR) ?5 Subunits and/or variants modulate function of ?6*-nAChR.  

PubMed

To further the understanding of functional ?6?5*-nicotinic acetylcholine receptors (nAChR; the asterisk (*) indicates known or possible presence of other subunits), we have heterologously expressed in oocytes different, mouse or human, nAChR subunit combinations. Coexpression with wild-type ?5 subunits or chimeric ?5/?3 subunits (in which the human ?5 subunit N-terminal, extracellular domain is linked to the remaining domains of the human ?3 subunit) almost completely abolishes the very small amount of function seen for ?6?4*-nAChR and does not induce function of ?6?2*-nAChR. Coexpression with human ?5(V9)'(S) subunits bearing a valine 290 to serine mutation in the 9' position of the second transmembrane domain does not rescue the function of ?6?4*-nAChR or induce function of ?6?2*-nAChR. However, coexpression with mutant chimeric ?5/?3(V9)'(S) subunits has a gain-of-function effect (higher functional expression and agonist sensitivity and spontaneous opening inhibited by mecamylamine) on ?6?4*-nAChR. Moreover, N143D + M145V mutations in the ?6 subunit N-terminal domain enable ?5/?3(V9)'(S) subunits to have a gain-of-function effect on ?6?2*-nAChR. nAChR containing chimeric ?6/?3 subunits plus either ?2 or ?4 subunits have some function that is modulated in the presence of ?5 or ?5/?3 subunits. Coexpression with ?5/?3(V9)'(S) subunits has a gain-of-function effect more pronounced than that in the presence of ?5(V9)'(S) subunits. Gain-of-function effects are dependent, sometimes subtly, on the nature and apparently the extracellular, cytoplasmic, and/or transmembrane domain topology of partner subunits. These studies yield insight into assembly of functional ?6?5*-nAChR and provide tools for development of ?6*-nAChR-selective ligands that could be important in the treatment of nicotine dependence, and perhaps other neurological diseases. PMID:21873428

Dash, Bhagirathi; Chang, Yongchang; Lukas, Ronald J

2011-11-01

123

On-line immobilized acetylcholinesterase microreactor for screening of inhibitors from natural extracts by capillary electrophoresis.  

PubMed

In this study we developed a simple capillary electrophoresis (CE) method with an on-line acetylcholinesterase (AChE) microreactor at the inlet of capillary for inhibitor screening. The fused-silica capillary surface was modified with a polycationic polyethylenimine coating. Solutions of the enzyme and chitosan were then injected to immobilize the enzyme in approximately 2.9 cm of the capillary inlet (total length of capillary 60.2 cm) by electrostatic interaction and the film overlay technique. Separation of enzyme reaction product (thiocholine, ThCh) and unreacted substrate (acetylthiocholine, AThCh) was achieved within 3.0 min. The conditions affecting the efficiency of reaction of the enzyme were optimized by measuring the peak area of ThCh. Under the optimum conditions, using Huperzine-A as model inhibitor, K (i) and IC (50) were 0.551 ?mol L(-1) and 1.52 ?mol L(-1), respectively, for immobilized AChE. Finally, screening of a small compound library containing two known AChE inhibitors and 30 natural extracts was conducted, and species with inhibition activity were directly identified. Compared with previous publications on screening for AChE inhibitors in natural products based on CE methods, the method developed in this work has the advantages of lower cost per analysis, less leakage, and better bioaffinity for the immobilized enzyme because of the unique properties of sodium alginate and chitosan. PMID:22932810

Min, Wenao; Wang, Weiping; Chen, Jianrong; Wang, Aijun; Hu, Zhide

2012-11-01

124

Analysis of free ACh and 5-HT in milk from four different species and their bioactivity on 5-HT3 and nACh receptors.  

PubMed

Milk is one of the most beneficial aliments and is highly recommended in normal conditions; however, in certain disorders, like irritable bowel syndrome, cow milk and dairy products worsen the gastric symptoms and their use is not recommended. Among the most recognized milk-induced gatrointestinal symptoms are abdominal pain, nausea and vomiting, which are processes controlled by cholinergic and serotonergic transmission. Whether the presence of bioavailable ACh and 5-HT in milk may contribute to normal peristalsis, or to the developing of these symptoms, is not known. In this work we attempt to determine whether the content of free ACh and 5-HT is of physiological significance in milk from four different species: cow (bovine), goat, camel and human. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to identify and quantify free ACh and 5-HT in milk, and activation of the serotonergic and cholinergic ionotropic receptors was investigated using electrophysiological experiments. Our principal hypothesis was that milk from these four species had sufficient free ACh and 5-HT to activate their correspondent receptors expressed in a heterologous system. Our results showed a more complex picture, in which free ACh and 5-HT and their ability to activate cholinergic and serotonergic receptors are not correlated. This work is a first step to elucidate whether 5-HT and ACh, at the concentrations present in the milk, can be associated to a direct function in the GI. PMID:24820623

Gallegos-Perez, Jose-Luis; Limon, Agenor; Reyes-Ruiz, Jorge M; Alshanqeeti, Ali S; Aljohi, Mohammad A; Miledi, Ricardo

2014-06-25

125

Exploring Different Virtual Screening Strategies for Acetylcholinesterase Inhibitors  

PubMed Central

The virtual screening problems associated with acetylcholinesterase (AChE) inhibitors were explored using multiple shape, and structure-based modeling strategies. The employed strategies include molecular docking, similarity search, and pharmacophore modeling. A subset from directory of useful decoys (DUD) related to AChE inhibitors was considered, which consists of 105 known inhibitors and 3732 decoys. Statistical quality of the models was evaluated by enrichment factor (EF) metrics and receiver operating curve (ROC) analysis. The results revealed that electrostatic similarity search protocol using EON (ET_combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Satisfactory performance was also observed for shape-based similarity search protocol using ROCS and PHASE. In contrast, the molecular docking protocol performed poorly with enrichment factors <30% in all cases. The shape- and electrostatic-based similarity search protocol emerged as a plausible solution for virtual screening of AChE inhibitors.

Mishra, Nibha; Basu, Arijit

2013-01-01

126

From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors.  

PubMed

The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD. PMID:23210783

Russo, P; Frustaci, A; Del Bufalo, A; Fini, M; Cesario, A

2013-01-01

127

Late Quaternary vegetation - climate feedbacks  

Microsoft Academic Search

Feedbacks between vegetation and other components of the climate system are discussed with respect to their influence on climate dynamics during the late Quaternary, i.e., the last glacial - interglacial cycles. When weighting current understanding based on interpretation of palaeobotanic and palaeoclimatic evidence by numerical climate system models, a number of arguments speak in favour of vegetation dynamics being an

M. Claussen

2009-01-01

128

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation  

PubMed Central

A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N?-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure–activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release.

Zheng, Guangrong; Zhang, Zhenfa; Pivavarchyk, Marharyta; Deaciuc, Agripina G.; Dwoskin, Linda P.; Crooks, Peter A.

2014-01-01

129

Sperm Epidermal Growth Factor Receptor (EGFR) Mediates ?7 Acetylcholine Receptor (AChR) Activation to Promote Fertilization  

PubMed Central

To attain fertilization the spermatozoon binds to the egg zona pellucida (ZP) via sperm receptor(s) and undergoes an acrosome reaction (AR). Several sperm receptors have been described in the literature; however, the identity of this receptor is not yet certain. In this study, we suggest that the ?7 nicotinic acetylcholine receptor (?7nAChR) might be a sperm receptor activated by ZP to induce epidermal growth factor receptor (EGFR)-mediated AR. We found that isolated ZP or ?7 agonists induced the AR in sperm from WT but not ?7-null spermatozoa, and the induced AR was inhibited by ?7 or EGFR antagonists. Moreover, ?7-null sperm showed very little binding to the egg, and microfluidic affinity in vitro assay clearly showed that ?7nAChR, as well as EGFR, interacted with ZP3. Induction of EGFR activation and the AR by an ?7 agonist was inhibited by a Src family kinase (SFK) inhibitor. In conclusion we suggest that activation of ?7 by ZP leads to SFK-dependent EGFR activation, Ca2+ influx, and the acrosome reaction.

Jaldety, Yael; Glick, Yair; Orr-Urtreger, Avi; Ickowicz, Debby; Gerber, Doron; Breitbart, Haim

2012-01-01

130

A Speculative Model of AChR Gating at the Frog Neuromuscular Junction  

NSDL National Science Digital Library

The animation depicts a speculative model of nicotinic acetylcholine receptor (AChR) gating at the frog neuromuscular junction. Following a nerve impulse, the neurotransmitter acetylcholine (ACh) is released from synaptic vesicles docked at the active zone of the presynaptic nerve terminal. ACh diffuses across the synaptic cleft to bind to AChRs, ligand-gated channels found at the lips of the postjunctional folds of the muscle, initiating gating, a conformational change that allows ions to flow through the channel and thereby elicit an electrical response in the muscle (the end-plate potential). In the AChR, gating involves a series of small conformational changes that propagate throughout the channel as it moves from "closed" to "open," rather than a synchronous switch in protein configuration. [Resource Details

Anthony Auerbach (State University of New York at Buffalo;Center for Single Molecule Biophysics REV)

2003-09-02

131

Marine natural products as acetylcholinesterase inhibitor: comparative quantum mechanics and molecular docking study.  

PubMed

Alzheimer's disease (AD) is the most common form of dementia which affects the elderly population throughout the world. The inhibition of acetylcholinesterase (AChE) has appeared as one of the most promising strategies for the AD treatment. In this study, the density functional theory and molecular docking studies have been carried out on seven halogenated sesquiterpenes derived from the Persian Gulf sea hare, Aplysia dactylomela, to reveal their electronic, structural and chemical properties. Moreover, influences of these properties on their AChE-inhibition properties have been investigated theoretically. The results indicate that these compounds have several interactions with important residues of AChE active sites. Three of the investigated molecules correlate better to well-known AD drugs such as huperzine A, galanthamine and donepezil which represent possible AChE inhibitors against Alzheimer disease. In conclusion, the information obtained from this theoretical study may aid in the discovery of new potential AChE inhibitors with marine origin. PMID:24712383

Farrokhnia, Maryam; Nabipour, Iraj

2014-03-01

132

Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor.  

PubMed

We previously demonstrated that ammonium- or guanidinium-phosphate interactions are key to forming noncovalent complexes (NCXs) through salt bridge formation with G-protein coupled receptors (GPCR), which are immersed in the cell membrane's lipids. The present work highlights MALDI ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI IM oTOF MS) as a method to determine qualitative and relative quantitative affinity of drugs to form NCXs with targeted GPCRs' epitopes in a model system using, bis-quaternary amine based drugs, ?- and ?- subunit epitopes of the nicotinic acetylcholine receptor' (nAChR) and phospholipids. Bis-quaternary amines proved to have a strong affinity for all nAChR epitopes and negatively charged phospholipids, even in the presence of the physiological neurotransmitter acetylcholine. Ion mobility baseline separated isobaric phosphatidyl ethanolamine and a matrix cluster, providing an accurate estimate for phospholipid counts. Overall this technique is a powerful method for screening drugs' interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties. PMID:22506649

Barbacci, Damon; Jackson, Shelley N; Muller, Ludovic; Egan, Thomas; Lewis, Ernest K; Schultz, J Albert; Woods, Amina S

2012-06-01

133

Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors.  

PubMed

Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as (1)H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50<10 ?M. The highest inhibitory activity (IC50=5.12 ?M for AChE and IC50=8.63 ?M for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure-activity relationship was discussed. PMID:23886696

Yoon, Yeong Keng; Ali, Mohamed Ashraf; Wei, Ang Chee; Choon, Tan Soo; Khaw, Kooi-Yeong; Murugaiyah, Vikneswaran; Osman, Hasnah; Masand, Vijay H

2013-08-01

134

Design, Synthesis, and Evaluation of 7H-thiazolo-[3,2-b]-1,2,4-triazin-7-one Derivatives as Dual Binding Site Acetylcholinesterase Inhibitors.  

PubMed

New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as a new drug candidate for the treatment of Alzheimer's disease (AD) through the binding to both catalytic and peripheral sites of the enzyme. Therefore, a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 6a-j were synthesized and investigated for their ability to inhibit the activity of human AChE (hAChE) in comparison with huperzine-A. All the compounds were found to inhibit AChE activity, especially compounds 6c and 6i with the inhibition value of 76.10% and 77.82%, respectively. The molecular docking study indicated that they were nicely accommodated by AChE. The molecular docking study revealed that 6c and 6i possessed a more optimal binding conformation than 6a and can perfectly fit into the active and peripheral site of hAChE, and consequently exhibited highly improved inhibitor potency to hAChE. PMID:24890706

Liu, Sijie; Shang, Ruofeng; Shi, Lanxiang; Zhou, Ran; He, Jingyu; Wan, David Chi-Cheong

2014-08-01

135

Synthesis of Novel 3-Aryl-N-Methyl-1,2,5,6-Tetrahydropyridine Derivatives by Suzuki coupling: As Acetyl Cholinesterase Inhibitors  

PubMed Central

Alzheimer’s disease (AD) is a neurodegenerative disorder affecting the central nervous system, which is also associated with progressive loss of memory and cognition. The development of numerous structural classes of compounds with different pharmacological profile could be an evolving, promising therapeutic approach for the treatment of AD. Thus, providing a symptomatic treatment for this disease are cholinomimetics with the pharmacological profile of Acetylcholinesterase (AChE) inhibitors. In view of this, we have synthesized novel 3-aryl-N-methyl-1,2,5,6-tetrahydropyridine derivatives 5a-k by Suzuki coupling and screened the efficacy of these derivatives for their AChE inhibitor activity.

Prasad, S.B. Benaka; Kumar, Y.C. Sunil; Kumar, C.S. Ananda; Sadashiva, C.T; Vinaya, K; Rangappa, K.S

2007-01-01

136

Regulatory role of the ?7nAChR in cancer.  

PubMed

Exposure to tobacco products is responsible for the majority of all human cancers. Nicotinic acetylcholine receptors (nAChRs) were identified as early as 1989 as important regulators of cancer cells. In analogy to its function in the brain, the homomeric ?7nAChR has "accelerator function" on the most common human cancers by stimulating the synthesis and release of excitatory neurotransmitters (serotonin in small cell lung cancer, noradrenaline/adrenaline in most other cancers) that drive cell proliferation, migration, angiogenesis, neurogenesis and metastasis while inhibiting apoptosis. These effects are not only caused by ?7nAChRs expressed in cancer cells but also by ?7nAChRs in ganglia and nerves of the sympathetic part of the autonomic nervous system that release noradrenaline/adrenaline into the tumor environment. In the nervous system, ?7nAChR protein undergoes paradoxical upregulation without concomitant desensitization upon chronic exposure to nicotine. The same phenomenon has been reported for ?7nAChR expressed in cancer cells of the lungs and pancreas where chronic nicotine or nicotine-derived nitrosamines upregulated the receptor protein, resulting in hyperactivity of its effectors. Strategies that target the ?7nAChR for cancer intervention are highly promising but should aim to reduce signaling downstream of the receptor rather than blocking the receptor because of its numerous vital functions in the mammalian organism. PMID:22300035

Schuller, Hildegard M

2012-05-01

137

Ni nanoparticle catalyzed growth of MWCNTs on Cu NPs @ a-C:H substrate  

NASA Astrophysics Data System (ADS)

NiCu NPs @ a-C:H thin films with different Cu content were prepared by co-deposition by RF-sputtering and RF-plasma enhanced chemical vapor deposition (RF-PECVD) from acetylene gas and Cu and Ni targets. The prepared samples were used as catalysts for growing multi-wall carbon nanotubes (MWCNTs) from liquid petroleum gas (LPG) at 825 °C by thermal chemical vapor deposition (TCVD). By addition of Cu NPs @ a-C:H thin layer as substrate for Ni NPs catalyst, the density of the grown CNTs is greatly enhanced in comparison to bare Si substrate. Furthermore the average diameter of the grown CNTs decreases by decreasing of Cu content of Cu NPs @ a-C:H thin layer. However Cu NPs @ a-C:H by itself has no catalytic property in MWCNTs growth. Morphology and electrical and optical properties of Cu NPs @ a-C:H thin layer is affected by Cu content and each of them is effective parameter on growth of MWCNTs based on Ni NPs catalyst. Moreover, adding of a low amount of Ni NPs doesn't vary optical, electrical and morphology properties of Cu NPs @ a-C:H thin layer but it has a profound effect on its catalytic activity. Finally the density and diameter of MWCNTs can be optimized by selection of the Cu NPs @ a-C:H thin layer as substrate of Ni NPs.

Ghodselahi, T.; Solaymani, S.; Akbarzadeh Pasha, M.; Vesaghi, M. A.

2012-11-01

138

Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.  

PubMed

Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

Pohanka, Miroslav

2014-01-01

139

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity  

PubMed Central

Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

Pohanka, Miroslav

2014-01-01

140

Screening of new huprines--inhibitors of acetylcholinesterases by electrospray ionization ion trap mass spectrometry.  

PubMed

Acetylcholinesterase inhibitors (AChEI) are one of the drugs families validated for clinical use in the treatment of Alzheimer's disease (AD). For this reason, finding new more potent and more selective AChEIs is always of interest. Since 1961, the inhibitory activity of AChEI is evaluated through the Ellman's method. Herein, we reported a MS-based evaluation of potential new AChEI with the determination of their inhibitory activity (IC(50) and K(I)). Compared to the Ellman's method, that uses the substrate analog acetylthiocholine, the electrospray ionization ion trap mass spectrometry (ESI-IT-MS) consists in monitoring the conversion ratio of a low concentration of the natural substrate - acetylcholine to choline. We present here the inhibition activity of huprine X and six of its derivates (bearing different functional groups at position 9) towards the recombinant human (rhAChE) and Electrophorus electricus acetylcholinesterase (EelAChE). Mechanisms of action of selected inhibitors were evaluated by means of Lineweaver-Burk plot analysis. The Michaelis-Menten constants (K(M)), inhibitory constants (K(I)) were examined as well as the IC(50) to allow classifying a series of huprine derivatives by inhibition potency by a comparison with a reference (huprine X). Our results demonstrate that these drugs are very potent AChE inhibitors, especially (±)-huprine 6 with an inhibitory activity on recombinant human AChE (rhAChE) in the picomolar range. This study reveals the interest of huprine compounds in the treatment of AD. PMID:22677656

Ziemianin, Anna; Ronco, Cyril; Dolé, Romain; Jean, Ludovic; Renard, Pierre-Yves; Lange, Catherine M

2012-11-01

141

Effect of Desiccating Environmental Stress Versus Systemic Muscarinic AChR Blockade on Dry Eye Immunopathogenesis  

PubMed Central

Purpose. A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. Methods. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b+ and conjunctival CD3+ T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. Results. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3+ T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. Conclusions. In vivo inhibition of mAChRs variably affects CD4+ T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

Chen, Yihe; Chauhan, Sunil K.; Lee, Hyun Soo; Stevenson, William; Schaumburg, Chris S.; Sadrai, Zahra; Saban, Daniel R.; Kodati, Shilpa; Stern, Michael E.; Dana, Reza

2013-01-01

142

Hydrogenated amorphous carbon (a:C-H) in the planetary nebula NGC 7027  

NASA Technical Reports Server (NTRS)

A spectroscopic identification of the infrared continuum radiation is proposed for the planetary nebula NGC 7027. Hydrogenated amorphous carbon (a:C-H) is shown to account for the undulating spectrum between 5 and 15 microns. The unidentified infrared emission bands lie at the peaks in the a:C-H spectrum, pointing to their association with a carbon polymorph, possibly a:C-H or polycyclic aromatic hydrocarbon molecules. Except for atomic emission lines, all the infrared emission from NGC 7027 comes from one or another polymorph of carbon.

Goebel, John H.

1987-01-01

143

Silver nanoparticles inhibit the gill Na(+)/K(+)-ATPase and erythrocyte AChE activities and induce the stress response in adult zebrafish (Danio rerio).  

PubMed

Silver nanoparticles (AgNPs) are the most commonly used metallic nanoparticles in industrial applications, including medical and consumer products. In the recent years, however, concerns regarding their environmental and health impacts have emerged. Aquatic organisms are of special concern since water bodies often serve as sinks for anthropogenic activities. This study assessed the effects of AgNPs on the activities of the gill Na(+)/K(+)-ATPase and erythrocyte acetylcholinestrase (AChE), as well as the plasma biochemistry in adult zebrafish (Danio rerio). In an acute exposure scenario the fish were exposed for 4d to 16.76mg/L AgNPs, which was the 96h LC50 value determined in preliminary experiments. In a prolonged exposure scenario the fish were exposed for 1, 2, or 3 weeks to AgNPs at concentrations of 2 and 4mg/L, corresponding to the 1/10th and 2/10th of the 96h LC50 value. Generally the activity of the gill Na(+)/K(+)-ATPase decreased, but this was only significant starting at 14d of the prolonged exposure scenario, whereas the activity of the erythrocyte AChE was significantly decreased in both exposure scenarios. Finally, the plasma electrolytes levels were reduced and the plasma glucose and cortisol levels were increased in exposed fish. This study demonstrates that AgNPs could inhibit the activities of Na(+)/K(+)-ATPase and AChE, thus interfering with the proper ionoregulation and neuroregulation, respectively, and act as stressors. PMID:24840880

Katuli, Kheyrollah Khosravi; Massarsky, Andrey; Hadadi, Ali; Pourmehran, Zahra

2014-08-01

144

Quaternary ecology: A paleoecological perspective  

SciTech Connect

This book considers issues and problems in ecology which may be illuminated, if not solved, by considering paleoecology. The five central chapters include a discussion of application of Quaternary ecology to future global climate change, including global warming. Other areas presented include: population dispersal, invasions, expansions, and migrations; plant successions; ecotones; factors in community structure; ecosystem patterns and processes. Published case studies are numerous. The role played by continuing climatic change in vegetation change is acknowledged but not stressed.

Delcourt, H.R.; Delcourt, P.A.

1991-01-01

145

Effect of cycloart-24-en-3beta-ol from Euphorbia royleana latex on neuroenzyme AChE and oxidative metabolism of freshwater fish, Channa punctatus.  

PubMed

Cycloart-24-en-3beta-ol isolated from Euphorbia royleana latex possesses potent piscicidal activity against freshwater predatory fish Channa punctatus. Their short as well as long-term exposure causes significant (P<0.05) time and dose-dependent reversible alteration in the oxidative metabolism of the fish Channa punctatus Cycloart-24-en-3beta-ol also shifts fish respiratory pathway, inhibits energy production and AChE activity reversibly may be advantageous for their use as environmentally safe piscicide for controlling the predatory fish C. punctatus population from carp culture ponds. PMID:20161954

Tiwari, Sudhanshu; Pandey, Rp; Singh, Ajay

2008-01-01

146

Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain.  

PubMed

A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC50 of 15.0, 11.5, 12.5 microM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 microM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE. PMID:17373546

Zheng, Zhi-Hui; Dong, Yue-Sheng; Zhang, Hua; Lu, Xin-Hua; Ren, Xiao; Zhao, Guiyu; He, Jian-Gong; Si, Shu-Yi

2007-02-01

147

Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression.  

PubMed

Two different signalling pathways mediate the localization of acetylcholine receptors (AChRs) to synaptic sites in skeletal muscle. The signal for one pathway is agrin, a protein that triggers a redistribution of previously unlocalized cell surface AChRs to synaptic sites. The signal for the other pathway is not known, but this signal stimulates transcription of AChR genes in myofibre nuclei near the synaptic site. Neuregulins, identified originally as a potential ligand for erbB2 (Neu differentiation factor, NDF), stimulate proliferation of Schwann cells (glial growth factor, GGF), increase the rate of AChR synthesis in cultured muscle cells (AChR-inducing activity) and are expressed in motor neurons. These results raise the possibility that neuregulin is the signal that activates AChR genes in synaptic nuclei. Here we show that neuregulin activates AChR gene expression in C2 muscle cells and that the neuregulin response element in the AChR delta-subunit gene is contained in the same 181 base pairs that confer synapse-specific expression in transgenic mice. We use antibodies to show that neuregulins are concentrated at synaptic sites and that, like the extracellular signal that stimulates synapse-specific expression, neuregulins remain at synaptic sites in the absence of nerve and muscle. We show that C2 muscle cells contain erbB2 and erbB3 messenger RNA but little or no erbB4 mRNA, and that neuregulin stimulates tyrosine phosphorylation of erbB2 and erbB3, indicating that neuregulin signalling in skeletal muscle may be mediated by a complex of erbB2 and erbB3. PMID:7816098

Jo, S A; Zhu, X; Marchionni, M A; Burden, S J

1995-01-12

148

40 CFR 721.10582 - Quaternary ammonium compound (generic).  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Quaternary ammonium compound (generic). 721.10582 Section... § 721.10582 Quaternary ammonium compound (generic). (a) Chemical substance...identified generically as quaternary ammonium compound (PMN P-10-571) is subject...

2013-07-01

149

40 CFR 721.655 - Ethoxylated alkyl quaternary ammonium compound.  

Code of Federal Regulations, 2013 CFR

...Ethoxylated alkyl quaternary ammonium compound. 721.655 Section 721.655 ...Ethoxylated alkyl quaternary ammonium compound. (a) Chemical substance and significant...ethoxylated alkyl quaternary ammonium compound (PMN P-96-573) is subject...

2013-07-01

150

Effect of low benzene exposure on neurobehavioral function, AChE in blood and brain and bone marrow picture in mice  

SciTech Connect

The purpose of this study was to examine the effect of low level benzene exposure on neurobehavioral functions, AChE in blood and brain, bone marrow picture in Kunming mice. Forty adult Kunming male mice were divided into 4 groups. They were exposed to 12.52, 3.13, 0.78 and 0 ppm benzene for 2 h.d-1 for 30 d. Central nervous system (CNS) function was inhibited by 12.52 ppm and excited by 0.78 ppm benzene exposure, but irregularly affected by 3.13 ppm. AChE in blood and brain was decreased in 12.52, 3.13 ppm group. The weight of liver to body weight ratios in 12.52 ppm group was higher than those of control group significantly. Bone marrow picture revealed inhibited proliferation of white and red cell systems, especially in 12.52 ppm group, consisting of decrease of percentage of myeloblast, premyelocytes, myelocytes, erythroblasts and megakaryocytes, especially in 12.52 ppm group.

Sun, W.; Gong, Z.; Li, X. (Beijing Medical Univ. (China))

1992-12-01

151

In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers.  

PubMed

A series of bis-pyridinium oximes connected by xylene linkers were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by nerve agent sarin and the data were compared with 2-PAM and obidoxime. Among the synthesized compounds, N,N'-p-xylene-bis-[(2,2'-hydroxyiminomethyl)pyridinium] dibromide (3c) was found to be the most potent reactivator for hAChE inhibited by sarin. The oxime 3c exhibited 45% regeneration of inhibited hAChE, in comparison to 34% and 24% regeneration by 2-PAM and obidoxime, respectively, at a concentration of 10(-3) M within 10 min. The higher reactivation efficacies of these oximes were attributed to their acid dissociation constants (pKa). The pKa values of all the oximes were determined spectrophotometrically and correlated with their observed reactivation potential. This method involving the in vitro reactivation of inhibited hAChE may be useful for the screening of new oximes as reactivators. PMID:20688148

Acharya, Jyotiranjan; Dubey, Devendra Kumar; Srivastava, Ashish Kumar; Raza, Syed Kalbey

2011-02-01

152

Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening  

PubMed Central

In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer's randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

Gupta, Shikhar; Mohan, C. Gopi

2014-01-01

153

[Acetylcholinesterase inhibitors for treatment of Alzheimer's disease].  

PubMed

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder, and is the commonest cause of dementia. Acetylcholinesterase inhibitors (AChEIs) were developed under the cholinergic hypothesis of AD. Therapeutic strategies with these drugs aimed to enhance cholinergic neurotransmission in specific parts of the brain, and to improve the clinical symptoms of AD. Donepezil, galantamine and rivastigmine are commonly used AChEIs in pharmacotherapy for AD, slowing the progression and controlling the symptoms of AD. Although these drugs have different pharmacological properties, there is no clear evidence of differences between them with respect to efficacy. It is possible to adapt AChEIs for the pharmacotherapy of other conditions, such as vascular dementia, dementia with Lewy bodies, and Down syndrome. PMID:24807367

Shinagawa, Shunichiro; Shigeta, Masahiro

2014-05-01

154

Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies.  

PubMed

One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC?? values of 2.36-9.43 ?M. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC?? values of lower than 10 ?M displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC?? values of 7.44-19.12 ?M. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC?? values of 2.35 and 3.21 ?M, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated Ki values of 2.01 and 6.76 ?M, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC?? values and free binding energy values of the synthesized compounds docked into the active site of the enzymes. PMID:24461561

Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Basiri, Alireza; Murugaiyah, Vikneswaran

2014-02-15

155

Kinetic inhibitor of hydrate crystallization.  

PubMed

We present the results of a combined theoretical/experimental study into a new class of kinetic inhibitor of gas hydrate formation. The inhibitors are based on quaternary ammonium zwitterions, and were identified from a computational screen. Molecular dynamics simulations were used to characterize the effect of the inhibitor on the interface between a type II hydrate and natural gas. These simulations show that the inhibitor is bifunctional, with the hydrophobic end being compatible with the water structure present at the hydrate interface, while the negatively charged functional group promotes a long ranged water structure that is inconsistent with the hydrate phase; the sulfonate-induced structure was found to propagate strongly over several solvation shells. The compound was subsequently synthesized and used in an experimental study of both THF and ethane hydrate formation, and was shown to have an activity that was comparable with an existing commercial kinetic inhibitor: PVP. PMID:14759217

Storr, Mark T; Taylor, Paul C; Monfort, Jean-Pierre; Rodger, P Mark

2004-02-11

156

Chemical chaperones exceed the chaperone effects of RIC-3 in promoting assembly of functional ?7 AChRs.  

PubMed

Functional ?7 nicotinic acetylcholine receptors (AChRs) do not assemble efficiently in cells transfected with ?7 subunits unless the cells are also transfected with the chaperone protein RIC-3. Despite the presence of RIC-3, large amounts of these subunits remain improperly assembled. Thus, additional chaperone proteins are probably required for efficient assembly of ?7 AChRs. Cholinergic ligands can act as pharmacological chaperones to promote assembly of mature AChRs and upregulate the amount of functional AChRs. In addition, we have found that the chemical chaperones 4-phenylbutyric acid (PBA) and valproic acid (VPA) greatly increase the amount of functional ?7 AChRs produced in a cell line expressing both ?7 and RIC-3. Increased ?7 AChR expression allows assay of drug action using a membrane potential-sensitive fluorescent indicator. Both PBA and VPA also increase ?7 expression in the SH-SY5Y neuroblastoma cell line that endogenously expresses ?7 AChRs. VPA increases expression of endogenous ?7 AChRs in hippocampal neurons but PBA does not. RIC-3 is insufficient for optimal assembly of ?7 AChRs, but provides assay conditions for detecting additional chaperones. Chemical chaperones are a useful pragmatic approach to express high levels of human ?7 AChRs for drug selection and characterization and possibly to increase ?7 expression in vivo. PMID:23638015

Kuryatov, Alexander; Mukherjee, Jayanta; Lindstrom, Jon

2013-01-01

157

Chemical Chaperones Exceed the Chaperone Effects of RIC-3 in Promoting Assembly of Functional ?7 AChRs  

PubMed Central

Functional ?7 nicotinic acetylcholine receptors (AChRs) do not assemble efficiently in cells transfected with ?7 subunits unless the cells are also transfected with the chaperone protein RIC-3. Despite the presence of RIC-3, large amounts of these subunits remain improperly assembled. Thus, additional chaperone proteins are probably required for efficient assembly of ?7 AChRs. Cholinergic ligands can act as pharmacological chaperones to promote assembly of mature AChRs and upregulate the amount of functional AChRs. In addition, we have found that the chemical chaperones 4-phenylbutyric acid (PBA) and valproic acid (VPA) greatly increase the amount of functional ?7 AChRs produced in a cell line expressing both ?7 and RIC-3. Increased ?7 AChR expression allows assay of drug action using a membrane potential-sensitive fluorescent indicator. Both PBA and VPA also increase ?7 expression in the SH-SY5Y neuroblastoma cell line that endogenously expresses ?7 AChRs. VPA increases expression of endogenous ?7 AChRs in hippocampal neurons but PBA does not. RIC-3 is insufficient for optimal assembly of ?7 AChRs, but provides assay conditions for detecting additional chaperones. Chemical chaperones are a useful pragmatic approach to express high levels of human ?7 AChRs for drug selection and characterization and possibly to increase ?7 expression in vivo.

Kuryatov, Alexander; Mukherjee, Jayanta; Lindstrom, Jon

2013-01-01

158

Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore  

SciTech Connect

Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 {angstrom} in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radi, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer (UCB); (UCSD)

2008-07-28

159

NMR Structures of the Transmembrane Domains of the ?4?2 nAChR  

PubMed Central

The ?4?2 nicotinic acetylcholine receptor (nAChR) is the predominant heteromeric subtype of nAChRs in the brain, which has been implicated in numerous neurological conditions. The structural information specifically for the ?4?2 and other neuronal nAChRs is presently limited. In this study, we determined structures of the transmembrane (TM) domains of the ?4 and ?2 subunits in lauryldimethylamine-oxide (LDAO) micelles using solution NMR spectroscopy. NMR experiments and size exclusion chromatography–multi-angle light scattering (SEC-MALS) analysis demonstrated that the TM domains of ?4 and ?2 interacted with each other and spontaneously formed pentameric assemblies in the LDAO micelles. The Na+ flux assay revealed that ?4?2 formed Na+ permeable channels in lipid vesicles. Efflux of Na+ through the ?4?2 channels reduced intra-vesicle Sodium Green™ fluorescence in a time-dependent manner that was not observed in vesicles without incorporating ?4?2. The study provides the structural insight into the TM domains of the ?4?2 nAChR. It offers a valuable structural framework for rationalizing extensive biochemical data collected previously on the ?4?2 nAChR and for designing new therapeutic modulators.

Bondarenko, Vasyl; Mowrey, David; Tillman, Tommy; Cui, Tanxing; Liu, Lu Tian; Xu, Yan; Tang, Pei

2012-01-01

160

Time-Resolved Photolabeling of the Nicotinic Acetylcholine Receptor by [3H]Azietomidate, an Open-State Inhibitor  

PubMed Central

Azietomidate is a photoreactive analog of the general anesthetic etomidate that acts as a nicotinic acetylcholine receptor (nAChR) noncompetitive antagonist. We used rapid perfusion electrophysiological techniques to characterize the state dependence and kinetics of azietomidate inhibition of Torpedo californica nAChRs and time-resolved photolabeling to identify the nAChR binding sites occupied after exposure to [3H]azietomidate and agonist for 50 ms (open state) or at equilibrium (desensitized state). Azietomidate acted primarily as an open channel inhibitor characterized by a bimolecular association rate constant of k+ = 5 × 105 M-1 s-1 and a dissociation rate constant of <3s-1. Azietomidate at 10 ?M, when perfused with acetylcholine (ACh), inhibited the ACh response by ?50% after 50 ms; when preincubated for 10 s, it decreased the peak initial response by ?15%. Comparison of the kinetics of recovery of ACh responses after exposure to ACh and azietomidate or to ACh alone indicated that at subsecond times, azietomidate inhibited nAChRs without enhancing the kinetics of agonist-induced desensitization. In nAChRs frozen after 50-ms exposure to agonist and [3H]azietomidate, amino acids were photolabeled in the ion channel [position M2-20 (?Glu-262, ?Asp-268, ?Gln-276)], in ?M1 (?Cys-236), and in ?MA/?M4 (?Glu-390, ?Cys-412) that were also photolabeled in nAChRs in the equilibrium desensitized state at approximately half the efficiency. These results identify azietomidate binding sites at the extracellular end of the ion channel, in the ? subunit helix bundle, and in the nAChR cytoplasmic domain that seem similar in structure and accessibility in the open and desensitized states of the nAChR.

Chiara, David C.; Hong, Filbert H.; Arevalo, Enrique; Husain, S. Shaukat; Miller, Keith W.; Forman, Stuart A.; Cohen, Jonathan B.

2009-01-01

161

Inhibitors of asparagine-linked oligosaccharide processing alter the kinetics of the nicotinic acetylcholine receptor  

PubMed Central

We used selective inhibitors of the asparagine-linked oligosaccharide processing pathway to study the effect of sugar trimming on the functional properties of the nicotinic acetylcholine (ACh) receptor expressed in clonal mammalian BC3H-1 cells. Inhibitors of initial steps of the processing pathway (1-deoxynojirimycin[DNJ] and castanospermine[CS]) reduced the density of ACh receptors on the cell surface (3- to 5-fold) but their responsiveness to ACh was more reduced (5- to 10-fold). These results suggest that the function of the ACh receptor was altered. When the ACh receptors were expressed in the presence of DNJ or CS, analysis of ACh-evoked single-channel currents (- 100 mV and 11 degrees C) revealed an approximate threefold reduction in the opening rate (control: 600-650 s(-1)), treated: 130-250 s(-1)) and an approximate twofold reduction in the rate of agonist dissociation (control: 900-1,000 s(-1), treated: 400-500 s(-1)). In addition, the proportion of brief duration bursts (tau = 50-100 microseconds) was increased (1.5- to 2-fold) by treatments with DNJ or CS. In contrast, an inhibitor of a late processing step (swainsonine) did not produce such alterations. The single-channel conductance was not altered by any of the three inhibitors, and the slopes of log-log dose-response curves at low concentrations and desensitization did not appear to be affected. Each inhibitor altered the electrophoretic mobility of the ACh receptor subunits. We conclude that early sugar trimming can influence the kinetics of the nicotinic ACh receptor in BC3H-1 cells.

1989-01-01

162

Discrimination of agonists versus antagonists of nicotinic ligands based on docking onto AChBP structures.  

PubMed

Numerous high-resolution crystallographic structures of the acetylcholine binding protein (AChBP), a molluscan cholinergic protein, homologous to the extracellular domain of nicotinic acetylcholine receptors, are available. This offers opportunities to model the interaction between various ligands and the acetylcholine binding site. Herein we present a study of the interplay between ligand binding and motions of the C-loop capping the binding site. Nicotinic agonists and antagonists were docked on AChBP X-ray structures. It is shown that the studied agonists and antagonists can be discriminated according to their higher affinities for structures respectively obtained in the presence of agonists or antagonists, highlighting the fact that AChBP structures retain a pharmacological footprint of the compound used in crystallography experiments. A detailed analysis of the binding site cavities suggests that this property is mainly related to the shape of the cavities. PMID:21764343

Taly, Antoine; Colas, Claire; Malliavin, Thérèse; Blondel, Arnaud; Nilges, Michael; Corringer, Pierre-Jean; Joseph, Delphine

2011-09-01

163

Treatment-responsive pandysautonomia in an adolescent with ganglionic ?3-AChR antibodies.  

PubMed

Autoimmune autonomic ganglionopathy (AAG) is a rare disorder that presents with pandysautonomia typically in middle age and elderly patients. AAG is typically associated with serum autoantibodies that bind to the alpha-3 subunit of the ganglionic acetylcholine receptor (?3-AChR Ab). We report a 13 year old girl who presented with gut pseudo-obstruction, bladder dysfunction and dilated pupils unresponsive to pilocarpine. She had positive ?3-AChR Ab plus other autoantibodies suggesting an autoimmune diathesis. Our patient was initially resistant to steroid therapy but responded to the addition of azathioprine resulting in a near complete clinical remission. We conclude that pandysautonomia associated with ?3-AChR Ab can occur in children and has multi-organ involvement. PMID:22130491

Dale, Russell C; Lang, Bethan; Brilot, Fabienne; Polfrit, Yann; Smith, Grahame H H; Wong, Melanie

2012-07-01

164

A mutation in the extracellular domain of the ?7 nAChR reduces calcium permeability.  

PubMed

The ?7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the ?7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat ?7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the ?7 nAChR plays a key role in calcium permeation. PMID:24177919

Colón-Sáez, José O; Yakel, Jerrel L

2014-08-01

165

Local neurotrophic repression of gene transcripts encoding fetal AChRs at rat neuromuscular synapses  

PubMed Central

The spatio-temporal expression patterns of mRNA transcripts coding for acetylcholine receptor (AChR) subunits and myogenic factors were measured in denervated rat soleus muscle and in soleus muscle chronically paralyzed for up to 12 d by conduction block of the sciatic nerve by tetrodotoxin (TTX). In denervated muscle the AChR alpha-, beta- , gamma-, and delta-subunit mRNAs were elevated with highest expression levels in the former synaptic and the perisynaptic region and with lower levels in the extrasynaptic fiber segments. In muscle paralyzed by nerve conduction block the alpha-, beta-, gamma-, and delta-subunit mRNA levels increased only in extrasynaptic fiber segments. Surprisingly, in the synaptic region the gamma-subunit mRNA that specifies the fetal-type AChR, and alpha-, beta-, delta-subunit mRNAs were not elevated. The expression of the gene encoding the epsilon- subunit, which specifies the adult-type AChR, was always restricted to synaptic nuclei. The mRNA for the regulatory factor myogenin showed after denervation similar changes as the subunit transcripts of the fetal AChR. When the muscle was paralyzed by nerve conduction block the increase of myogenin transcripts was also less pronounced in synaptic regions compared to extrasynaptic fiber segments. The results suggest that in normal soleus muscle a neurotrophic signal from the nerve locally down-regulates the expression of fetal-type AChR channel in the synaptic and perisynaptic muscle membrane by inhibiting the expression of the gamma-subunit gene and that inhibition of the myogenin gene expression may contribute to this down-regulation.

1995-01-01

166

Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages  

PubMed Central

Background Due to the emergency of multidrug-resistant strains of Mycobacterium tuberculosis, is necessary the evaluation of new compounds. Findings Tedizolid, a novel oxazolidinone, and ACH-702, a new isothiazoloquinolone, were tested against M. tuberculosis infected THP-1 macrophages. These two compounds significantly decreased the number of intracellular mycobacteria at 0.25X, 1X, 4X and 16X the MIC value. The drugs were tested either in nanoparticules or in free solution. Conclusion Tedizolid and ACH-702 have a good intracellular killing activity comparable to that of rifampin or moxifloxacin.

2014-01-01

167

Tribological Properties of Nanocomposite CrC x \\/aC:H Thin Films  

Microsoft Academic Search

Recently we showed that coatings, prepared by unbalanced magnetron sputtering from a metallic Cr target in an Ar\\/CH4 discharge are composed of nanocrystalline CrC\\u000a x\\u000a embedded in an a-C:H matrix. This work investigates the structural correlation of such nanocomposite CrC\\u000a x\\u000a \\/a-C:H coatings to their tribological properties. Raman spectroscopy and X-ray photoelectron spectroscopy (XPS) were used\\u000a to characterize the phase

Gert Gassner; Jörg Patscheider; Paul H. Mayrhofer; Saso Šturm; Christina Scheu; Christian Mitterer

2007-01-01

168

Factors associated with severity of symptoms in patients with chronic unexplained muscular aching.  

PubMed Central

Subjects with chronic, diffuse, unexplained muscular aching were recruited--21 from a primary care practice, nine from a rheumatology practice, and two from a pain clinic. No additional criteria were used to select subjects. Subjects with mild or moderate symptoms differed from those with severe symptoms with respect to the following characteristics: the presence of fatigue on awakening, the number of tender points, difficulty in sleeping, and the degree of tenderness in typical fibromyalgia areas as measured by a dolorimeter. These findings suggest that muscular aching is likely to be of greater severity if other symptoms or signs of fibromyalgia are also present.

Kolar, E; Hartz, A; Roumm, A; Ryan, L; Jones, R; Kirchdoerfer, E

1989-01-01

169

Calcium/Calmodulin Kinase II-dependent AChR Cycling at the Mammalian Neuromuscular Junction in Vivo  

PubMed Central

At the mammalian skeletal neuromuscular junction, cycling of nicotinic acetylcholine receptors (nAChRs) is critical for the maintenance of a high postsynaptic receptor density. However, the mechanisms that regulate nAChRs recycling in living animals remain unknown. Using in vivo time-lapse imaging, fluorescence recovery after photobleaching, and biochemical pull down assays, we demonstrated that recycling of internalized nAChRs into fully functional and denervated synapses was promoted by both direct muscle stimulation and pharmacologically induced intracellular calcium elevations. Most of internalized nAChRs are recycled directly into synaptic sites. Chelating of intracellular calcium below resting level drastically decreased cycling of nAChRs. Furthermore we found that calcium-dependent AChR recycling is mediated by Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of CaMKII selectively blocked recycling and caused intracellular accumulation of internalized nAChRs, whereas internalization of surface receptors remained unaffected. Electroporation of CaMKII-GFP isoforms into the sternomastoid muscle showed that muscle-specific CaMKII?m isoform is highly expressed at NMJ and precisely co-localized with nAChRs at crests of synaptic folds while the CaMKII? and ? isoforms are poorly expressed in synaptic sites. These results indicate that Ca2+ along with CaMKII activity are critical for receptor recycling and may provide a mechanism by which the postsynaptic AChR density is maintained at the NMJ in vivo.

Martinez-Pena y Valenzuela, Isabel; Mouslim, Chakib; Akaaboune, Mohammed

2010-01-01

170

Role of ACh-GABA cotransmission in detecting image motion and motion direction.  

PubMed

Starburst amacrine cells (SACs) process complex visual signals in the retina using both acetylcholine (ACh) and gamma-aminobutyric acid (GABA), but the synaptic organization and function of ACh-GABA corelease remain unclear. Here, we show that SACs make cholinergic synapses onto On-Off direction-selective ganglion cells (DSGCs) from all directions but make GABAergic synapses onto DSGCs only from the null direction. ACh and GABA were released differentially in a Ca(2+) level-specific manner, suggesting the two transmitters were released from different vesicle populations. Despite the symmetric cholinergic connection, the light-evoked cholinergic input to a DSGC, detected at both light onset and offset, was motion- and direction-sensitive. This input was facilitated by two-spot apparent motion in the preferred direction but supressed in the null direction, presumably by a GABAergic mechanism. The results revealed a high level of synaptic intricacy in the starburst circuit and suggested differential, yet synergistic, roles of ACh-GABA cotransmission in motion sensitivity and direction selectivity. PMID:21172616

Lee, Seunghoon; Kim, Kyongmin; Zhou, Z Jimmy

2010-12-22

171

Role of ACh-GABA co-transmission in detecting image motion and motion direction  

PubMed Central

Summary Starburst amacrine cells (SACs) process complex visual signals in the retina using both ACh and GABA, but the synaptic organization and function of ACh-GABA corelease remain unclear. Here, we show that SACs make cholinergic synapses onto On-Off direction-selective ganglion cells (DSGCs) from all directions, but make GABAergic synapses onto DSGCs only from the null direction. ACh and GABA were released differentially in a Ca2+ level-specific manner, suggesting the two transmitters were released from different vesicle populations. Despite the symmetric cholinergic connection, the light-evoked cholinergic input to a DSGC, detected at both light onset and offset, was motion- and direction-sensitive. This input was facilitated by two-spot apparent motion in the preferred direction, but supressed in the null direction, presumably by a GABAergic mechnism. The results revealed a new level of synaptic intricacy in the starburst circuit and suggest differential, yet synergistic, roles of ACh-GABA cotransmission in motion sensitivity and direction selectivity.

Lee, Seunghoon; Kim, Kyongmin; Zhou, Z. Jimmy

2010-01-01

172

Genome Sequence of the Octopine-Type Agrobacterium tumefaciens Strain Ach5  

PubMed Central

We have sequenced the complete genome of the plant pathogen Agrobacterium tumefaciens strain LBA4213, a derivative of the wild-type strain A. tumefaciens Ach5 and the ancestor of A. tumefaciens strain LBA4404 used in genetic engineering. The genome consists of a circular chromosome and a linear chromosome, as well as a megaplasmid and a tumor-inducing plasmid.

Henkel, Christiaan V.; den Dulk-Ras, Amke; Zhang, Xiaorong

2014-01-01

173

Age-dependency in hunting ability among the Ache of Eastern Paraguay  

Microsoft Academic Search

This paper examines changes in hunting ability across the lifespan for the Ache of eastern Paraguay. Hunting ability is decomposed into two components—finding prey and probability of kill upon encounter— and analyzed for important prey species. Results support the argument that skill acquisition is an important aspect of the human foraging niche with hunting outcome variables reaching peaks surprisingly late

Robert Walker; Kim Hill; Hillard Kaplan; Garnett McMillan

2002-01-01

174

Acrodermatitis continua of Hallopeau (ACH): two cases successfully treated with adalimumab.  

PubMed

Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare acropustular eruption, characterized by sterile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes. While some consider ACH a distinct entity, many believe it to be a variant of pustular psoriasis, especially as cases of ACH progressing to generalized pustular psoriasis. The treatment options used are various; however, its typical cyclic recurrences, which induce important physical and psychological morbidity, may render this pathology difficult to treat. Hence, it was considered important to review the evolution of?treatment?options available thus far including use of biologics. Hereby, we report two patients with ACH who were successfully treated with adalimumab. By analogy to the efficacy of TNF-? antagonists in the?treatment?of generalized pustular psoriasis, the two patients we report illustrate the long-term efficacy and safety of adalimumab in the?treatment?of? Hallopeau's acrodermatitis refractory to therapies. PMID:24215490

Di Costanzo, Luisa; Napolitano, Maddalena; Patruno, Cataldo; Cantelli, Mariateresa; Balato, Nicola

2014-12-01

175

Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition  

Microsoft Academic Search

Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and

Jeroen C. Verheijen; Kjesten A. Wiig; Shoucheng Du; Stacie L. Connors; Ashley N. Martin; Jennifer P. Ferreira; Vladimir I. Slepnev; Ulrike Kochendörfer

2009-01-01

176

Metaproterenol, isoproterenol, and their bisdimethylcarbamate derivatives as human cholinesterase inhibitors.  

PubMed

Metaproterenol and isoproterenol are bronchodilators that provide a structural basis for many other bronchodilators currently in use. One of these structurally related bronchodilators is terbutaline; it is administered as a prodrug, bambuterol, and is metabolized (bioconverted) into terbutaline by butyrylcholinesterase (BChE). The metabolism rate can be affected by BChE gene polymorphism in the human population and BChE stereoselectivity. The aim of our study was to investigate inhibition of human BChE and acetylcholinesterase (AChE) with metaproterenol, isoproterenol, and newly synthesized racemic bisdimethylcarbamate derivatives of metaproterenol (metacarb) and isoproterenol (isocarb) and their (R)-enantiomers to see if their bioconversion is affected by BChE inhibition in the same way as that for bambuterol. Metacarb and isocarb proved to be selective BChE inhibitors, as they progressively inhibited AChE 960 to 80 times more slowly than BChE(UU). All studied cholinesterases displayed poor affinity for metaproterenol and isoproterenol, yet BChE(UU) had an affinity about five times higher than that of AChE. PMID:22817559

Bosak, Anita; Gazi? Smilovi?, Ivana; Sinko, Goran; Vinkovi?, Vladimir; Kovarik, Zrinka

2012-08-01

177

Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer's Disorders Using Molecular Docking and Molecular Dynamics Simulation  

PubMed Central

Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000?ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000?ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential.

Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

2014-01-01

178

Identification of potential herbal inhibitor of acetylcholinesterase associated Alzheimer's disorders using molecular docking and molecular dynamics simulation.  

PubMed

Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000?ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000?ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential. PMID:25054066

Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

2014-01-01

179

Colocalization of ATP and nicotinic ACh receptors in the identified vagal preganglionic neurone of rat.  

PubMed Central

1. Effects of exogenous adenosine 5'-triphosphate (ATP) and acetylcholine (ACh) were investigated on acutely dissociated preganglionic neurones in the dorsal motor nucleus of vagus (DMV) of rats using whole-cell patch clamp recording methods. 2. The DMV neurones identified by retrograde transport of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) fixed onto the cervical vagal nerve bundle were large in size (25-35 microns diameter) and bipolar or tripolar in shape. 3. About 90% of DiI labelled DMV neurones responded to both ATP (10(-4) M) and ACh (10(-4) M) with inward currents at a holding potential (Vh) of -40 mV. 4. The ATP-induced current (IATP) and the ACh-induced current (IACh) reversed their polarities at membrane potentials between +5 and +15 mV, indicating that ATP and ACh increase the membrane permeability to cations. 5. The inhibitory potency of Reactive Blue on 5 x 10(-4) M IATP is more effective (concentration for half-inhibition (IC50), 4.4 x 10(-7) M) than suramin (IC50, 6.0 x 10(-6) M). In addition, alpha,beta-methylene ATP up to 10(-4) M could not induce any current. As intracellular application of guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) did not block the IATP, the IATP was mediated not by guanosine triphosphate (GTP) binding protein, but rather by ligand-gated ionic channels, presumably via P2X receptors. 6. Currents produced by ACh were due to activation of nicotinic receptors because they were mimicked by nicotine and carbachol, and blocked by hexamethonium. In addition, muscarine evoked no response. 7. Only 25% of nucleus tractus solitarii (NTS) neurones and no hypoglossal neurones responded to the exogenous application of ATP. 8. These results suggest that vagal preganglionic neurones colocalize functionally nicotinic and P2X purinergic receptors. Images Figure 1

Nabekura, J; Ueno, S; Ogawa, T; Akaike, N

1995-01-01

180

Analysis of rare variations reveals roles of amino acid residues in the N-terminal extracellular domain of nicotinic acetylcholine receptor (nAChR) alpha6 subunit in the functional expression of human alpha6*-nAChRs  

PubMed Central

Background Functional heterologous expression of naturally-expressed and apparently functional mammalian ?6*-nicotinic acetylcholine receptors (nAChRs; where ‘*’ indicates presence of additional subunits) has been difficult. Here we wanted to investigate the role of N-terminal domain (NTD) residues of human (h) nAChR ?6 subunit in the functional expression of h?6*-nAChRs. To this end, instead of adopting random mutagenesis as a tool, we used 15 NTD rare variations (i.e., Ser43Pro, Asn46Lys, Asp57Asn, Arg87Cys, Asp92Glu, Arg96His, Glu101Lys, Ala112Val, Ser156Arg, Asn171Lys, Ala184Asp, Asp199Tyr, Asn203Thr, Ile226Thr and Ser233Cys) in nAChR h?6 subunit to probe for their effect on the functional expression of h?6*-nAChRs. Results N-terminal ?-helix (Asp57); complementary face/inner ?-fold (Arg87 or Asp92) and principal face/outer ?-fold (Ser156 or Asn171) residues in the h?6 subunit are crucial for functional expression of the h?6*-nAChRs as variations in these residues reduce or abrogate the function of h?6h?2*-, h?6h?4- and h?6h?4h?3-nAChRs. While variations at residues Ser43 or Asn46 (both in N-terminal ?-helix) in h?6 subunit reduce h?6h?2*-nAChRs function those at residues Arg96 (?2-?3 loop), Asp199 (loop F) or Ser233 (?10-strand) increase h?6h?2*-nAChR function. Similarly substitution of NTD ?-helix (Asn46), loop F (Asp199), loop A (Ala112), loop B (Ala184), or loop C (Ile226) residues in h?6 subunit increase the function of h?6h?4-nAChRs. All other variations in h?6 subunit do not affect the function of h?6h?2*- and h?6h?4*-nAChRs. Incorporation of nAChR h?3 subunits always increase the function of wild-type or variant h?6h?4-nAChRs except for those of h?6(D57N, S156R, R87C or N171K)h?4-nAChRs. It appears Asp57Lys, Ser156Arg or Asn171Lys variations in h?6 subunit drive the h?6h?4h?3-nAChRs into a nonfunctional state as at spontaneously open h?6(D57N, S156R or N171K)h?4h?3V9’S-nAChRs (V9’S; transmembrane II 9’ valine-to-serine mutation) agonists act as antagonists. Agonist sensitivity of h?6h?4- and/or h?6h?4h?3-nAChRs is nominally increased due to Arg96His, Ala184Asp, Asp199Tyr or Ser233Cys variation in h?6 subunit. Conclusions Hence investigating functional consequences of natural variations in nAChR h?6 subunit we have discovered additional bases for cell surface functional expression of various subtypes of h?6*-nAChRs. Variations (Asp57Asn, Arg87Cys, Asp92Glu, Ser156Arg or Asn171Lys) in h?6 subunit that compromise h?6*-nAChR function are expected to contribute to individual differences in responses to smoked nicotine.

2014-01-01

181

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

PubMed

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 ?M 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 ?M. 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). PMID:24675179

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

2014-05-01

182

New quaternary pyridine aldoximes as casual antidotes against nerve agents intoxications.  

PubMed

In this work, the ability of four newly synthesized oximes--K005 (1,3-bis(2-hydroxyiminomethylpyridinium) propane dibromide), K027 (1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide), K033 (1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide) and K048 (1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide) to reactivate acetylcholinesterase (AChE, EC 3.1.1.7) inhibited by nerve agents is summarized. Reactivation potency of these compounds was tested using standard in vitro reactivation test. Tabun, sarin, cyclosarin and VX agent were used as appropriate testing nerve agents. Rat brain AChE was used as a source of the enzyme. Efficacies of new reactivators to reactivate tabun-, sarin-, cyclosarin- and VX-inhibited AChE were compared with the currently used AChE reactivators (pralidoxime, obidoxime and HI-6). Oxime K048 seems to be promising reactivator of tabun-inhibited AChE. Its reactivation potency is significantly higher than that of HI-6 and pralidoxime and comparable with the potency of obidoxime. The best reactivator of sarin-inhibited AChE seems to be oxime HI-6. None of the new AChE reactivators reached comparable reactivation potency. The same results were obtained for cyclosarin-inhibited AChE. However, oxime K033 is also potent reactivator of AChE inhibited by this nerve agent. In the case of VX inhibition, obidoxime and new oximes K027 and K048 seem to be the best AChE reactivators. None from the currently tested AChE reactivators is able to reactivate AChE inhibited by all nerve agents used and, therefore, the search for new potential broad spectrum AChE reactivators is needed. PMID:16170392

Kuca, Kamil; Bartosová, Lucie; Jun, Daniel; Patocka, Jirí; Cabal, Jirí; Kassa, Jirí; Kunesová, Gabriela

2005-06-01

183

Quaternary glaciation of Mount Everest  

NASA Astrophysics Data System (ADS)

The Quaternary glacial history of the Rongbuk valley on the northern slopes of Mount Everest is examined using field mapping, geomorphic and sedimentological methods, and optically stimulated luminescence (OSL) and 10Be terrestrial cosmogenic nuclide (TCN) dating. Six major sets of moraines are present representing significant glacier advances or still-stands. These date to >330 ka (Tingri moraine), >41 ka (Dzakar moraine), 24-27 ka (Jilong moraine), 14-17 ka (Rongbuk moraine), 8-2 ka (Samdupo moraines) and ˜1.6 ka (Xarlungnama moraine), and each is assigned to a distinct glacial stage named after the moraine. The Samdupo glacial stage is subdivided into Samdupo I (6.8-7.7 ka) and Samdupo II (˜2.4 ka). Comparison with OSL and TCN defined ages on moraines on the southern slopes of Mount Everest in the Khumbu Himal show that glaciations across the Everest massif were broadly synchronous. However, unlike the Khumbu Himal, no early Holocene glacier advance is recognized in the Rongbuk valley. This suggests that the Khumbu Himal may have received increased monsoon precipitation in the early Holocene to help increase positive glacier mass balances, while the Rongbuk valley was too sheltered to receive monsoon moisture during this time and glaciers could not advance. Comparison of equilibrium-line altitude depressions for glacial stages across Mount Everest reveals asymmetric patterns of glacier retreat that likely reflects greater glacier sensitivity to climate change on the northern slopes, possibly due to precipitation starvation.

Owen, Lewis A.; Robinson, Ruth; Benn, Douglas I.; Finkel, Robert C.; Davis, Nicole K.; Yi, Chaolu; Putkonen, Jaakko; Li, Dewen; Murray, Andrew S.

2009-07-01

184

Ice Age refugia and Quaternary extinctions: An issue of Quaternary evolutionary palaeoecology  

NASA Astrophysics Data System (ADS)

Quaternary palaeoecology, as a discipline, involves the analysis of a large range of fossil organisms from the last ca. 2 million years. This paper considers the role that these Quaternary records can take in better understanding the evolution of those organisms. We also discuss the surprisingly low uptake of evolutionary biology in Quaternary palaeoecological studies. This leads us to encourage an advance on both these fronts with a greater degree of collaboration with phylogeographic and ancient DNA researchers. These discussions accompany a summary of a special issue of Quaternary Science Reviews representing the proceedings of the XVII INQUA held in Cairns Australia in 2007. This special issue includes papers on a wide variety of Quaternary evolutionary palaeoecological and population dynamic subjects including extinct Pacific Island palm trees, Beringian beetles, Scandinavian trees, and the effects on human and animal populations of an extraterrestrial impact event in the Late Glacial of North America.

Stewart, John R.; Cooper, Alan

2008-12-01

185

Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.  

PubMed

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 30?M. 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. PMID:24853320

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

2014-07-01

186

Tobacco nitrosamine N-nitrosonornicotine as inhibitor of neuronal nicotinic acetylcholine receptors.  

PubMed

Nitrosamines are well known for their carcinogenic potential. Recently, it was found that some of them may also interact with human nicotinic acetylcholine receptor (nAChR) subtypes. This work studied the effects of N-nitrosonornicotine (NNN) on recombinant rat ?3?4 nAChR in HEK cells as well as on nAChR endogenously expressed in PC12 pheochromocytoma cells and in BC3H1 muscle-type cells. Whole-cell recording in combination with the cell-flow technique for agonist and inhibitor application in the millisecond time region revealed that NNN inhibits the activity of neuronal nAChR expressed in HEK or PC12, whereas weak inhibitory effects on muscle-type nAChR were observed at NNN concentrations up to 3 mM. Pharmacological actions of NNN and the inhibition mechanism were studied in detail using recombinant ?3?4 nAChR expressed in HEK cells as a model. NNN-induced inhibition of nicotine-evoked ?3?4 nAChR activity was dose-dependent with an inhibitory constant (IC(50)) of 0.92?±?0.05 mM. Analysis based on mathematical models indicated a noncompetitive inhibition mechanism of the rat ?3?4 nAChR by NNN. NNN's mechanism of action involves acceleration of conversion of the receptor from active to desensitized forms. In summary, this work shows that NNN inhibits rat ?3?4 nAChR in a noncompetitive way and interacts weakly with muscular nAChR. PMID:22847530

Nunes-Alves, Ariane; Nery, Arthur A; Ulrich, Henning

2013-01-01

187

Miniaturized electrochemical system for cholinesterase inhibitor detection.  

PubMed

The utility of a simple, low-cost detection platform for label-free electrochemical characterization of acetylcholinesterase (AChE) inhibition is demonstrated as a potential tool for screening of small-molecule therapeutic agents for Alzheimer's disease (AD). Technique validation was performed against the standard Ellman's colorimetric assay using the clinically established cholinesterase inhibitor (ChEI), Donepezil (Aricept(®)). Electrochemical measurements were obtained by differential pulse voltammetry (DPV) performed using a portable potentiostat system for detection of the enzymatic product, thiocholine (TCh), by direct oxidation on unmodified gold screen-printed electrodes. The IC50 profiles for Donepezil measured in vitro were found to be comparable between both colorimetric and electrochemical detection methods for the analysis of purified human erythrocyte-derived AChE (28±7 nM by DPV; 26±8 nM by Ellman's method). The selectivity of this unmodified electrode system was compared to a range of biological sulfur-containing compounds including cysteine, homocysteine, glutathione and methionine as well as ascorbic acid. Preliminary studies also demonstrated the potential applicability of this electrochemical technique for the analysis of Donepezil in crude cholinesterase samples from anterior cortex homogenates of C57BL/6J mice. PMID:23567119

Veloso, Anthony J; Nagy, Paul M; Zhang, Biao; Dhar, Devjani; Liang, Anqi; Ibrahim, Tarek; Mikhaylichenko, Svetlana; Aubert, Isabelle; Kerman, Kagan

2013-04-24

188

Sound localisation ability of soldiers wearing infantry ACH and PASGT helmets.  

PubMed

Helmets provide soldiers with ballistic and fragmentation protection but impair auditory spatial processing. Missed auditory information can be fatal for a soldier; therefore, helmet design requires compromise between protection and optimal acoustics. Twelve soldiers localised two sound signals presented from six azimuth angles and three levels of elevation presented at two intensity levels and with three background noises. Each participant completed the task while wearing no helmet and with two U.S. Army infantry helmets - the Personnel Armor System for Ground Troops (PASGT) helmet and the Advanced Combat Helmet (ACH). Results showed a significant effect of helmet type on the size of both azimuth and elevation error. The effects of level, background noise, azimuth and elevation were found to be significant. There was no effect of sound signal type. As hypothesised, localisation accuracy was greatest when soldiers did not wear helmet, followed by the ACH. Performance was worst with the PASGT helmet. PMID:24840132

Scharine, Angelique A; Binseel, Mary S; Mermagen, Timothy; Letowski, Tomasz R

2014-08-01

189

Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor  

PubMed Central

Background and Purpose Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’. Experimental Approach Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies. Key Results In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi/Gs signalling competence. In the orthosteric loss-of-function mutant M2-Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC-5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points. Conclusion and Implications Supraphysiological agonist efficacy at muscarinic M2 ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo-like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators. Linked Article This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142

Schrage, R; Seemann, WK; Klockner, J; Dallanoce, C; Racke, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K

2013-01-01

190

Direct and GABA-mediated indirect effects of nicotinic ACh receptor agonists on striatal neurones  

PubMed Central

Choline acetyltransferase-expressing interneurones (ChAT)+ of the striatum influence the activity of medium spiny projecting neurones (MSNs) and striatal output via a disynaptic mechanism that involves GABAergic neurotransmission. Using transgenic mice that allow visual identification of MSNs and distinct populations of GABAergic interneurones expressing neuropeptide Y (NPY)+, parvalbumin (PV)+ and tyrosine hydroxylase (TH)+, we further elucidate this mechanism by studying nicotinic ACh receptor (nAChR)-mediated responses. First, we determined whether striatal neurones exhibit pharmacologically induced nicotinic responses by performing patch-clamp recordings. With high [Cl?]i, our results showed increased spontaneous IPSC frequency and amplitude in MSNs as well as in the majority of interneurones. However, direct nAChR-mediated activity was observed in interneurones but not MSNs. In recordings with physiological [Cl?]i, these responses manifested as inward currents in the presence of tetrodotoxin and bicuculline methobromide. Nicotinic responses in MSNs were primarily mediated through GABAA receptors in feedforward inhibition. To identify the GABAergic interneurones that mediate the response, we performed dual recordings from GABAergic interneurones and MSNs. Both TH+ and neurogliaform subtypes of NPY+ (NPY+ NGF) interneurones form synaptic connections with MSNs, although the strength of connectivity, response kinetics and pharmacology differ between and within the two populations. Importantly, both cell types appear to contribute to nAChR-mediated GABAergic responses in MSNs. Our data offer insight into the striatal network activity under cholinergic control, and suggest that subclasses of recently identified TH+ and NPY+ interneurones are key mediators of striatal nicotinic responses via GABAergic tonic and phasic currents.

Luo, Ruixi; Janssen, Megan J; Partridge, John G; Vicini, Stefano

2013-01-01

191

Influence of hydrocarbon gasses on PECVD aC:H film deposition  

Microsoft Academic Search

Hydrogenated amorphous carbon layers (a-C:H) deposited at near room temperature by CH4 and C2H2-Ar rf discharges have been studied. Discharge processes were investigated using growth kinetics and optical emission spectroscopy\\u000a (OES). The role of plasma chemistry and of ion bombardment is discussed. Addition of argon, necessary to stabilize the C2H2 discharge, is found to enhance susbstantially gas phase processes such

N. Fourches; G. Turban

1996-01-01

192

Water-repellency of aC:H films deposited by rf plasma-enhanced CVD  

Microsoft Academic Search

Hydrogenated amorphous carbon (a-C:H) films with high water-repellency were deposited on Si and glass substrates by rf (13.56MHz) plasma-enhanced chemical vapor deposition using CH4 and H2 as raw materials. The films had a contact angle for a water drop of 94° and showed no dependence on the rf power and substrate. Thus, these films show high water-repellency due to the

Je-Deok Kim; Hiroyuki Sugimura; Osamu Takai

2002-01-01

193

Evidence for aging theories from the study of a hunter-gatherer people (Ache of Paraguay).  

PubMed

In the late seventies, a small tribal population of Paraguay, the Ache, living under natural conditions, was studied. Data from this population turn out to be useful for considerations about evolutionary hypotheses on the aging phenomenon. 1) Ache show an age-related increasing mortality, which strongly limits the mean duration of life, as observed in other studies on mammal and bird species. 2) According to current theories on aging, in the wild very few or no individual reach old age and, so, aging cannot be directly influenced by natural selection. However, data from our population show that a significant proportion of the population reaches in the wild 60 and 70 years of age. 3) Data from Ache are also in agreement with the observation about an inverse correlation between extrinsic mortality and deaths due to the age-related increasing mortality. 4) For many gerontologists, the age-related decline of vital functions is a consequence of the gradual decline of cell turnover, genetically determined and regulated by the declining duplication capacities of stem cells. The current interpretation is that these restrictions are a general defense against the proliferation of any tumoral mass. However, among wild Ache cancer is virtually unknown in non-elderly subjects, and only among older individuals are there deaths attributable to oncological diseases. Moreover, fitness decline begins long before oncological diseases have fatal effects in significant numbers. This completely disproves the current hypothesis, because a supposed defense against a deadly disease cannot exterminate a population before the disease begins to kill. These data are consistent with similar data from other species studied under natural conditions, and they bring new arguments against the non-adaptive interpretation of aging and in support of the adaptive interpretation. PMID:24228924

Libertini, G

2013-09-01

194

Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) ?2 subunit influence nAChR function.  

PubMed

There occur two rare variations, Asp(D)478Asn(N) and Asp(D)478Glu(E), in the putative cytoplasmic amphipathic ?-helices of human nicotinic acetylcholine receptor (nAChR) ?2 subunit as a result of mutation in the 1st (G ? A: rs141072985) and 3rd (C ? A: rs56344740) nucleotide of its 478th triplet codon (GAC). We assessed the effects of these two variations on the function of ?2?2- and ?2?4-nAChRs as they could alter the electronegativity and/or the structure of the cytoplasmic 'portals' (framed by subunit amphipathic ?-helices) necessary for obligate ion permeation from extracellular space to cytoplasm. We injected decreasing ratio of subunit cRNAs (?:?; 10:1, 1:1 and 1:10) into Xenopus oocytes to express putative low-sensitivity (LS; 10:1), intermediate-sensitivity (IS; 1:1) and high sensitivity (HS; 1:10) isoforms of wild type and variant ?2?2- and ?2?4-nAChRs. Two-electrode voltage clamp analyses indicate that the agonist (ACh or nicotine) induced peak current responses (Imax) of ?2?2-nAChR isoforms and those of ?2?4-nAChR isoforms are increased (1.3-4.7-fold) as a result of D478E variation. The ?2 subunit D478N variation only increases the Imax of IS (?2-fold) or HS (1.4-2.1-fold) ?2?2-nAChRs. Concentration-response curves constructed indicate no effect on agonist sensitivities of LS and HS isoforms of ?2?2- or ?2?4-nAChRs as a result of either variation in ?2 subunit. Between the two variant nAChRs, ?2(D478E)*-nAChR isoforms generally yield higher Imax than those of respective ?2(D478N)*-nAChR isoforms. These effects could be attributed to alteration in cytoplasmic 'portals' and/or ion permeation through it owing to change in amino acid electronegativity (D ? N) and side chain length (D ? E) in nAChR ?2 subunit. PMID:24950454

Dash, Bhagirathi; Li, Ming D

2014-10-01

195

Production of pediocin AcH by Lactobacillus plantarum WHE 92 isolated from cheese.  

PubMed Central

Among 1,962 bacterial isolates from a smear-surface soft cheese (Munster cheese) screened for activity against Listeria monocytogenes, six produced antilisterial compounds other than organic acids. The bacterial strain WHE 92, which displayed the strongest antilisterial effect, was identified at the DNA level as Lactobacillus plantarum. The proteinaceous nature, narrow inhibitory spectrum, and bactericidal mode of action of the antilisterial compound produced by this bacterium suggested that it was a bacteriocin. Purification to homogeneity and sequencing of this bacteriocin showed that it was a 4.6-kDa, 44-amino-acid peptide, the primary structure of which was identical to that of pediocin AcH produced by different Pediococcus acidilactici strains. We report the first case of the same bacteriocin appearing naturally with bacteria of different genera. Whereas the production of pediocin AcH from P. acidilactici H was considerably reduced when the final pH of the medium exceeded 5.0, no reduction in the production of pediocin AcH from L. plantarum WHE 92 was observed when the pH of the medium was up to 6.0. This fact is important from an industrial angle. As the pH of dairy products is often higher than 5.0, L. plantarum WHE 92, which develops particularly well in cheeses, could constitute an effective means of biological combat against L. monocytogenes in this type of foodstuff.

Ennahar, S; Aoude-Werner, D; Sorokine, O; Van Dorsselaer, A; Bringel, F; Hubert, J C; Hasselmann, C

1996-01-01

196

Reactivation of organophosphate-inhibited acetylcholinesterase by quaternary pyridinium aldoximes.  

PubMed

We investigated the relationship between the chemical structure of acetylcholinesterase (AChE; EC 3.1.1.7) reactivators and their potency in reactivating this enzyme, after prior inhibition by VX (O-ethyl-S-(2-diisopropylaminoethyl)-methylthiophosphonate), tabun, sarin, and cyclosarin. The oximes, pralidoxime (2-PAM), HI-6 [1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride], obidoxime and HS-6 [1-(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride] were used as representatives of the group of AChE reactivators. Rat brain AChE was used as the appropriate source of the enzyme. Our results confirm that there is no single broad-spectrum oxime suitable for the treatment of poisoning with all highly toxic organophosphorus agents. PMID:15639788

Kuca, Kamil; Patocka, Jirí; Cabal, Jirí; Jun, Daniel

2004-01-01

197

Selective activation of ?7 nicotinic acetylcholine receptor (nAChR?7) inhibits muscular degeneration in mdx dystrophic mice.  

PubMed

Amount evidence indicates that ?7 nicotinic acetylcholine receptor (nAChR?7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChR?7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChR?7(+/+) wild-type and nAChR?7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChR?7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChR?7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNF? and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WT?7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on ?7KO, and MLA abolished the nAChR?7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChR?7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChR?7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration. PMID:24833065

Leite, Paulo Emílio Correa; Gandía, Luís; de Pascual, Ricardo; Nanclares, Carmen; Colmena, Inés; Santos, Wilson C; Lagrota-Candido, Jussara; Quirico-Santos, Thereza

2014-07-21

198

A fluorometric assay for acetylcholinesterase activity and inhibitor detection based on DNA-templated copper/silver nanoclusters.  

PubMed

A novel label-free, rapid, cost-effective, and highly sensitive fluorometric sensor has been constructed for the detection of acetylcholinesterase (AChE) activity and its inhibitor based on the fluorescence quenching of DNA-templated copper/silver nanoclusters (DNA-Cu/AgNCs). In this assay, AChE catalyzes the hydrolysis of acetylthiocholine (ATCh) to form thiocholine which induces fluorescence quenching of DNA-Cu/AgNCs. The AChE activity could be detected as low as 0.05mU/mL and with a linear range from 0.05 to 2.0mU/mL. This assay offers a very convenient "mix and detect" approach for AChE activity. On the other hand, tacrine and organophosphorus pesticides (OPPs) were employed to inhibit the hydrolysis of ATCh, which could eliminate the fluorescence quenching of DNA-Cu/AgNCs. The IC50 of tacrine and methamidophos were estimated to be 16.9nM and 0.075mg/L, respectively. This method was also used to detect spiked OPPs in agricultural products successfully. The present work may expand the use of DNA-Cu/AgNCs to the field of enzyme sensors. PMID:23603132

Li, Wenhua; Li, Wang; Hu, Yufang; Xia, Yalin; Shen, Qinpeng; Nie, Zhou; Huang, Yan; Yao, Shouzhuo

2013-09-15

199

Anionic Lipid and Cholesterol Interactions with ?4?2 nAChR  

PubMed Central

Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel ?4?2 nAChR by over 10-ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1. On average there were 65 and 74 interfacial lipids around the closed- and open-channel ?4?2 nAChR, respectively, in the equilibrated simulation systems. 42% of the interfacial POPA in the open-channel system had acyl chains partially inserted into intra- or inter-subunit cavities, as compared to only 7% in the closed-channel ?4?2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller head group, POPA could access some non-annular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA not only acted as an acceptor for hydrogen bonding (H-bonding) as POPC did, but also as a donor through its hydroxyl group for H-bonding with the backbone of the protein. The charged head group of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the ?4?2. A higher number of salt bridges and hydrogen bonds (H-bonds) between POPA and the ?4?2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR.

Cheng, Mary H.; Xu, Yan; Tang, Pei

2009-01-01

200

Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.  

PubMed Central

1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by otilonium. This extraordinary potency of otilonium in blocking nicotinic AChR, unrecognised until now, might account in part for its well known spasmolytic effects. Images Figure 8

Gandia, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; Lopez, M. G.; Martinez-Sierra, R.; Borges, R.; Garcia, A. G.

1996-01-01

201

PET imaging of acetylcholinesterase inhibitor-induced effects on ?4?2 nicotinic acetylcholine receptor binding.  

PubMed

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo ?4?2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The ?4?2 nAChR-specific radioligand [(18)F]nifene was used to examine the effects of 0.1-0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60-min bolus-infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [(18) F]nifene. Significant [(18) F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [(18) F]nifene in detecting increases in synaptic ACh induced by AChEIs. PMID:23913347

Hillmer, Ansel T; Wooten, Dustin W; Farhoud, Mohammed; Higgins, Andrew T; Lao, Patrick J; Barnhart, Todd E; Mukherjee, Jogeshwar; Christian, Bradley T

2013-12-01

202

Investigation of the Soret effect in binary, ternary and quaternary hydrocarbon mixtures: New expressions for thermodiffusion factors in quaternary mixtures  

Microsoft Academic Search

Thermodiffusion or the Soret effect in binary, ternary and quaternary hydrocarbon mixtures is studied. Using the linear non-equilibrium thermodynamic (LNET) approach, expressions are derived for the estimation of the thermodiffusion coefficients or factors in quaternary mixtures using different approaches. New series of experimental data for binary, ternary and quaternary mixtures are used to evaluate the performance of the Firoozabadi, Kempers

Morteza Eslamian; M. Ziad Saghir; M. Mounir Bou-Ali

2010-01-01

203

Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents.  

PubMed

Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 ± 0.06 µM) and it was also showed to be a potent AChEI (IC50 = 31.0 ± 0.09 µM) when compared to galantamine (IC50 = 211.8 ± 9.5 µM). PMID:24950437

Seca, Ana M L; Leal, Stephanie B; Pinto, Diana C G A; Barreto, Maria Carmo; Silva, Artur M S

2014-01-01

204

Enantioselective construction of remote quaternary stereocentres.  

PubMed

Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted ?-, ?-, ?-, ?- or ?-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre. PMID:24717439

Mei, Tian-Sheng; Patel, Harshkumar H; Sigman, Matthew S

2014-04-17

205

Enantioselective construction of remote quaternary stereocentres  

NASA Astrophysics Data System (ADS)

Small molecules that contain all-carbon quaternary stereocentres--carbon atoms bonded to four distinct carbon substituents--are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted ?-, ?-, ?-, ?- or ?-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

Mei, Tian-Sheng; Patel, Harshkumar H.; Sigman, Matthew S.

2014-04-01

206

ADSORPTION MECHANISM OF QUATERNARY AMINES BY SEPIOLITE  

Microsoft Academic Search

A series of adsorption tests examined the uptake of typical quaternary cationic surfactants, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide from water by a clay mineral, sepiolite. Adsorption tests conducted under different conditions revealed that sepiolite is highly receptive to adsorption of cationic surfactants. Adsorption of cationic surfactants on sepiolite exhibits two distinct regions. The first stage is characterized by low rate

E. Sabah; M. S. Çelik

2002-01-01

207

Quaternary deformation mapping with ground penetrating radar  

Microsoft Academic Search

Ground penetrating radar (GPR) was used in a programme of geological and hydrogeological investigations into the Quaternary of west Cumbria, UK. The investigations were part of an extensive programme to determine the suitability of the area for a deep radioactive waste repository. The hydrogeological characteristics of the drift deposits are important since they affect both recharge and discharge. The glacially

J. P Busby; J. W Merritt

1999-01-01

208

Quaternary Phosphonium Salts Bearing Carbamate Groups.  

National Technical Information Service (NTIS)

Novel quaternary phosphonium salts, bearing one or more carbamate groups attached through nitrogen, are prepared by condensing a hydroxymethyl phosphonium salt having the formula (R(4-n)P(CH2OH)n)(+)X(-) with an alkyl carbamate having the formula NH2CO2R'...

A. Frank

1979-01-01

209

Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.  

PubMed

Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 ?M onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease. PMID:24819955

Huang, Guozheng; Kling, Beata; Darras, Fouad H; Heilmann, Jörg; Decker, Michael

2014-06-23

210

1H NMR Relaxation Investigation of Inhibitors Interacting with Torpedo californica Acetylcholinesterase  

NASA Astrophysics Data System (ADS)

Two naphthyridines interacting with Torpedo californica acetylcholinesterase (AChE) were investigated. 1H NMR spectra were recorded and nonselective, selective, and double-selective spin-lattice relaxation rates were measured. The enhancement of selective relaxation rates could be titrated by different ligand concentrations at constant AChE (yielding 0.22 and 1.53 mM for the dissociation constants) and was providing evidence of a diverse mode of interaction. The double-selective relaxation rates were used to evaluate the motional correlation times of bound ligands at 34.9 and 36.5 ns at 300 K. Selective relaxation rates of bound inhibitors could be interpreted also in terms of dipole-dipole interactions with protons in the enzyme active site.

Delfini, Maurizio; Gianferri, Raffaella; Dubbini, Veronica; Manetti, Cesare; Gaggelli, Elena; Valensin, Gianni

2000-05-01

211

Schwann cells and myasthenia gravis. Preferential uptake of soluble and membrane-bound AChR by normal and immortalized Schwann cells, and immunogenic presentation to AChR-specific T line lymphocytes.  

PubMed

The normal neuromuscular synapse is formed by the intimate association of nerve endings, postsynaptic end-plate foldings in the muscle fiber, and nonmyelinating Schwann cells (SC) sealing the synaptic ramifications. Because SC have been recognized recently to have an immunogenic potential inducible to present protein autoantigens to autoimmune T lymphocytes, and considering their close proximity to the acetylcholine receptor (AChR)-bearing postsynaptic membranes, presentation of soluble and membrane vesicle-bound AChR to appropriate T cells was investigated. Short-term monolayer cultures of SC isolated from neonatal rat sciatic nerves, as well as cells of an immortalized SC line of similar origin, were fully able to present the relevant molecular epitopes to major histocompatibility complex (MHC) compatible AChR-specific T line lymphocytes immunogenically. Presentation of AChR was restricted by RT1.B (I-A) MHC class II products. Both types of cultured rat SC were inducible to expression of MHC class I and II products, and they were able to phagocytose AChR-enriched membrane vesicles preferentially. In contrast, phagocytosis of latex particles by SC was negligible. These data qualify perisynaptic SC as potential presenter cells of autoimmunogenic AChR in myasthenia gravis. Thus, SC may play a critical and as-yet unpredicted regulatory role in the cellular pathogenesis of myasthenia gravis. PMID:1688688

Zhang, Y P; Porter, S; Wekerle, H

1990-01-01

212

Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon.  

PubMed

Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR?=?0.30) or the oxime K-27 (RR?=?0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR?=?0.67), ranitidine (RR?=?0.72), pyridostigmine (RR?=?0.76), tiapride (RR?=?0.80) and 7-MEOTA (RR?=?0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR???1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. PMID:22611016

Petroianu, Georg A; Nurulain, Syed M; Shafiullah, Mohamed; Hasan, Mohamed Y; Ku?a, Kamil; Lorke, Dietrich E

2013-09-01

213

UltraHigh Tribological Performance of Magnetron Sputtered aC:H Films in Sand-Dust Environment  

Microsoft Academic Search

The hydrogenated amorphous carbon (a-C:H) films were prepared on AISI 440C steel substrates using a RF magnetron sputtering\\u000a graphite target in the CH4 and Ar mixture atmosphere. The friction and wear behavior of a-C:H films were comparatively investigated by pin-on-disc tester\\u000a under dry sliding and simulated sand-dust wear conditions. In addition, the effects of applied load, amount of sand and

Jianwei Qi; Liping Wang; Fengyuan Yan; Qunji Xue

2010-01-01

214

Cholinesterase inhibitors and memory.  

PubMed

A consensus exists that cholinesterase inhibitors (ChEIs) are efficacious for mild to moderate Alzheimer's Disease (AD). Unfortunately, the number of non-responders is large and the therapeutic effect is usually short-lasting. In experimental animals, ChEIs exert three main actions: inhibit cholinesterase (ChE), increase extracellular levels of brain acetylcholine (ACh), improve cognitive processes, particularly when disrupted in models of AD. In this overview we shall deal with the cognitive processes that are improved by ChEI treatment because they depend on the integrity of brain cholinergic pathways and their activation. The role of cholinergic system in cognition can be investigated using different approaches. Microdialysis experiments demonstrate the involvement of the cholinergic system in attention, working, spatial and explicit memory, information encoding, sensory-motor gating, skill learning. No involvement in long-term memory has yet been demonstrated. Conversely, memory consolidation is facilitated by low cholinergic activity. Experiments on healthy human subjects, notwithstanding caveats concerning age, dose, and different memory tests, confirm the findings of animal experiments and demonstrate that stimulation of the cholinergic system facilitates attention, stimulus detection, perceptual processing and information encoding. It is not clear whether information retrieval may be improved but memory consolidation is reduced by cholinergic activation. ChEI effects in AD patients have been extensively investigated using rating scales that assess cognitive and behavioural responses. Few attempts have been made to identify which scale items respond better to ChEIs and therefore, presumably, depend on the activity of the cholinergic system. Improvement in attention and executive functions, communication, expressive language and mood stability have been reported. Memory consolidation and retrieval may be impaired by high ACh levels. Therefore, considering that in AD the degeneration of the cholinergic system is associated with alteration of other neurotransmitter systems and a diffuse synaptic loss, a limited efficacy of ChEIs on memory processes should be expected. PMID:19941841

Pepeu, Giancarlo; Giovannini, Maria Grazia

2010-09-01

215

Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.  

PubMed

Acetylcholinesterase (AChE) is a primary target for Alzheimer's therapy while recently sodium glucose cotransporter 2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). Docking study was performed using 'Autodock4.2'. Both hydrophobic and ?-? interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and catalytic site (CAS) of AChE to permit docking. Free energy of binding (?G) for 'Canagliflozin-SGLT2' interaction and 'Canagliflozin - CAS domain of AChE' interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively. During 'Canagliflozin-SGLT2' interaction, Canagliflozin was found to interact with the most important amino acid residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However, 'Canagliflozin-CAS domain of AChE' interaction revealed that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana (Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE-Canagliflozin complexes by X-ray crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against diabetes associated neurological disorders. PMID:24059302

Rizvi, Syed M D; Shakil, Shahnawaz; Biswas, Deboshree; Shakil, Shazi; Shaikh, Sibhghatulla; Bagga, Paramdeep; Kamal, Mohammad A

2014-04-01

216

Possible mechanisms underlying the vasodilatation induced by olprinone, a phosphodiesterase III inhibitor, in rabbit coronary artery  

PubMed Central

The possible mechanisms underlying the vasodilatation induced by olprinone, a phosphodiesterase type III inhibitor, were investigated in smooth muscle of the rabbit coronary artery. Isometric force and membrane potential were measured simultaneously using endothelium-denuded smooth muscle strips. Acetylcholine (ACh, 3??M) produced a contraction with a membrane depolarization (15.2±1.1?mV). In a solution containing 5.9?mM K+, olprinone (100??M) hyperpolarized the resting membrane and (i) caused the absolute membrane potential level reached with ACh to be more negative (but did not reduce the delta membrane potential seen with ACh, 15.2±1.8 mV) and (ii) attenuated the ACh-induced contraction. In a solution containing 30?mM K+, these effects were not seen with olprinone. Glibenclamide (10??M) blocked the olprinone-induced membrane hyperpolarization. 4-AP (0.1?mM) significantly attenuated the olprinone-induced resting membrane hyperpolarization but TEA (1?mM) had no such effect. Glibenclamide (10??M), TEA (1?mM) and 4-AP (0.1?mM), given separately, all failed to modify the inhibitory actions of olprinone on (i) the absolute membrane potential level seen with ACh and (ii) the ACh-induced contraction. It is suggested that olprinone inhibits the ACh-induced contraction through an effect on the absolute level of membrane potential achieved with ACh in smooth muscle of the rabbit coronary artery. It is also suggested that glibenclamide-sensitive, ATP-sensitive K+ channels do not play an important role in the olprinone-induced inhibition of the ACh-induced contraction.

Ohashi, Masuo; Dohi, Yasuaki; Itoh, Takeo

2000-01-01

217

Structure dependent electronic sputtering of a-C:H films by swift heavy ions  

NASA Astrophysics Data System (ADS)

Electronic sputtering of a-C:H films by elastic recoil detection analysis technique is studied under 80 MeV Ni 8+ and 150 MeV Ag 13+ ion irradiations. These studies show that electronic sputtering yield of C and H from the films varies with film structure quite significantly. The structure of the films is analyzed from the characteristic graphitic (G) and disordered (D) modes of Raman vibration. Atomic force microscopy was performed on two films for grain size determination. The difference in electronic sputtering yields is discussed on the basis of structural influence of the films on swift heavy ion and solid interaction.

Ghosh, S.; Avasthi, D. K.; Som, T.; Tripathi, A.; Kabiraj, D.; Ingale, A.; Mishra, S.; Ganesan, V.; Zhang, S.; Hong, X.

2002-05-01

218

An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study.  

PubMed

Series of hitherto unreported piperidone grafted pyridopyrimidines synthesized through ionic liquid mediated multi-component reaction. These compounds were evaluated for their inhibitory activities against AChE and BChE enzymes. All the compounds displayed considerable potency against AChE with IC50 values ranging from 0.92 to 9.11 ?M, therein compounds 6a, 6h and 6i displayed superior enzyme inhibitory activities compared to standard drug with IC50 values of 0.92, 1.29 and 2.07 ?M. Remarkably, all the compounds displayed higher BChE inhibitory activity compared to galantamine with IC50 values of 1.89-8.13 ?M. Molecular modeling, performed for the most active compounds using three dimensional crystal structures of TcAChE and hBChE, disclosed binding template of these inhibitors into the active site of their respective enzymes. PMID:23871902

Basiri, Alireza; Murugaiyah, Vikneswaran; Osman, Hasnah; Kumar, Raju Suresh; Kia, Yalda; Awang, Khalijah Binti; Ali, Mohamed Ashraf

2013-09-01

219

The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors.  

PubMed Central

The role of the functional architecture of the human acetylcholinesterase (HuAChE) active centre in accommodating the non-covalent inhibitors tacrine and huperzine A, or the carbamates pyridostigmine and physostigmine, was analysed using 16 mutants of residues lining the active-centre gorge. Despite the structural diversity of the ligands, certain common properties of the complexes could be observed: (a) replacement of aromatic residues Tyr133, Tyr337 and especially Trp86, resulted in pronounced changes in stability of all the complexes examined; (b) effects due to replacements of the five other aromatic residues along the active-centre gorge, such as the acyl pocket (Phe295, Phe297) or at the peripheral anionic site (Tyr124, Trp286, Tyr341) were relatively small; (c) effects due to substitution of the carboxylic residues in the gorge (Glu202, Glu450) were moderate. These results and molecular modelling indicate that the aromatic side chains of residues Trp86, Tyr133 and Tyr337 form together a continuous 'aromatic patch' lining the wall of the active-centre gorge, allowing for the accommodation of the different ligands via multiple modes of interaction. Studies with HuAChE mutants carrying replacements at positions 86, 133 and 337 indicate that the orientations of huperzine A and tacrine in the HuAChE complexes in solution are significantly different from those observed in X-ray structures of the corresponding complexes with Torpedo californica AChE (TcAChE). These discrepancies may be explained in terms of structural differences between the complexes of HuAChE and TcAChE or, more likely, by the enhanced flexibility of the AChE active-centre gorge in solution as compared with the crystalline state.

Ariel, N; Ordentlich, A; Barak, D; Bino, T; Velan, B; Shafferman, A

1998-01-01

220

Novel acetylcholinesterase inhibitor as increasing agent on rhythmic bladder contractions: SAR of 8-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propanoyl}-1,2,5,6-tetrahydro-4 H-pyrrolo[3,2,1- ij]quinolin-4-one (TAK-802) and related compounds  

Microsoft Academic Search

As part of an on-going investigation to develop an increasing agent on rhythmic bladder contractions, 1-aryl-3-(1-benzylpiperidin-4-yl)propanones were synthesized and examined as noncarbamate acetylcholinesterase (AChE) inhibitors. Among compounds with various aryl groups, 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one derivative 9c was found to possess a potent AChE inhibition activity with an IC50 value of 1.3nM. The compound 9c increased rhythmic bladder contractions in Guinea pigs and

Yuji Ishichi; Mitsuru Sasaki; Masaki Setoh; Tetsuya Tsukamoto; Seiji Miwatashi; Hiroshi Nagabukuro; Satoshi Okanishi; Shigemitsu Imai; Reiko Saikawa; Takayuki Doi; Yuji Ishihara

2005-01-01

221

Quaternary neotectonics of the South Aegean arc  

Microsoft Academic Search

The sedimentary and tectonic Quaternary evolution of the South Aegean arc has been interpreted from 8000 line-km of sparker seismic reflection profiles. The older parts of basins formed by E–W-trending faults and accumulated hemipelagic sediment. Younger active faulting trends NNW in the western part of the arc and ENE in the eastern arc. The ENE-trending faults record sinistral strike-slip motion

D. J. W. Piper; C. Perissoratis

2003-01-01

222

Quaternary phylogeography: the roots of hybrid zones  

Microsoft Academic Search

The older history of hybrid zones is explored through consideration of recent advances in climatology, paleontology and phylogeography\\u000a in the Late Cenozoic, particularly the Quaternary Period with its major climatic cycles. The fossil record shows that these\\u000a ice ages and their nested millennial oscillations caused substantial changes in species distributions and with genetic evidence\\u000a allows deduction of refugia and colonization

Godfrey M. Hewitt

2011-01-01

223

Quaternary glaciations in the Northern Hemisphere  

SciTech Connect

This volume presents the final report of Project 24 of the International Geological Correlation Programme. The publication is drawn from the contributions of leading individual scientist as well as from scientific research teams. It reflects the present state of knowledge of the Quaternary Glaciations in the Northern Hemisphere and their correlation in space and time, as well as providing a unique summary of climatic change.

Sibrava, V.; Bowen, D.Q.; Richmond, G.M.

1987-01-01

224

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice.  

PubMed

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of ?7 and ?2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in ?7?2nAChR(-/-) mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. ?7?2nAChR(-/-) mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in ?7?2nAChR(-/-) mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to ?7nAChR(-/-) mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of ?7?2nAChR(-/-) mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central ?2nAChR deficiency. PMID:24685552

Somm, Emmanuel; Guérardel, Audrey; Maouche, Kamel; Toulotte, Audrey; Veyrat-Durebex, Christelle; Rohner-Jeanrenaud, Françoise; Maskos, Uwe; Hüppi, Petra S; Schwitzgebel, Valérie M

2014-05-01

225

Scaffold Ranking and Positional Scanning Utilized in the Discovery of nAChR-Selective Compounds Suitable for Optimization Studies  

PubMed Central

Nicotine binds to nicotinic acetylcholine receptors (nAChR), which can exist as many different subtypes. The ?4?2 nAChR is the most prevalent subtype in the brain and possesses the most evidence linking it to nicotine seeking behavior. Herein we report the use of mixture based combinatorial libraries for the rapid discovery of a series of ?4?2 nAChR selective compounds. Further chemistry optimization provided compound 301, which was characterized as a selective ?4?2 nAChR antagonist. This compound displayed no agonist activity but blocked nicotine-induced depolarization of HEK cells with an IC50 of approximately 430 nM. 301 demonstrated nearly 500-fold selectivity for binding and 40-fold functional selectivity for ?4?2 over ?3?4 nAChR. In total over 5 million compounds were assessed through the use of just 170 samples in order to identify a series of structural analogues suitable for future optimization toward the goal of developing clinically relevant smoking cessation medications.

Wu, Jinhua; Zhang, Yaohong; Maida, Laura E.; Santos, Radleigh G.; Welmaker, Gregory S.; LaVoi, Travis M.; Nefzi, Adel; Yu, Yongping; Houghten, Richard A.; Toll, Lawrence; Giulianotti, Marc A.

2014-01-01

226

Memantine Inhibits ?3?2-nAChRs-Mediated Nitrergic Neurogenic Vasodilation in Porcine Basilar Arteries  

PubMed Central

Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited ?3?2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing ?3?2-, ?7- or ?4?2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting ?3?2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease.

Wu, Celeste Yin-Chieh; Chen, Po-Yi; Chen, Mei-Fang; Kuo, Jon-Son; Lee, Tony Jer-Fu

2012-01-01

227

Nicotinic acetylcholine receptors: a comparison of the nAChRs of Caenorhabditis elegans and parasitic nematodes.  

PubMed

Nicotinic acetylcholine receptors (nAChRs) play a key role in the normal physiology of nematodes and provide an established target site for anthelmintics. The free-living nematode, Caenorhabditis elegans, has a large number of nAChR subunit genes in its genome and so provides an experimental model for testing novel anthelmintics which act at these sites. However, many parasitic nematodes lack specific genes present in C. elegans, and so care is required in extrapolating from studies using C. elegans to the situation in other nematodes. In this review the properties of C. elegans nAChRs are reviewed and compared to those of parasitic nematodes. This forms the basis for a discussion of the possible subunit composition of nAChRs from different species of parasitic nematodes. Currently our knowledge on this is largely based on studies using heterologous expression and pharmacological analysis of receptor subunits in Xenopus laevis oocytes. It is concluded that more information is required regarding the subunit composition and pharmacology of endogenous nAChRs in parasitic nematodes. PMID:23500392

Holden-Dye, Lindy; Joyner, Michelle; O'Connor, Vincent; Walker, Robert J

2013-12-01

228

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:  

PubMed Central

Background: Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for AChE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy. Objective: The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice. Methods: Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine. Results: All ChE inhibitors have the potential to induce centrally mediated cholinergic adverse events (AEs), such as nausea and vomiting, if the dose is increased too rapidly or in increments that are too large. These AEs, which are most likely to occur during the “getting on,” or dose-escalation, phase of treatment, may result in patients discontinuing treatment early without achieving optimum therapeutic benefit. To reduce the incidence of these AEs, a slow dose-escalation schedule has been established in clinical practice, consisting of a “start low, go slow” procedure with a minimum of 4 weeks between dose increases. After “getting on” treatment, maintaining treatment in the long term, or “staying on,” may be achieved with good safety, tolerability, and sustained symptomatic efficacy across the key symptom domains (activities of daily living, behavior, and cognition). Conclusions: ChE inhibitors provide symptomatic benefit in AD across key symptom domains. Factors influencing the safety, tolerability, and efficacy of these agents in clinical practice include ChE enzymes inhibited, brain and brain-region ChE selectivity, and metabolism route. Class-specific cholinergic AEs can be minimized using slow, flexible dose escalation.

Grossberg, George T

2003-01-01

229

Activation of volume-regulated Cl? channels by ACh and ATP in Xenopus follicles  

PubMed Central

Osmolarity-dependent ionic currents from follicle-enclosed Xenopus oocytes (follicles) were studied using electrophysiological techniques. Whole follicle currents were monitored using a two-electrode voltage clamp and single-channel activity was measured using the patch-clamp technique.In follicles held at -60 mV two chloride currents were activated in external hyposmotic solutions. One was the habitual volume-regulated current elicited by external hyposmolarity (ICl,swell), and the second was a slow and smooth current (Sin) generated by ACh or ATP application.In follicles, the permeability ratios for different anions with respect to Cl? were similar for both ICl,swell and Sin, with a sequence of: SCN? > I? > Br?? NO3?? Cl? > gluconate ? cyclamate > acetate > SO42?.Extracellular ATP blocked the outward component of Sin. Also, extracellular pH modulated the inactivation kinetics of Sin elicited by ACh; e.g. inactivation at +80 mV was ?100% slower at pH 8.0 compared with that at pH 6.0.Lanthanides inhibited ICl,swell and Sin. La3+ completely inhibited ICl,swell with a half-maximal inhibitory concentration (IC50) of 17 ± 1.9 ?m, while Sin was blocked up to 55% with an apparent IC50 of 36 ± 2.6 ?m.Patch-clamp recordings in follicular cells showed that hyposmotic challenge opened inward single-channel currents. The single channel conductance (4.7 ± 0.4 pS) had a linear current-voltage relationship with a reversal membrane potential close to ?20 mV. This single-channel activity was increased by application of ACh or ATP.The ICl,swell generation was not affected by pirenzepine or metoctramine, and did not affect the purinergic activation of the chloride current named Fin. Thus, ICl,swell was not generated via neurotransmitters released during cellular swelling.All together, equal discrimination for different anions, similar modulatory effects by extracellular pH, the blocking effects by ATP and La3+, and the same single-channel activity, strongly suggest that ICl,swell and Sin currents depend on the opening of the same type or a closely related class of volume-regulated chloride channels.

Perez-Samartin, Alberto L; Miledi, Ricardo; Arellano, Rogelio O

2000-01-01

230

Quaternary Geologic Map of Connecticut and Long Island Sound Basin  

USGS Publications Warehouse

The Quaternary geologic map (sheet 1) and explanatory figures and cross sections (sheet 2) portray the geologic features formed in Connecticut during the Quaternary Period, which includes the Pleistocene (glacial) and Holocene (postglacial) Epochs. The Quaternary Period has been a time of development of many details of the landscape and of all the surficial deposits. At least twice in the late Pleistocene, continental ice sheets swept across Connecticut. Their effects are of pervasive importance to the present occupants of the land. The Quaternary geologic map illustrates the geologic history and the distribution of depositional environments during the emplacement of glacial and postglacial surficial deposits and the landforms resulting from those events.

Stone, Janet Radway; Schafer, John P.; London, Elizabeth Haley; DiGiacomo-Cohen, Mary L.; Lewis, Ralph S.; Thompson, Woodrow B.

2005-01-01

231

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

PubMed

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-?-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. PMID:23529036

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

2013-01-01

232

40 CFR 721.10666 - Quaternary ammonium compounds, bis(fattyalkyl) dimethyl, salts with tannins (generic).  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Quaternary ammonium compounds, bis(fattyalkyl) dimethyl, salts... § 721.10666 Quaternary ammonium compounds, bis(fattyalkyl) dimethyl, salts...identified generically as quaternary ammonium compounds, bis(fattyalkyl) dimethyl,...

2013-07-01

233

40 CFR 721.10342 - Quaternary ammonium compounds, fatty alkyl dialkyl hydroxide (generic).  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Quaternary ammonium compounds, fatty alkyl dialkyl hydroxide (generic... § 721.10342 Quaternary ammonium compounds, fatty alkyl dialkyl hydroxide (generic...identified generically as quaternary ammonium compounds, fatty alkyl dialkyl...

2013-07-01

234

40 CFR 721.10479 - Quaternary ammonium compounds, tris(hydrogenated tallow alkyl)methyl, chlorides.  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Quaternary ammonium compounds, tris(hydrogenated tallow alkyl... § 721.10479 Quaternary ammonium compounds, tris(hydrogenated tallow alkyl...substance identified as quaternary ammonium compounds, tris(hydrogenated tallow...

2013-07-01

235

40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.  

Code of Federal Regulations, 2011 CFR

...2011-07-01 false Quaternary ammonium salt of fluorinated alkylaryl amide. 721...Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl amide. ...identified generically as quaternary ammonium salt of fluorinated alkylaryl amide...

2011-07-01

236

40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.  

Code of Federal Regulations, 2010 CFR

...2010-07-01 false Quaternary ammonium salt of fluorinated alkylaryl amide. 721...Substances § 721.9075 Quaternary ammonium salt of fluorinated alkylaryl amide. ...identified generically as quaternary ammonium salt of fluorinated alkylaryl amide...

2010-07-01

237

Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties as cholinesterases inhibitors  

Microsoft Academic Search

The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds’ selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16–25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC50 = 5.00) while a series of carbamate derivatives of N-benzylpiperidine

Anna Wi?ckowska; Marek Bajda; Natalia Guzior; Barbara Malawska

2010-01-01

238

Upregulation of Lhx8 increase VAChT expression and ACh release in neuronal cell line SHSY5Y.  

PubMed

Lhx8 is a transcription factor for cholinergic differentiation. Our previous experiments found upregulation of Lhx8 promoted cholinergic neuronal differentiation of hippocampal neural stem/progenitor cells or hippocampal newborn neurons in vitro. However, the role of Lhx8 in VAChT expression and ACh release is still less understood. In this report, we transfected Lhx8 cDNA into neuronal cell line SHSY5Y by lentiviral vectors to acquire the cells which stably expressed high level of Lhx8. Using this cell model, we provided experimental evidence that increasing Lhx8 upregulated the expression of ChAT and VAChT, and also increased the ACh release in culture medium. We suggested that Lhx8 overexpression is a useful strategy to increase the release of ACh and maybe of therapeutic value to neurodegenerative diseases. PMID:24316404

Li, Haoming; Jin, Guohua; Zhu, Peipei; Zou, Linqing; Shi, Jinhong; Yi, Xin; Zhang, Xinhua; Tian, Meiling; Qin, Jianbing

2014-01-24

239

Improving the tribological performance of a-C:H film in a high vacuum by surface texture  

NASA Astrophysics Data System (ADS)

In this study, a new synergy lubricating system was designed by combining the surface texture and film deposition technology to improve the tribological performances of amorphous hydrogenated carbon (a-C:H) films in a ball-on-disk tribometer under vacuum conditions. Tribological behaviours of the untextured and textured films in a vacuum environment were investigated in detail. The results suggest that the wear life of a-C:H film is dramatically prolonged by surface texture with appropriate interval distances. A comprehensive friction and wear mechanism model is proposed based on substantial structural characterization and wear trace analyses. In this model, the generation of the hard and brittle wear debris is considered as the key unfavourable factor resulting in the rapid failure of a-C:H films, while the surface texture is beneficial in reducing the formation of wear debris, and further trapping it during the friction process.

Song, Hui; Ji, Li; Li, Hongxuan; Liu, Xiaohong; Zhou, Huidi; Liu, Liu; Chen, Jianmin

2014-06-01

240

Auger electron spectroscopy, secondary ion mass spectroscopy and optical characterization of a-C-H and BN films  

NASA Technical Reports Server (NTRS)

The amorphous dielectrics a-C:H and BN were deposited on III-V semiconductors. Optical band gaps as high as 3 eV were measured for a-C:H generated by C4H10 plasmas; a comparison was made with bad gaps obtained from films prepared by CH4 glow discharges. The ion beam deposited BN films exhibited amorphous behavior with band gaps on the order of 5 eV. Film compositions were studied by Auger electron spectroscopy (AES), x-ray photoelectron spectroscopy (XPS) and secondary ion mass spectrometry (SIMS). The optical properties were characterized by ellipsometry, UV/VIS absorption, and IR reflection and transmission. Etching rates of a-C:H subjected to O2 dicharges were determined.

Pouch, J. J.; Alterovitz, S. A.; Warner, J. D.

1986-01-01

241

Electron cyclotron resonance deposition and plasma diagnostics of a-Si:H and a-C:H films  

NASA Technical Reports Server (NTRS)

Amorphous silicon (a-Si:H) and amorphous carbon (a-C:H) films deposited by electron cyclotron resonance (ECR) microwave plasma-enhanced chemical vapor deposition are discussed. It is shown that the ECR microwave plasma deposition technique can produce a-Si:H films with material qualities similar to and with a deposition rate one order of magnitude higher than for films deposited by radio-frequency glow discharge. The ECR-deposited a-C:H films are characterized by fluorescence, IR, and Raman spectroscopy. In situ optical emission spectroscopy plasma diagnostics indicates that ECR plasmas have a strong emission at 434 nm, which indicates a higher chemical reactivity than radio-frequency glow discharge plasmas. The radio frequency bias to the substrate is found to play a critical role in determining the film structure and the carbon bonding configuration of ECR-deposited a-C:H films.

Shing, Y. H.

1989-01-01

242

Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation.  

PubMed

A new series of tacrine-multialkoxybenzene hybrids (9a-9n) were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced ?-amyloid (A?) aggregation. All the synthesized compounds had high acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity with IC?? values at the nanomolar range, which were much better than tacrine alone. A Lineweaver-Burk plot and molecular modeling study showed that these hybrids targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compounds 9a-9f with methylenedioxybenzene moiety showed higher self-induced A? aggregation inhibitory activity than a reference compound, curcumin. These compounds could be selected as multi-potent agents for further investigation to treat AD. PMID:21211982

Luo, Wen; Li, Yan-Ping; He, Yan; Huang, Shi-Liang; Tan, Jia-Heng; Ou, Tian-Miao; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

2011-01-15

243

Rapid thermal annealing of Amorphous Hydrogenated Carbon (a-C:H) films  

NASA Technical Reports Server (NTRS)

Amorphous hydrogenated carbon (a-C:H) films were deposited on silicon and quartz substrates by a 30 kHz plasma discharge technique using methane. Rapid thermal processing of the films was accomplished in nitrogen gas using tungsten halogen light. The rapid thermal processing was done at several fixed temperatures (up to 600 C), as a function of time (up to 1800 sec). The films were characterized by optical absorption and by ellipsometry in the near UV and the visible. The bandgap, estimated from extrapolation of the linear part of a Tauc plot, decreases both with the annealing temperature and the annealing time, with the temperature dependence being the dominating factor. The density of states parameter increases up to 25 percent and the refractive index changes up to 20 percent with temperature increase. Possible explanations of the mechanisms involved in these processes are discussed.

Alterovitz, Samuel A.; Pouch, John J.; Warner, Joseph D.

1987-01-01

244

Proteinase inhibitors  

Microsoft Academic Search

Enzymatic protein hydrolysis plays a major role in various physiological processes, including digestion, and is regulated by proteinase inhibitors. Inhibitors in foods and food ingredients can reduce the absorption of free amino acids, and can impair protein hydrolysis in industrial processes. However, inhibitors can be useful tools in pest control, in the prevention and treatment of diseases such as cancers

Fernando Luis García-Carreño

1996-01-01

245

NMR study of general anesthetic interaction with nAChR beta2 subunit.  

PubMed

The molecular basis of anesthetic interaction with membrane proteins has been explored via determination of anesthetic effects on the structure and dynamics of the extended second transmembrane domain (TM2e) of the human neuronal nicotinic acetylcholine receptor (nAChR) beta(2) subunit in dodecylphosphocholine (DPC) micelles by (1)H and (15)N solution-state NMR. Both 1-chloro-1,2,2-trifluorocyclobutane (F3) and isoflurane, two volatile general anesthetics, induced nonuniform changes in chemical shifts among residues in TM2e. Saturation transfer difference NMR experiments further confirmed the direct anesthetic interaction with TM2e. A significant and more specific anesthetic interaction was observed on three leucine residues at the helix C-terminus. Although the TM2e helical structure remained after addition of anesthetics, plausible shortening and lengthening of helix hydrogen bonds were evidenced by periodic changes in backbone amide chemical shifts. The TM2e backbone dynamics were determined on the basis of the (15)N relaxation rate constants, R(1) and R(2), and the (15)N-[(1)H] NOE using the model-free approach. The global tumbling time (11.7 ns) of TM2e in micelles slightly increased ( approximately 12.3-12.5 ns) in the presence of anesthetics. The order parameter, S(2), exceeded 0.9 for all (15)N-labeled residues, showing a restricted internal motion. Anesthetics appear to have minor effect on the TM2e's internal motion. This study provided the basis for subsequent more comprehensive studies of anesthetic effects on the transmembrane domain complex of neuronal nAChR. PMID:17993502

Bondarenko, Vasyl; Yushmanov, Victor E; Xu, Yan; Tang, Pei

2008-03-01

246

Effect of cryopreservation on acetylation patterns of lysine 12 of histone H4 (acH4K12) in mouse oocytes and zygotes  

PubMed Central

Purpose To determine the effect of cryopreservation on acH4K12 in oocytes and their respective zygotes. Methods AcH4K12 in fresh or vitrified-warmed oocytes and their respective zygotes at 70 min–12 h post-fertilization were assessed using fluorescent staining. Results 1. AcH4K12 levels increased significantly in vitrified oocytes compared to controls. 2. Respective zygotes derived from vitrified oocytes had abnormal chromatin distribution or acH4K12 patterns before and after pronuclear formation. Conclusion Cryopreservation alters AcH4K12 patterns in oocytes, which subsequently affect the chromatin distribution and acH4K12 in fertilized oocytes.

Suo, Lun; Meng, QingGang; Pei, Yan; Fu, XiangWei; Wang, YanPing; Bunch, Thomas D.

2010-01-01

247

Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology.  

PubMed

A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization. PMID:20684567

Chaudhaery, Shailendra S; Roy, Kuldeep K; Shakya, Neeraj; Saxena, Gunjan; Sammi, Shreesh Raj; Nazir, Aamir; Nath, Chandishwar; Saxena, Anil K

2010-09-01

248

Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).  

PubMed

Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 ?g/ml), the stem chloroform extract (LC50=407.34 ± 68.05 ?g/ml) and kaempferol (LC50=762.41 ± 45.09 ?g/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD. PMID:24479629

Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

2014-02-01

249

Characterization of Quaternary and suspected Quaternary faults, regional studies, Nevada and California  

Microsoft Academic Search

This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies

R. E. Anderson; R. C. Bucknam; A. J. Crone; K. M. Haller; M. N. Machette; S. F. Personius; T. P. Barnhard; M. J. Cecil; R. L. Dart

1995-01-01

250

Quaternary and pre-Quaternary( ) materials and processes of southeast Ohio: Overview, speculations, and recommendations  

Microsoft Academic Search

Investigations and mapping of surficial deposits in Ohio have focused largely on the glacial deposits which cover nearly two-thirds of the state. Research on Quaternary deposits beyond the glacial border has been done by Foster, Hildreth, Andrews, Leverett, Tight, Stout, Goldthwait, Forsyth, Lessig, White, Totten, Hoyer, and Noltimier. However, growing human interaction with surficial materials of southeast Ohio now requires

1992-01-01

251

Late Quaternary history of southern Chesapeake Bay  

SciTech Connect

More than 700 km of high-resolution, seismic-reflection profiles and sidescan-sonar images provide new information about the late Quaternary history of southern Chesapeake Bay. Sidescan-sonar images show that, excluding the nearshore zone, most of the bay bottom has a monotonously smooth surface, except that sand waves, ripples, and other bedforms occur in local areas affected by tidal currents. Seismic-reflection data show that the Quaternary stratigraphy of the southern part of the Bay is related primarily to the last cycle of sea-level change. The Quaternary section overlies an erosion surface cut deeply into gently seaward-dipping marine beds of Neogene age. Fluvial paleochannels, related to the last major low sea-level stand, are characterized by as much as 55 m of incision and by thin, irregular, terrace and channel-bottom deposits. Marine and estuarine deposits related to the Holocene transgression partially or fully bury the fluvial valleys and overlie the interfluves. A prominent feature of the Bay-mouth area is a wedge of sediment that has prograded into the Bay from the inner shelf. The common assumption--that the Chesapeake Bay is the drowned valley of the Pleistocene Susquehanna River--is only partially valid for the southern part of the Bay. The Bay mouth area, in general, is relatively young. The axial channel of the Bay is a modern tidal channel that is actively eroding Tertiary deposits and migrating toward the south and west; it is unrelated to older fluvial channels. Also, the positions of the modern axial channel and the last two fluvial paleochannels indicate long-term southward migration of the Bay mouth.

Colman, S.M.; Hobbs, C.H. III; Halka, J.P.

1985-01-01

252

Towards a quaternary time scale*1  

NASA Astrophysics Data System (ADS)

Nine first-appearance datums (FADs), twenty-three last-appearance datums (LADs), and three other micropaleontological datums are related to the magnetic-reversal, oxygen-isotope, and calcite-dissolution/coarse-fraction time scales to provide a preliminary basis for subdivision of the Quaternary in deep-sea sediments. The magnetic-reversal, oxygen-isotope, and calcite-dissolution/coarse-fraction scales have been correlated by determination on the same core materials, and absolute dates applied by {40K}/{40Ar} or 14C dating of materials in known positions on one or another of these scales. FADS and LADs have been determined in cores for which either a magnetic-reversal, oxygen-isotope, or calcite-dissolution/coarse-fraction scale has also been available. Altogether 3 FADs and 5 LADs based on diatoms, 4 FADs and 5 LADs based on calcareous nannoplankton, 1 FAD and 8 LADs based on radiolarians, 1 FAD and 5 LADs based on planktonic foraminifers, 2 acme datums, and 1 ratio reversal datum have been determined, and absolute dates inferred by interpolation from known dates on the reference time scales. Some of the FADs and LADs apply or are synchronous only over limited areas of the oceans; others appear to be synchronous throughout the oceans. The base of the Quaternary is set at the top of the Olduvai event at 1.7 my. Four FADs, twelve LADs, two acme datums, and one ratio reversal datum occur above the base of the Quaternary at an average rate of about 1 per 100,000 yr. Five FADs and twelve LADs are recognized in the 0.8-my interval between the top of the Olduvai event and the Gauss/Matuyama Boundary at 2.5 my at an average incidence of about 1 per 50,000 yr.

Berggren, W. A.; Burckle, L. H.; Cita, M. B.; Cooke, H. B. S.; Funnell, B. M.; Gartner, S.; Hays, J. D.; Kennett, J. P.; Opdyke, N. D.; Pastouret, L.; Shackleton, N. J.; Takayanagi, Y.

1980-05-01

253

Quaternary isoquinoline alkaloids from Xylopia parviflora.  

PubMed

From the quaternary alkaloidal fraction of the bark and the root of Xylopia parviflora (Annonaceae), four isoquinoline alkaloids, xylopinidine, dehydrocoreximine, N, N-dimethylanomurine and N-methylphoebine were isolated along with the known compounds, pycnarrhine, lotusine, 6,7-dimethoxy-2-methyl-isoquinolinium salt, 1,2-dehydroreticuline, (-)-phellodendrine, (+)-tembetarine, (-)-litcubine, (+)-magnoflorine, tetradehydroreticuline, (-)-oblongine, (+)-menisperine, (+)-N-methylcorydine, stepharanine, (+)-xanthoplanine, dehydrodiscretine, jatrorrhizine and palmatine. 3,4-Dihydro-6,7-dimethoxy-2-methyl-isoquinolinium and N-methylpurpuerine were isolated as natural products for the first time. Their structures were determined on the basis of spectroscopic evidence. PMID:15081299

Nishiyama, Yumi; Moriyasu, Masataka; Ichimaru, Momoyo; Iwasa, Kinuko; Kato, Atsushi; Mathenge, Simon G; Chalo Mutiso, Patrick B; Juma, Francis D

2004-04-01

254

Prediction of Refractive Index of Quaternary Liquid Mixtures  

Microsoft Academic Search

Refractive index data for three quaternary liquid mixtures have been analysed after extending the mixing rules for index of refraction available in literature. Relative merits and interrelations of various important mixing rules for these quaternary liquid mixtures have been discussed in detail. Surprisingly the extended equations yield fairly good agreement between theoretical and experimental values of refractive indices.

J. D. Pandey; A. K. Shukla; R. K. Shukla; R. D. Rai

1988-01-01

255

The first enzymatic resolution of quaternary ?-acetoxy ?-substituted cyclic ketones  

Microsoft Academic Search

The enantioselective resolution of quaternary ?-acetoxy ?-substituted indanone and 1-tetralone derivatives was performed with commercially available enzyme CRL in pH=8.0 phosphate buffer. Various parameters that would affect the enantoselectivities were tested, and the optimal enzymatic resolution condition was found to afford the enantiomerically enriched quaternary acetoxylated substrates with high ees (varied between 81% and 85%).

Cihangir Tanyeli; ?dris M. Akhmedov; Çi?dem ?yigün

2006-01-01

256

New insights on the molecular recognition of imidacloprid with Aplysia californica AChBP: a computational study.  

PubMed

The binding of imidacloprid (IMI), the forerunner of neonicotinoid insecticides, with the acetylcholine binding protein (AChBP) from Aplysia californica, the established model for the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a two-layer ONIOM partition approach (M06-2X/6-311G(d):PM6). Our calculations allow delineating the contributions of the key residues of AChBP for IMI binding. In particular, the importance of Trp147 and Cys190-191, through weak CH···? interactions and both van der Waals and hydrogen-bond (H-bond) interactions, respectively, are highlighted. Furthermore, H-bonds between hydroxyl groups of both Ser189 and Tyr55 and the IMI nitro group are pointed out. The participation of Ile118, whose main chain NH and carbonyl group are hydrogen-bonded with the IMI pyridinic nitrogen through a water molecule, is characterized. Our simulations also indicate the presence of a significant contribution of this residue through van der Waals interactions. The various trends obtained by the calculations of the pairwise interaction energies are confirmed through a complementary noncovalent interaction (NCI) analysis of selected IMI-AChBP amino acid pairs. Indeed, the contribution of a halogen-bond interaction between IMI and AChBP, recently proposed in the literature, is corroborated by our NCI analysis. PMID:23521537

Cerón-Carrasco, José P; Jacquemin, Denis; Graton, Jérôme; Thany, Steeve; Le Questel, Jean-Yves

2013-04-18

257

Investigation of the structure and properties of a-C:H coatings with metal and silicon containing interlayers  

NASA Astrophysics Data System (ADS)

The structure of the interface of a-C:H coatings deposited with metal and Si-containing interlayers has been studied. Carbide forming metals (Al, Ti, Cr) can improve the chemical bonding compared with a substrate material which does not form carbides extensively by itself. In addition, a graded transition zone enlarges the interface between the carbon layer and the interlayer metal. In the present work the metal atoms were evaporated and ionized into a dense Ar plasma and deposited onto Si (100) substrates. A graded interface between the metal interlayer and the a-C:H coating was produced by introducing C 2H 2 with increasing amount into the Ar/He plasma during the PAPVD metal deposition process. The PACVD a-C:H deposition process was continued after the termination of metal evaporation to produce the pure a-C:H top layer. Further to Al-, Cr-, Ti- and Cu-interlayers, Si-containing interlayers were investigated. The Si-containing interlayers were deposited by a PACVD process using tetraethoxysilane Si(OC 2H 5) 4 (TEOS) and tetramethylsilane Si(CH 3) 4 (TMS). The characterization of the deposited layer systems was performed by SIMS, SNMS and XPS analyses as well as SEM and analytical TEM methods.

Nöthe, M.; Breuer, U.; Koch, F.; Penkalla, H. J.; Rehbach, W. P.; Bolt, H.

2001-07-01

258

Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease.  

PubMed

Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established. PMID:24657052

Pudlo, Marc; Luzet, Vincent; Ismaïli, Lhassane; Tomassoli, Isabelle; Iutzeler, Anne; Refouvelet, Bernard

2014-04-15

259

HDAC Inhibitors  

Microsoft Academic Search

Natural and synthetic inhibitors of histone deacetylases (HDACs) have not only contributed to the discovery of HDAC enzyme\\u000a molecules and the elucidation of their functions but have also developed as attractive therapeutic agents for diseases including\\u000a cancer. After the disclosure of the crystal structure of the HDAC-like protein bound to the inhibitor, the momentum of research\\u000a on HDAC inhibitors increased,

Akihiro Ito; Norikazu Nishino; Minoru Yoshida

260

Inhibition of ACh release at an Aplysia synapse by neurotoxic phospholipases A2: specific receptors and mechanisms of action.  

PubMed Central

1. Monochain (OS2) and multichain (taipoxin) neurotoxic phospholipases A2 (PLA2), purified from taipan snake venom, both inhibited ACh release at a concentration of 20 nM (90% inhibition in 2 h) at an identified synapse from buccal ganglion of Aplysia californica. 2. The Na+ current was unchanged upon application of either OS2 or taipoxin. Conversely, presynaptic K+ currents (IA and IK) were increased by taipoxin but not by OS2. In addition, OS2 induced a significant decrease of the presynaptic Ca2+ current (30%) while taipoxin increased this latter current by 20-30%. 3. Bee venom PLA2, another monochain neurotoxic PLA2, also inhibited ACh release while non-toxic enzymatically active PLA2s like OS1 (also purified from taipan snake venom) or porcine pancreatic PLA2 elicited a much weaker inhibition of ACh release, suggesting a specific action of neurotoxic PLA2s versus non-toxic PLA2s on ACh release. 4. Using iodinated OS2, specific high affinity binding sites with molecular masses of 140 and 18 kDa have been identified on Aplysia ganglia. The maximal binding capacities were 55 and 300-400 fmol (mg protein)-1 for membrane preparations from whole and buccal ganglia, respectively. These binding sites are of high affinity for neurotoxic PLA2s (Kd values, 100-800 pM) and of very low affinity for non-toxic PLA2s (Kd values in the micromolar range), thus indicating that these binding sites are presumably involved in the blockade of ACh release by neurotoxic PLA2s. Images Figure 8 Figure 9

Fossier, P; Lambeau, G; Lazdunski, M; Baux, G

1995-01-01

261

Development of radiohalogenated muscarinic ligands for the in vivo imaging of m-AChR by nuclear medicine techniques  

SciTech Connect

Alterations in the density of acetylcholinergic muscarinic receptors (m-AChR) have been observed in various dementias. This has spurred interest in the development of radiohalogenated ligands which can be used for the non-invasive in vivo detection of m-AChR by nuclear medicine techniques. We have developed a new ligand 1-azabicyclo[2.2.2]oct-3-yl ({alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (IQNP,12) which demonstrates high affinity for the muscarinic receptor. When labeled with radioiodine it has been shown to be selective and specific for m-ACHR. Initial studies on the separation and in vivo evaluation of the various isomers of IQNP have shown that the stereochemistry of the chiral centers and the configuration around the double bond play an important role in m-AChR subtype specificity. In vivo evaluation of these stereoisomers demonstrate that E-(R,R)-IQNP has a high affinity for the M{sub 1} muscarinic subtype while Z-(R,R)-IQNP demonstrate a high affinity for M{sub 1} and M{sub 2} receptor subtypes. These data demonstrate IQNP (12) has potential for use in the non-evasive in vivo detection of m-AChR by single photon emission computed tomography (SPECT). A brominated analogue, ``BrQNP,`` in which the iodine has been replaced by a bromine atom, has also been prepared and was shown to block the in vivo uptake of IQNP in the brain and heart and therefore has potential for positron emission tomographic (PET) studies of m-AChR.

McPherson, D.W.; Luo, H.; Knapp, F.F. Jr.

1994-06-01

262

Inhibition of ACh release at an Aplysia synapse by neurotoxic phospholipases A2: specific receptors and mechanisms of action.  

PubMed

1. Monochain (OS2) and multichain (taipoxin) neurotoxic phospholipases A2 (PLA2), purified from taipan snake venom, both inhibited ACh release at a concentration of 20 nM (90% inhibition in 2 h) at an identified synapse from buccal ganglion of Aplysia californica. 2. The Na+ current was unchanged upon application of either OS2 or taipoxin. Conversely, presynaptic K+ currents (IA and IK) were increased by taipoxin but not by OS2. In addition, OS2 induced a significant decrease of the presynaptic Ca2+ current (30%) while taipoxin increased this latter current by 20-30%. 3. Bee venom PLA2, another monochain neurotoxic PLA2, also inhibited ACh release while non-toxic enzymatically active PLA2s like OS1 (also purified from taipan snake venom) or porcine pancreatic PLA2 elicited a much weaker inhibition of ACh release, suggesting a specific action of neurotoxic PLA2s versus non-toxic PLA2s on ACh release. 4. Using iodinated OS2, specific high affinity binding sites with molecular masses of 140 and 18 kDa have been identified on Aplysia ganglia. The maximal binding capacities were 55 and 300-400 fmol (mg protein)-1 for membrane preparations from whole and buccal ganglia, respectively. These binding sites are of high affinity for neurotoxic PLA2s (Kd values, 100-800 pM) and of very low affinity for non-toxic PLA2s (Kd values in the micromolar range), thus indicating that these binding sites are presumably involved in the blockade of ACh release by neurotoxic PLA2s. PMID:8583413

Fossier, P; Lambeau, G; Lazdunski, M; Baux, G

1995-11-15

263

Continuing Education in the Era of Quantum Change. 2003 ACHE Proceedings. (65th Annual Meeting, Charlottesville, VA, November 8-12, 2003)  

ERIC Educational Resources Information Center

This document presents the proceedings of the 2003 annual meeting of the Association for Continuing Higher Education (ACHE). These proceedings record the 65th Annual Meeting of ACHE held in Charlottesville, Virginia. President Allen Varner's theme for this annual meeting was, "Continuing Education in the Era of Quantum Change." The theme was…

Barrineau, Irene T., Ed.

2003-01-01

264

Biocompatible Silver-containing a-C:H and a-C coatings: AComparative Study  

SciTech Connect

Hydrogenated diamond-like-carbon (a-C:H) and hydrogen-free amorphous carbon (a-C) coatings are known to be biocompatible and have good chemical inertness. For this reason, both of these materials are strong candidates to be used as a matrix that embeds metallic elements with antimicrobial effect. In this comparative study, we have incorporated silver into diamond-like carbon (DLC) coatings by plasma based ion implantation and deposition (PBII&D) using methane (CH4) plasma and simultaneously depositing Ag from a pulsed cathodic arc source. In addition, we have grown amorphous carbon - silver composite coatings using a dual-cathode pulsed filtered cathodic-arc (FCA) source. The silver atomic content of the deposited samples was analyzed using glow discharge optical spectroscopy (GDOES). In both cases, the arc pulse frequency of the silver cathode was adjusted in order to obtain samples with approximately 5 at.% of Ag. Surface hardness of the deposited films was analyzed using the nanoindentation technique. Cell viability for both a-C:H/Ag and a-C:/Ag samples deposited on 24-well tissue culture plates has been evaluated.

Endrino, Jose Luis; Allen, Matthew; Escobar Galindo, Ramon; Zhang, Hanshen; Anders, Andre; Albella, Jose Maria

2007-04-01

265

Defying aches and revaluating daily doing: occupational perspectives on adjusting to chronic pain.  

PubMed

The aim of this study was to investigate how people with chronic pain experience their daily doing, with a special focus on possible adjustment to pain and altered life conditions in order to cope with pain and maintain well-being. In-depth interviews were guided by themes concerning daily occupation, ways to maintain well-being, and future expectations. Using qualitative content analysis a core concept "Reappraising daily doing" was arrived at, containing the categories of altering doing processes and altering values, each in turn containing four subcategories. The findings showed that along with the grief of having to abandon jobs and former social networks, the participants coped with their everyday lives in ways that opened up the use of imagination and improvisation and the valuing of non-material and altruistic behaviour. An occupation was generally given up when aches (participants' term) became worse, except for when the occupations were so enjoyed that the pain was put out of focus. Using the concept of Occupational Value to enhance coping ability seems a reasonable strategy for occupational therapists when assisting clients in finding or maintaining meaningful daily doing and effective coping strategies for experiencing well-being. This could in turn limit the use of health care resources, which is extensive. PMID:20704468

Persson, Dennis; Andersson, Ingemar; Eklund, Mona

2011-09-01

266

Synthesis and evaluation of novel 4-[(3H,3aH,6aH)-3-phenyl)-4,6-dioxo-2-phenyldihydro-2H-pyrrolo[3,4-d]isoxazol-5(3H,6H,6aH)-yl]benzoic acid derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents.  

PubMed

The present study was designed to synthesize and evaluate pyrrolo-isoxazole benzoic acid derivatives as potential acetylcholinesterase (AChE) inhibitors for the management of Alzheimer's disease. The synthesis of pyrrolo-isoxazole benzoic acid derivatives involved ring opening cyclization of p-aminobenzoic acid with maleic anhydride to yield maleanilic acid, which in turn afforded N-arylmaleimide via ring closed cyclization. Azomethine-N-oxides were obtained by condensation of N-arylhydroxylamine with differently substituted benzaldehydes followed by refluxing of N-arylmaleimide with differently substituted azomethine-N-oxides to pyrrolo-isoxazole benzoic acid derivatives as cis- and trans-stereoisomers. The synthesized compounds were evaluated in vitro for AChE inhibitory activity in rat brain homogenate with donepezil as standard AChE inhibitor. Thereafter, the most potent test compound was evaluated for in vitro butyrylcholinesterase inhibitory activity and in vivo memory evaluation in scopolamine (0.4mg/kg)-induced amnesia in mice by employing Morris water maze test. All pyrrolo-isoxazole benzoic acid derivatives demonstrated potent AChE inhibitory activity. Most of compounds exhibited similar activity to donepezil and four of them (7h, 7i, 8i, and 8h, IC(50)=19.1±1.9-17.5±1.5nM) displayed higher inhibitory activity as compared to donepezil (21.5±3.2nM) with compound 8ia (IC(50)=17.5±1.5nM) being the most active one. The test compound 8ia also ameliorated scopolamine-induced amnesia in mice in terms of restoration of time spent in target quadrant (TSTQ) and escape latency time (ELT). It may be concluded that pyrrolo-isoxazole benzoic acid derivatives may be employed as potential AChE inhibitors. PMID:22172310

Anand, Preet; Singh, Baldev

2012-01-01

267

Quaternary coral reef refugia preserved fish diversity.  

PubMed

The most prominent pattern in global marine biogeography is the biodiversity peak in the Indo-Australian Archipelago. Yet the processes that underpin this pattern are still actively debated. By reconstructing global marine paleoenvironments over the past 3 million years on the basis of sediment cores, we assessed the extent to which Quaternary climate fluctuations can explain global variation in current reef fish richness. Comparing global historical coral reef habitat availability with the present-day distribution of 6316 reef fish species, we find that distance from stable coral reef habitats during historical periods of habitat loss explains 62% of the variation in fish richness, outweighing present-day environmental factors. Our results highlight the importance of habitat persistence during periods of climate change for preserving marine biodiversity. PMID:24876495

Pellissier, Loïc; Leprieur, Fabien; Parravicini, Valeriano; Cowman, Peter F; Kulbicki, Michel; Litsios, Glenn; Olsen, Steffen M; Wisz, Mary S; Bellwood, David R; Mouillot, David

2014-05-30

268

Antifungal activity of gemini quaternary ammonium salts.  

PubMed

A series of gemini quaternary ammonium chlorides and bromides with various alkyl chain and spacer lengths was synthesized. The most active compounds against fungi were chlorides with 10 carbon atoms within the hydrophobic chain. Among these compounds were few with no hemolytic activity at minimal inhibitory concentrations. None of the tested compounds were cytotoxic and mutagenic. Cationic gemini surfactants poorly reduced the adhesion of microorganisms to the polystyrene plate, but inhibited the filamentation of Candida albicans. One of the tested compounds eradicated C. albicans and Rodotorula mucilaginosa biofilm, what could be important in overcoming catheter-associated infections. It was also shown that gemini surfactants enhanced the sensitivity of C. albicans to azoles and polyenes, thus they might be potentially used in combined therapy against fungi. PMID:23827647

Ob??k, Ewa; Piecuch, Agata; Krasowska, Anna; Luczy?ski, Jacek

2013-12-14

269

Biosedimentology of Quaternary stromatolites in intertropical Africa  

NASA Astrophysics Data System (ADS)

Mineralizations of microbial origin constitute a non-negligeable part of Quaternary limestones in intertropical Africa. Stromatolites have colonized a wide range of environments corresponding to different hydroclimatic situations: travertines in fluviatile environments, oncolites in flood plains, encrustations in sebkha areas and shorelines of deep, fresh water lakes. The developed morphologies represent a complete catalogue of the microbial carbonated mineralizations: oncolites, chemneys, pool-rim dams, biocherms, planar or cylindrical encrustations. The building organisms may be either pure bacterial colonies (hydrothermal and lacustrine environments), cyanophyte associations (fluviatile and lacustrine environments) or complex microbial biocoenoses. Stromatolites have recorded the hydrologic, climatic and sedimentologic evolution of the continental environment in intertropical Africa for the past 240 000 years.

Casanova, J.

270

Phosphodiesterase inhibitors  

PubMed Central

Phosphodiesterases are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. Theophylline and papaverine have historically been used therapeutically and are known to be weak inhibitors of PDE, but to what extent this contributed toward their clinical efficacy was poorly defined. However, the discovery of 11 isoenzyme families and our increased understanding of their function at the cell and molecular level provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. This review focuses on the development of PDE3 inhibitors for congestive heart failure, PDE4 inhibitors for inflammatory airways disease and most successfully, PDE5 inhibitors for erectile dysfunction

Boswell-Smith, Victoria; Spina, Domenico; Page, Clive P

2006-01-01

271

Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating ?7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade.  

PubMed

Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09 ?M) and to block the NMDA receptor (21.8 ?M) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (?7nAChR), but not muscarinic acetylcholine receptor (mAChR) or ?4?2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3?. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating ?7nAChR/PI3-K/Akt cascade. PMID:23085120

Cui, Wei; Hu, Shengquan; Chan, Hugh H N; Luo, Jialie; Li, Wenming; Mak, Shinghung; Choi, Tony Chunglit; Rong, Jianhui; Carlier, Paul R; Han, Yifan

2013-03-25

272

Late Quaternary temperature change velocity in Mesoamerica  

NASA Astrophysics Data System (ADS)

Quaternary climate has been highly variable, and yet few quantitative continental reconstructions are available for tropical areas. Quantitative records of temperature change during the Quaternary are especially relevant for putting modern climate change into a historic context. Within this perspective, two aspects are of singular relevance: i) Identifying and quantifying past climatic variability, and ii) Providing a means to estimate the seed at which climate change happened in the past. Here we show temperature reconstructions and temperature change velocity calculations for two locations in northern tropical America. Temperature reconstruction was based on two sedimentary records form Lake Chalco (30,000 years), central Mexican highlands, and Lake Petén-Itzá, Guatemalan lowlands (86,000 years). Temperature reconstruction was based on the analysis of fossil pollen on the light of pollen-temperature transfer functions. These functions were calibrated through an extensive survey of modern pollen samples covering an elevational gradient from 0 to 4,218 m asl. Derived temperature profiles show a parallel long-term trend and a similar cooling of approximately 5 oC during the Last Glacial Maximum in the lowlands and highlands of Mexico and Guatemala. Using a digital elevation model, we ere able to reconstruct the velocity at which isotherms displaced to produce the observed temperature anomalies. Spatial velocities of temperature change in the studied areas were at least four times slower than values reported for the last 50 years, but also at least twice as fast as those obtained from recent models. This study demonstrates that modern temperature change has no precedent within the last 86,000 years, but also that tropical climate has been more variable than it has been assumed to date.

Correa-Metrio, A.; Lozano, S.; Sosa-Nájera, S.; Bush, M. B.

2013-05-01

273

?7 Nicotinic Acetylcholine Receptor (?7nAChR) Expression in Bone Marrow-Derived Non-T Cells Is Required for the Inflammatory Reflex  

PubMed Central

The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the ?7 nicotinic acetylcholine receptor (?7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of ?7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and ?7nAChR-deficient mice. Deficiency of ?7nAChR in bone marrow–derived cells significantly impaired vagus nerve–mediated regulation of tumor necrosis factor (TNF), whereas ?7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell ?7nAChR, we adoptively transferred ?7nAChR-deficient or WT T cells to nude mice. Transfer of WT and ?7nAChR-deficient T cells restored function, indicating that ?7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that ?7nAChR expression in bone marrow–derived non–T cells is required for the integrity of the inflammatory reflex.

Olofsson, Peder S; Katz, David A; Rosas-Ballina, Mauricio; Levine, Yaakov A; Ochani, Mahendar; Valdes-Ferrer, Sergio I; Pavlov, Valentin A; Tracey, Kevin J; Chavan, Sangeeta S

2012-01-01

274

ACh-induced depolarization in inner ear artery is generated by activation of a TRP-like non-selective cation conductance and inactivation of a potassium conductance.  

PubMed

Adequate cochlear blood supply by the spiral modiolar artery (SMA) is critical for normal hearing. ACh may play a role in neuroregulation of the SMA but several key issues including its membrane action mechanisms remain poorly understood. Besides its well-known endothelium-dependent hyperpolarizing action, ACh can induce a depolarization in vascular cells. Using intracellular and whole-cell recording techniques on cells in guinea pig in vitro SMA, we studied the ionic mechanism underlying the ACh-depolarization and found that: (1) ACh induced a DAMP-sensitive depolarization when intermediate conductance KCa channels were blocked by charybdotoxin or nitrendipine. The ACh-depolarization was associated with a decrease in input resistance (R(input)) in high membrane potential (V(m)) ( approximately -40 mV) cells but with no change or an increase in R input in low Vm ( approximately -75 mV) cells. ACh-depolarization was attenuated by background membrane depolarization from approximately -70 mV in the majority of cells; (2) ACh-induced inward current in smooth muscle cells embedded in a SMA segment often showed a U-shaped I/V curve, the reversal potential of its two arms being near EK and 0 mV, respectively; (3) ACh-depolarization was reduced by low Na+, zero K+ or 20mM K+ bath solutions; (4) ACh-depolarization was inhibited by La3+ in all cells tested, by 4-AP and flufenamic acid in low Vm cells, but was not sensitive to Cd2+, Ni2+, nifedipine, niflumic acid, DIDS, IAA94, linopirdine or amiloride. We conclude that ACh-induced vascular depolarization was generated mainly by activation of a TRP-like non-selective cation channel and by inactivation of an inward rectifier K+ channel. PMID:18313244

Ma, Ke-Tao; Guan, Bing-Cai; Yang, Yu-Qin; Zhao, Hui; Jiang, Zhi-Gen

2008-05-01

275

7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies.  

PubMed

A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment. PMID:24929293

Korabecny, Jan; Dolezal, Rafael; Cabelova, Pavla; Horova, Anna; Hruba, Eva; Ricny, Jan; Sedlacek, Lukas; Nepovimova, Eugenie; Spilovska, Katarina; Andrs, Martin; Musilek, Kamil; Opletalova, Veronika; Sepsova, Vendula; Ripova, Daniela; Kuca, Kamil

2014-07-23

276

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors.  

PubMed

A novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH4OAc, using InCl3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE. PMID:23422935

da Costa, Jessé Sobieski; Lopes, João Paulo Bizarro; Russowsky, Dennis; Petzhold, Cesar Liberato; Borges, Antonio César de Amorim; Ceschi, Marco Antonio; Konrath, Eduardo; Batassini, Cristiane; Lunardi, Paula Santana; Gonçalves, Carlos Alberto Saraiva

2013-04-01

277

Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease.  

PubMed

A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC?? values of 0.76 and 0.46 ?M, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD. PMID:24461494

Luo, Zonghua; Liang, Liang; Sheng, Jianfei; Pang, Yanqing; Li, Jianheng; Huang, Ling; Li, Xingshu

2014-02-15

278

Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum.  

PubMed Central

1. The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [3H]-dopamine. In this preparation, nicotinic cholinoceptor activation evoked [3H]-dopamine release. 2. Antagonist activity was examined by giving a brief nicotine (1 microM) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3-300 microM). Physostigmine, neostigmine and tacrine produced a concentration-dependent blockade. Physostigmine and tacrine were particularly potent (IC50S approx. 10 microM and 1 microM, respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 microM). 3. Nicotinic blockade produced by superfusion with physostigmine (30 microM) was insurmountable when tested against nicotine (0.1-100 microM). 4. Physostigmine (30 microM) also reduced responses to the nicotinic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K+ or (+)-amphetamine. A higher concentration of physostigmine (300 microM) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K+. Tacrine (3 microM) reduced responses to nicotine and to high K+ but did not affect responses to amphetamine. 5. Physostigmine (0.3-300 microM), given as a brief pulse, did not produce a nicotinic agonist-like effect. 6. Physostigmine, neostigmine, tacrine and DFP (all at 30 microM) each produced near-total (> 96%) inhibition of AChE activity. However, DFP at a concentration (60 microM) that produced a degree of AChE inhibition equal to that of physostigmine 30 microM, did not significantly reduce nicotine-induced dopamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Clarke, P. B.; Reuben, M.; el-Bizri, H.

1994-01-01

279

Role of L- and N-type Ca2+ channels in muscarinic receptor-mediated facilitation of ACh and noradrenaline release in the rat urinary bladder.  

PubMed Central

1. 3H-Noradrenaline (NA) and 14C-acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. omega-Conotoxin GVIA (omega-CgTX; 20-100 nM) suppressed the non-facilitated transmitter release evoked by intermittent stimulation (IS), whereas nifedipine (1 microM) did not affect release. 3. Continuous electrical stimulation (CS) facilitated NA and ACh release via an atropine-sensitive mechanism. omega-CgTX reduced the facilitated release of NA (44% depression) but did not affect ACh release. Nifedipine depressed ACh release (43%) but not NA release. Combined administration of nifedipine and omega-CgTX (20 nM) produced a greater suppression of NA and ACh release (86 and 91%, respectively). 4. Maximal muscarinic facilitation of NA (5-fold) and ACh (17-fold) release occurred following administration of eserine, an anticholinesterase agent. Release of both NA and ACh was depressed by nifedipine (70 and 83%, respectively) but not by omega-CgTX. Combined application of omega-CgTX and nifedipine elicited a further depression of NA (95%) but not ACh release. 5. When NA and ACh release was facilitated with phorbol dibutyrate (0.5 microM), nifedipine inhibited ACh (67%) but not NA release, whereas omega-CgTX inhibited NA (73%) but not ACh release. Combined administration of both Ca2+ channel blockers did not elicit greater inhibition. 6. Bay K 8644, the L-type Ca2+ channel activator, increased ACh release in a dose-dependent manner (up to 5-fold) but did not significantly change NA release. 7. Both omega-CgTX (20-100 nM) and nifedipine (100 nM-1 microM) significantly decreased (50-80%) the neurally evoked contractions of the bladder strips. 8. It is concluded that L-type Ca2+ channels play a major role in muscarinic facilitation of NA and ACh release in the urinary bladder but are not essential for non-facilitated release. Other types of Ca2+ channels, including N-type, are involved to varying degrees in non-facilitated and facilitated release under different experimental conditions.

Somogyi, G T; Zernova, G V; Tanowitz, M; de Groat, W C

1997-01-01

280

Seismic tomographic mapping of the Earth's interior — Back to basics revisiting the ACH inversion  

NASA Astrophysics Data System (ADS)

It is now more than 35 years since our original work on seismic tomography commenced in June 1974 upon Keiiti Aki's arrival at Kjeller near Oslo. It was published by Aki et al. (1977) and has found wide-spread applications in numerous studies of the Earth's interior from crust to core and in addition triggered many theoretical ones as well. In those times, computer technologies were rather crude and this hampered our tomographic research. In particular, we were somewhat unhappy about both our Generalized Inverse (GI) and the Stochastic Inverse (SI) solutions because of the former being too bumpy and the latter involving vertical smoothing. These problems remain in evidence also in recent studies as will be demonstrated in this review work. We start with re-examining the ACH-original work and then introduce Gauss-Markov (GM) filtering offsetting the defects of both the generalized and stochastic inverses. We highlight the relative merits of our novel inversion method by real tests on the original Norsar P-residuals and the corresponding 5 layered lithosphere model using synthetic velocity anomalies. Then we repeated the original inversion experiment adding the GM solution. The outcome was that the original SI solution was useless; GI too bumpy while the GM solution was appealing both computationally and in the context of geotectonic interpretation. We found that alternative inversion procedures like those forwarded by Backus and Gilbert (1968) and by Pijpers and Thompson (1992), the latter for helioseismology, were not applicable. The reason is that our unknowns are relative velocity anomalies within separate model layers and thus violate basic assumptions in the mentioned procedures. We also discuss source and structure parameter separation and the recent 'double difference' approach in tomography based on local earthquake data.

Christoffersson, Anders; Husebye, Eystein S.

2011-06-01

281

NMR resolved multiple anesthetic binding sites in the TM domains of the ?4?2 nAChR  

PubMed Central

The ?4?2 nicotinic acetylcholine receptor (nAChR) has significant roles in nervous system function and disease. It is also a molecular target of general anesthetics. Anesthetics inhibit the ?4?2 nAChR at clinically relevant concentrations, but their binding sites in ?4?2 remain unclear. The recently determined NMR structures of the ?4?2 nAChR transmembrane (TM) domains provide valuable frameworks for identifying the binding sites. In this study, we performed solution NMR experiments on the ?4?2 TM domains in the absence and presence of halothane and ketamine. Both anesthetics were found in an intra-subunit cavity near the extracellular end of the 2 transmembrane helices, homologous to a common anesthetic binding site observed in X-ray structures of anesthetic-bound GLIC (Nury, et. al. 2011). Halothane, but not ketamine, was also found in cavities adjacent to the common anesthetic site at the interface of ?4 and ?2. In addition, both anesthetics bound to cavities near the ion selectivity filter at the intracellular end of the TM domains. Anesthetic binding induced profound changes in protein conformational exchanges. A number of residues, close to or remote from the binding sites, showed resonance signal splitting from single to double peaks, signifying that anesthetics decreased conformation exchange rates. It was also evident that anesthetics shifted population of two conformations. Altogether, the study comprehensively resolved anesthetic binding sites in the ?4?2 nAChR. Furthermore, the study provided compelling experimental evidence of anesthetic-induced changes in protein dynamics, especially near regions of the hydrophobic gate and ion selectivity filter that directly regulate channel functions.

Bondarenko, Vasyl; Mowrey, David; Liu, Lu Tian; Xu, Yan; Tang, Pei

2012-01-01

282

Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function ?6* nAChRs.  

PubMed

?6?2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function ?6?2* nAChRs (?6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in ?6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and ?6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing ?6?2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as ?-conotoxin MII completely abolished evoked DA release in ?6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, ?6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in ?6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in ?6L9'S NAc. Overall, these results show that enhanced ?6?2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. PMID:24266758

Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R; McIntosh, J Michael; Brunzell, Darlene H; Cannon, Jason R; Drenan, Ryan M

2014-04-01

283

Crystalline molecular sieve synthesis using quaternary ammonium-functionalized organosiliconate  

US Patent & Trademark Office Database

This invention relates to a method for preparing crystalline silicates such as zeolites from a forming mixture containing quaternary ammonium-functionalized organosiliconate as a directing agent. The products prepared depend, inter alia, on reaction conditions such as temperature, crystallization time, and pH. More particularly, this invention relates to the use of a quaternary ammonium-functionalized organosiliconate in the preparation of ZSM-5, ZSM-48, ZSM-51 and the ZSM-48 composition thus prepared.

1993-03-16

284

Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme  

PubMed Central

An in vitro evaluation of the Johns Hopkins Clinical Compound Library demonstrates that certain drugs can alter the quaternary structure of an essential human protein. Human porphobilinogen synthase (HsPBGS) is an essential enzyme involved in heme biosynthesis; it exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. Reduced HsPBGS activity is implicated in toxicities associated with lead poisoning and ALAD porphyria, the latter of which involves hexamer-favoring HsPBGS variants. A medium-throughput native PAGE mobility shift screen, coupled with evaluation of hits as HsPBGS inhibitors, revealed twelve drugs that stabilize the HsPBGS hexamer and inhibit HsPBGS activity in vitro. A detailed characterization of these effects is presented. Drug inhibition of HsPBGS in vivo by inducing hexamer formation would constitute an unprecedented mechanism for side effects. We suggest that small molecule perturbation of quaternary structure equilibria be considered as a general mechanism for drug action and side effects.

Lawrence, Sarah H.; Selwood, Trevor; Jaffe, Eileen K.

2011-01-01

285

Process of inhibiting scale formation in aqueous systems using quaternary ammonium salts of. cap alpha. -1,4-thiazine  

SciTech Connect

Quaternary ammonium salts of ..cap alpha..-1,4-thiazine alkanephosphonic acids are described which inhibit scale formation in aqueous systems. The compounds also can be used in formation of acid corrosion inhibitors, as sequestering agents, and as microbiocides. These compounds are prepared by reacting an ..cap alpha..-1,4-thiazine alkanephosphonic acid compound with an alkylating agent in a suitable polar solvent or a mixture of polar solvents. Examples of solvents are water, mixtures of water and lower alcohols, lower alcohols, dimethyl formamide, dimethyl sulfoxide, and hexamethyulphosphorotrimide. 10 claims.

Quinlan, P.M.

1982-04-06

286

Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways  

SciTech Connect

Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K. [Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong (Hong Kong); Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong (Hong Kong); Cho, C.H. [Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong (Hong Kong); Department of Pharmacology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong (Hong Kong); Sung, J.J.Y. [Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong (Hong Kong); Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR (Hong Kong)], E-mail: joesung@cuhk.edu.hku

2008-12-01

287

Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the l-Type Calcium Channel  

PubMed Central

Type II vestibular hair cells (VHCs II) contain big-conductance Ca2+-dependent K+ channels (BK) and l-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca2+ ions through l-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC50 value of 36.3 ± 7.8 ?M. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]o) could antagonize it. Moreover, 50 ?M GM potently blocked Ca2+ currents activated by (?)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II.

Yu, Hong; Guo, Chang-Kai; Wang, Yi; Zhou, Tao; Kong, Wei-Jia

2014-01-01

288

Is ?7-nAChR a possible target for lung cancer and malignant pleural mesothelioma treatment?  

PubMed

This paper discusses the potential therapeutic effect of ?7-nAChR antagonists for NSCLC (non small cell lung cancer) and MPM (malignant pleural mesothelioma). This therapeutic approach is based on the experimental observations that: (a) functional ?7-nAChR are expressed in NSCLC and MPM cells, (b) the activation of these receptors by agonists, namely nicotine, induces cell proliferation and inhibits apoptosis, whereas antagonists have a pro-apoptotic effect. Among competitive ?7-nAChR antagonists, d-tubocurarine and -cobratoxin (?-CbT), from the snake venom of Naja, emerged as possible drug candidates. However, some aspects of the samples must be particularly taken into account, such as the particular nature of the sample. Thus, when using natural compounds purified from snake venom, it is important to take into account the factors such as whether the venom sample was derived from different animals, purified by different methods, or contained contaminants of the same molecular weight. Finally, biological activity may be different for different batches, which could also have been stored under different conditions (e.g. temperature, dilution, suspension medium etc.). These factors, affecting the experimental results, are also discussed. PMID:22300036

Cesario, Alfredo; Russo, Patrizia; Nastrucci, Candida; Granone, Pierluigi

2012-05-01

289

CFTR inhibitors.  

PubMed

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl- channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease. PMID:23331030

Verkman, Alan S; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R; Anderson, Marc O

2013-01-01

290

CFTR Inhibitors  

PubMed Central

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl? channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease.

Verkman, Alan S.; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R.; Anderson, Marc O.

2014-01-01

291

Chymase inhibitors.  

PubMed

Chymase, a chymotrypsin-like serine protease that is abundant in secretory granules from mast cells, has been identified to be a key enzyme in the local renin-angiotensin system (RAS) that generates angiotensin II (Ang II) independent of angiotensin converting enzyme (ACE). The pathophysiological significance of alternative Ang II-forming pathways in human cardiovascular disease remains controversial. Although chymase inhibitors, unlike ACE inhibitors and Ang II type 1 receptor blockers (ARBs), may only play a small role in the regulation of the systemic RAS, the possible applications of chymase inhibitors as new drugs that inhibit the local RAS to prevent cardiovascular diseases are described in animal models. In this review, we discuss the possible application of chymase inhibitors as new drugs to inhibit the RAS in mainly cardiovascular diseases. PMID:23176221

Yahiro, Eiji; Miura, Shin-ichiro; Imaizumi, Satoshi; Uehara, Yoshinari; Saku, Keijiro

2013-01-01

292

Sorption and desorption of quaternary amine cations on clays  

SciTech Connect

The authors have studied the sorption and desorption of three quaternary amines, namely, nonyltrimethylammonium, dodecyltrimethylammonium, and hexadecyltrimethylammonium, on homoionic Na- and K-montmorillonite using a titration procedure. More than 99% of all three of the quaternary amine cations studied were sorbed on the montmorillonite when the added amines were less than 70% of the cation-exchange capacity of the montmorillonite. Sorption of quaternary amine cations involves at least two types of reactions, namely, an exchange reaction and the adsorption of amines at nonexchangeable sites. The exchange reaction proceeded almost to completion when Na[sup +] was the exchangeable cation. Exchangeable K[sup +] was much more difficult to replace. The adsorbed quaternary amine cations were not easily desorbed in the presence of 0.1 M NaCl and KCl solutions. In addition, desorption of quaternary amines did not increase with prolonged equilibrium time, up to 180 days. Therefore, it appears that there is good promise in using quaternary amine-modified clays as effective sorbents for removing organic pollutants or mitigating their mobilities in the environment. 26 refs., 5 figs., 6 tabs.

Zhang, Z.Z.; Sparks, D.L. (Univ. of Delaware, Newark, DE (United States)); Scrivner, N.C. (DuPont Engineering, Newark, DE (United States))

1993-08-01

293

A Quaternary Geomagnetic Instability Time Scale  

NASA Astrophysics Data System (ADS)

Reversals and excursions of Earth's geomagnetic field create marker horizons that are readily detected in sedimentary and volcanic rocks worldwide. An accurate and precise chronology of these geomagnetic field instabilities is fundamental to understanding several aspects of Quaternary climate, dynamo processes, and surface processes. For example, stratigraphic correlation between marine sediment and polar ice records of climate change across the cryospheres benefits from a highly resolved record of reversals and excursions. The temporal patterns of dynamo behavior may reflect physical interactions between the molten outer core and the solid inner core or lowermost mantle. These interactions may control reversal frequency and shape the weak magnetic fields that arise during successive dynamo instabilities. Moreover, weakening of the axial dipole during reversals and excursions enhances the production of cosmogenic isotopes that are used in sediment and ice core stratigraphy and surface exposure dating. The Geomagnetic Instability Time Scale (GITS) is based on the direct dating of transitional polarity states recorded by lava flows using the 40Ar/39Ar method, in parallel with astrochronologic age models of marine sediments in which O isotope and magnetic records have been obtained. A review of data from Quaternary lava flows and sediments yields a GITS comprising 10 polarity reversals and 27 excursions during the past 2.6 million years. Nine of the ten reversals bounding chrons and subchrons are associated with 40Ar/39Ar ages of transitionally-magnetized lava flows. The tenth, the Guass-Matuyama chron boundary, is tightly bracketed by 40Ar/39Ar dated ash deposits. Of the 27 well-documented excursions, 14 occurred during the Matuyama chron and 13 during the Brunhes chron; 19 have been dated directly using the 40Ar/39Ar method on transitionally-magnetized volcanic rocks and form the backbone of the GITS. Excursions are clearly not the rare phenomena once thought. Rather, during the Quaternary period, they occur nearly three times as often as full polarity reversals. I will address analytical issues, including the size and consistency of system blanks, that have led to the recognition of minor (1%) discrepencies between the 40Ar/39Ar age for a particular reversal or excursion and the best astrochronologic estimates from ODP sediment cores. For example, re-analysis of lava flows from Haleakala volcano, Maui that record in detail the Matuyama-Brunhes polarity reversal have been undertaken with blanks an order of magntitude smaller and more stable than was common a decade ago. Using the modern astrochronologic calibration of 28.201 Ma for the age of the Fish Canyon sanidine standard, results thus far yield an 40Ar/39Ar age of 772 × 11 ka for the reversal that is identical to the most precise and accurate astrochronologic age of 773 × 2 ka for this reversal from ODP cores. Similarly, new dating of sanidine in the Cerro Santa Rosa I rhyolite dome, New Mexico reveals an age of 932 × 5 ka for the excursion it records, in perfect agreement with astrochronologically dated ODP core records. Work underway aims at refining the 40Ar/39Ar ages that underpin the entire GITS by further eliminating the bias between the radioisotopic and astrochronologically determined ages for several reversals and excursions.

Singer, B. S.

2013-12-01

294

Single particle tracking of alpha7 nicotinic AChR in hippocampal neurons reveals regulated confinement at glutamatergic and GABAergic perisynaptic sites.  

PubMed

Alpha7 neuronal nicotinic acetylcholine receptors (alpha7-nAChR) form Ca(2+)-permeable homopentameric channels modulating cortical network activity and cognitive processing. They are located pre- and postsynaptically and are highly abundant in hippocampal GABAergic interneurons. It is unclear how alpha7-nAChRs are positioned in specific membrane microdomains, particularly in cultured neurons which are devoid of cholinergic synapses. To address this issue, we monitored by single particle tracking the lateral mobility of individual alpha7-nAChRs labeled with alpha-bungarotoxin linked to quantum dots in live rat cultured hippocampal interneurons. Quantitative analysis revealed different modes of lateral diffusion of alpha7-nAChR dependent on their subcellular localization. Confined receptors were found in the immediate vicinity of glutamatergic and GABAergic postsynaptic densities, as well as in extrasynaptic clusters of alpha-bungarotoxin labeling on dendrites. alpha7-nAChRs avoided entering postsynaptic densities, but exhibited reduced mobility and long dwell times at perisynaptic locations, indicative of regulated confinement. Their diffusion coefficient was lower, on average, at glutamatergic than at GABAergic perisynaptic sites, suggesting differential, synapse-specific tethering mechanisms. Disruption of the cytoskeleton affected alpha7-nAChR mobility and cell surface expression, but not their ability to form clusters. Finally, using tetrodotoxin to silence network activity, as well as exposure to a selective alpha7-nAChR agonist or antagonist, we observed that alpha7-nAChRs cell surface dynamics is modulated by chronic changes in neuronal activity. Altogether, given their high Ca(2+)-permeability, our results suggest a possible role of alpha7-nAChR on interneurons for activating Ca(2+)-dependent signaling in the vicinity of GABAergic and glutamatergic synapses. PMID:20634896

Bürli, Thomas; Baer, Kristin; Ewers, Helge; Sidler, Corinne; Fuhrer, Christian; Fritschy, Jean-Marc

2010-01-01

295

Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.  

PubMed

The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 ?M depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 ?M, respectively. PMID:23151013

Yanovsky, Inessa; Finkin-Groner, Efrat; Zaikin, Andrey; Lerman, Lena; Shalom, Hila; Zeeli, Shani; Weill, Tehilla; Ginsburg, Isaac; Nudelman, Abraham; Weinstock, Marta

2012-12-13

296

Design, synthesis and evaluation of 2,4-disubstituted pyrimidines as cholinesterase inhibitors.  

PubMed

A group of 2,4-disubstituted pyrimidine derivatives (7a-e, 8a-e and 9a-d) that possess a variety of C-2 aliphatic five- and six-membered heterocycloalkyl ring in conjunction with a C-4 arylalkylamino substituent were designed, synthesized and evaluated as cholinesterase (ChE) inhibitors. The steric and electronic properties at C-2 and C-4 positions of the pyrimidine ring were varied to investigate their effect on ChE inhibitory potency and selectivity. The structure-activity relationship (SAR) studies identified N-benzyl-2-thiomorpholinopyrimidin-4-amine (7c) as the most potent cholinesterase inhibitor (ChEI) with an IC(50)=0.33 microM (acetylcholinesterase, AChE) and 2.30muM (butyrylcholinesterase, BuChE). The molecular modeling studies indicate that within the AChE active site, the C-2 thiomorpholine substituent was oriented toward the cationic active site region (Trp84 and Phe330) whereas within the BuChE active site, it was oriented toward a hydrophobic region closer to the active site gorge entrance (Ala277). Accordingly, steric and electronic properties at the C-2 position of the pyrimidine ring play a critical role in ChE inhibition. PMID:20472431

Mohamed, Tarek; Rao, Praveen P N

2010-06-15

297

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.  

PubMed

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test. PMID:16231039

Tzavara, E T; Bymaster, F P; Overshiner, C D; Davis, R J; Perry, K W; Wolff, M; McKinzie, D L; Witkin, J M; Nomikos, G G

2006-02-01

298

Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors.  

PubMed

Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The ?-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-?-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE. PMID:24604285

Schwarz, S; Csuk, R; Rauter, A P

2014-04-21

299

Quaternary phylogeography: the roots of hybrid zones.  

PubMed

The older history of hybrid zones is explored through consideration of recent advances in climatology, paleontology and phylogeography in the Late Cenozoic, particularly the Quaternary Period with its major climatic cycles. The fossil record shows that these ice ages and their nested millennial oscillations caused substantial changes in species distributions and with genetic evidence allows deduction of refugia and colonization routes in arctic, temperate, desert and tropical regions. The age of divergence between hybridizing lineages varies from the Late Pleistocene to the Late Miocene, implying much range change and varying selection on sister lineages. Hybridizing lineages in the Tropical and Temperate regions range in age from young to old, but those studied in the Arctic are no more than a few ice ages old and their refugial roots are not clear. Mid to low latitude regions often show parapatric patchworks of lineages and multiple refugia stable through many climatic oscillations. Particular hybrid zones may have formed more than once; while some expansions were not the same, producing reticulation and introgression in previous glacial cycles. Hybrid-zone roots are complex and deep, and considerations of their complexity can reveal evolutionary pathways of species. They are indeed windows on evolution. PMID:21234647

Hewitt, Godfrey M

2011-05-01

300

Ototoxic effect of quaternary ammonium compounds.  

PubMed

In earlier investigations by the author it has been shown that chlorhexidine, when introduced into the middle ear of guinea pigs, caused serious damage to the inner ear. The present investigation was performed in order to study if the quaternary ammonium compounds benzethonium chloride and benzalkonium chloride, frequently used for skin disinfection, can also induce inner ear damage when introduced into the tympanic cavity of guinea pigs. The disinfectants in question, at a concentration of 0.1% and in a solution of aqua dest. or 70% alcohol, were introduced into the animals' middle ear for exposure times of 10, 30, or 60 min. The animals were sacrificed 2 or 9 weeks after the exposure and the organ of Corti and vestibular neuroepithelia were studied as surface preparations with phase contrast microscopy. It was found that most of the ears exposed to the disinfectants had suffered damage, affecting both the vestibular and cochlear parts of the inner ear. The extent of the damage was related both to the duration of exposure and to the length of the animals' survival after the exposure. Furthermore it was found that the tympanic cavity and the perilymphatic spaces of vestibulum and cochlea were pathologically changed. PMID:6125078

Aursnes, J

1982-01-01

301

Surface modification of sepiolite with quaternary amines.  

PubMed

This study was aimed at elucidating the mechanism of adsorption of quaternary amines, stearyldimethylbenzylammoniumchloride (SDBAC), as monomers and as micelles, distearyldimethylammoniumchloride (DDAC) and hexadecyltrimethylammoniumchloride (HTAC), on the surface of sepiolite. The adsorption capacity for these surfactants onto sepiolite, calculated by fitting the experimental data to the Langmuir-Freundlich equation, were 324% (SDBAC), 278% (DDAC), and 258% (HTAC) of the cation exchange capacity of sepiolite. The Mg(2+) ions released during the exchange process were higher than the CEC value of sepiolite because of the simultaneous dissolution of the present minerals. The water adsorption decreased with the increasing surfactant loading up to 250 mmol/kg of sepiolite, which can be ascribed to an intensification of the hydrophobic properties. With loadings above 250 mmol/kg, the water adsorption increases. Simple kinetic analysis of SDBAC adsorption was performed. The properties and the type of bonding between the surfactants and sepiolite were investigated by DT, TG, and DTG analysis. During the gradual heating in oxidizing atmosphere, the adsorbed organic material is oxidized giving rise to significant exothermic peaks. The exothermic peak temperatures in the range 200-500 degrees C depended on the surfactant loadings and provided evidence of the formation of multilayers on the sepiolite surface. PMID:16045916

Lemi?, Jovan; Tomasevi?-Canovi?, Magdalena; Djurici?, Mirjana; Stani?, Tanja

2005-12-01

302

Quaternary glaciations of the southern Andes  

NASA Astrophysics Data System (ADS)

The southern Andes comprise the southernmost portion of the Andean Cordillera, beginning at the edge of the Puna Altiplano (lat.27°S) and ending at Isla de los Estados (lat.55°S). The late Cainozoic glacial record of these mountains spans the interval from the Late Miocene to the present and is one of the most complete to be found anywhere in the world. This has arisen for several reasons: (i) the conterminous mountain ice cap extended to the piedmont zone on both flanks of the range, where the sedimentary and morphological record has been well preserved; (ii) periodic volcanism, mainly from monogenetic fissure eruptions of basalt east of the range and from central tephra-producing cones along the mountain crest, has provided opportunity for the preservation and radiometric dating of interbedded glacial deposits; (iii) a tectonically-induced interval of stream incision in the Mid Pleistocene and simultaneous uplift has preserved glacial sediments on interfluves; (iv) in the Chilean lakes region west of the mountains, Late Quaternary glaciers terminated in a well-vegetated landscape, thus creating scope for radiocarbon dating of interbedded and incorporated organic materials; consequently, the last glaciation in the Llanquihue area of Chile is one of the best dated sequences in South America; thus the 'Llanquihue' Glaciation is proposed as the South American equivalent of the 'Wisconsin' and 'Weichsel' glaciations of North America and north west Europe respectively.

Rabassa, Jorge; Clapperton, Chalmers M.

303

Comparison of HDAC inhibitors in clinical development  

PubMed Central

Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ?belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8–31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.

Rasmussen, Thomas Aagaard; S?gaard, Ole Schmeltz; Brinkmann, Christel; Wightman, Fiona; Lewin, Sharon R.; Melchjorsen, Jesper; Dinarello, Charles; ?stergaard, Lars; Tolstrup, Martin

2013-01-01

304

Antimitotic inhibitors.  

PubMed

Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other mechanisms involving the microtubule and its role in mitosis is an area of continued interest. This review will focus on novel microtubule-targeted agents, both recently approved (eg, ixabepilone and eribulin) and in later-stage clinical trials, and kinase inhibitors that aim to directly inhibit the mitotic spindle, such as the aurora kinase, pololike kinase, and kinsein-spindle protein inhibitors. PMID:22520982

Campos, Susana M; Dizon, Don S

2012-06-01

305

Preclinical pharmacology of the ?4?2 nAChR partial agonist varenicline related to effects on reward, mood and cognition  

Microsoft Academic Search

The pharmacological properties and pharmacokinetic profile of the ?4?2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since ?4?2 and other nAChR subtypes play important roles in mediating central processes that control reward,

Hans Rollema; Mihály Hajós; Patricia A. Seymour; Rouba Kozak; Mark J. Majchrzak; Victor Guanowsky; Weldon E. Horner; Doug S. Chapin; William E. Hoffmann; David E. Johnson; Stafford Mclean; Jody Freeman; Kathryn E. Williams

2009-01-01

306

Improved crystallization characteristics of ZnO thin film grown onto aC:H film used as a buffer layer  

Microsoft Academic Search

We employed a-C:H buffer layer to improve the crystalline property of ZnO thin film for the membrane film bulk acoustic resonator (FBAR). The a-C:H film as a buffer layer is prepared by applying dc bias of 200 V and also this sample showed a smoother surface roughness, higher hardness and Young's modulus when compared to the other samples. In addition, the

Eung Kwon Kim; Tae Yong Lee; Yong Seob Park; Somnath Ghosh; Byungyou Hong; Young Sung Kim; Joon Tae Song

2007-01-01

307

Lack of nAChR Activity Depresses Cochlear Maturation and Up-Regulates GABA System Components: Temporal Profiling of Gene Expression in alpha9 Null Mice  

Microsoft Academic Search

BackgroundIt has previously been shown that deletion of chrna9, the gene encoding the ?9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and

Sevin Turcan; Donna K. Slonim; Douglas E. Vetter; Huibert D. Mansvelder

2010-01-01

308

Bacterial adhesion inhibition of the quaternary ammonium functionalized silica nanoparticles.  

PubMed

Quaternary ammonium compounds have been considered as excellent antibacterial agents due to their effective biocidal activity, long term durability and environmentally friendly performance. In this work, 3-(trimethoxysilyl)-propyldimethyloctadecylammonium chloride as a quaternary ammonium silane was applied for the surface modification of silica nanoparticles. The quaternary ammonium silane provided silica surface with hydrophobicity and antibacterial properties. In addition, the glass surface which was coated with the surface modified silica nanoparticles presented bacterial growth inhibition activity. For comparison of bacterial growth resistance, hydrophobic silane (alkyl functionalized silane) modified silica nanoparticles and pristine silica nanoparticles were prepared. As a result of bacterial adhesion test, the quaternary ammonium functionalized silica nanoparticles exhibited the enhanced inhibition performance against growth of Gram-negative Escherichia coli (96.6%), Gram-positive Staphylococcus aureus (98.5%) and Deinococcus geothermalis (99.6%) compared to pristine silica nanoparticles. These bacteria resistances also were stronger than that of hydrophobically modified silica nanoparticles. It could be explained that the improved bacteria inhibition performance originated from the synergistic effect of hydrophobicity and antibacterial property of quaternary ammonium silane. Additionally, the antimicrobial efficacy of the fabricated nanoparticles increased with decreasing size of the nanoparticles. PMID:21115282

Song, Jooyoung; Kong, Hyeyoung; Jang, Jyongsik

2011-02-01

309

Chronic ethanol (EtOH) feeding increases muscarinic receptor (mAChR) density in esophagus without parallel change in dose response (D-R) to cholinergic agonists  

SciTech Connect

The mAChR/effector pathway for signal transduction is important in the physiology of esophagus and mAChR alterations are involved in EtOH induced changes in several organs. To see if EtOH-induced increases in lower esophageal sphincter pressure (LESP) are due to upregulation of mAChR, the authors evaluated mAChR binding and D-R curves for bethanechol (IV) induced increases in LESP, and compared these values to changes in LESP after acute and chronic EtOH. EtOH was given to cats acutely or chronically. The number of mAChR sites (Bmax) in esophagus was lowered by acute EtOH, withdrawal from chronic EtOH raised Bmax. Acute injection of EtOH to cats in withdrawal reversed this increase in mAChR density. These changes correlated with the earlier data on EtOH-induced changes in LESP. In contrast, the D-R curve for bethanechol shifted to the right. Thus, the withdrawal-associated increase in Bmax is more likely to be a compensatory response to deficits distal to the receptor recognition site than to proximal deficits and doesn't cause LESP hyperactivity. Also, receptor binding changes do not necessarily translate into physiological changes.

Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. (Loyola Univ., Maywood (United States) VA Hospital, Hines, IL (United States))

1991-03-11

310

Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors.  

PubMed

Alzheimer's disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (A?) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials. PMID:22198801

Tayeb, Haythum O; Yang, Hyun Duk; Price, Bruce H; Tarazi, Frank I

2012-04-01

311

The Role of Structured Water in Mediating General Anesthetic Action on ?4?2 nAChR  

PubMed Central

Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within ?4?2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structure-derived closed- and open-channel nAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in ?4?2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathrate-like water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonist binding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated protein-protein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming water clathrates around anesthetics.

Willenbring, Dan; Xu, Yan; Tang, Pei

2010-01-01

312

?7-nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis  

PubMed Central

Controlled clinical trials of nicotine transdermal patch for treatment of ulcerative colitis have been shown to improve histological and global clinical scores of colitis. Here we report that nicotine (1 ?M) suppresses in vitro hyperexcitability of colonic dorsal root ganglia (DRG) (L1–L2) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation. Nicotine gradually reduced regenerative multiple-spike action potentials in colitis mice to a single action potential. Nicotine's effect on hyperexcitability of inflamed neurons was blocked in the presence of an ?7-nicotinic acetylcholine receptor (nAChR) antagonist, methyllicaconitine, while choline, the ?7-nAChR agonist, induced a similar effect to that of nicotine. Consistent with these findings, nicotine failed to suppress hyperexcitability in colonic DRG neurons from DSS-treated ?7 knockout mice. Furthermore, colonic DRG neurons from DSS-treated ?7 knockout mice were characterized by lower rheobase (10 ± 5 vs. 77 ± 13 pA, respectively) and current threshold (28 ± 4 vs. 103 ± 8 pA, respectively) levels than DSS-treated C57BL/J6 mice. An interesting observation of this study is that 8 of 12 colonic DRG (L1–L2) neurons from control ?7 knockout mice exhibited multiple-spike action potential firing while no wild-type neurons did. Overall, our findings suggest that nicotine at low 1 ?M concentration suppresses in vitro hyperexcitability of inflamed colonic DRG neurons in a mouse model of acute colonic inflammation via activation of ?7-nAChRs.

AlSharari, Shakir; Kang, Minho; Damaj, M. Imad; Akbarali, Hamid I.

2010-01-01

313

Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.  

PubMed

Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients. PMID:21814823

Pevzner, Alexandra; Schoser, Benedikt; Peters, Katja; Cosma, Nicoleta-Carmen; Karakatsani, Andromachi; Schalke, Berthold; Melms, Arthur; Kröger, Stephan

2012-03-01

314

A geometricla error in some Computer Programs based on the Aki-Christofferson-Husebye (ACH) Method of Teleseismic Tomography  

USGS Publications Warehouse

Some computer programs based on the Aki-Christofferson-Husebye (ACH) method of teleseismic tomography contain an error caused by identifying local grid directions with azimuths on the spherical Earth. This error, which is most severe in high latitudes, introduces systematic errors into computed ray paths and distorts inferred Earth models. It is best dealt with by explicity correcting for the difference between true and grid directions. Methods for computing these directions are presented in this article and are likely to be useful in many other kinds of regional geophysical studies that use Cartesian coordinates and flat-earth approximations.

Julian, B. R.; Evans, J. R.; Pritchard, M. J.; Foulger, G. R.

2000-01-01

315

Aconitum and Delphinium alkaloids of curare-like activity. QSAR analysis and molecular docking of alkaloids into AChBP.  

PubMed

Early studies have shown that some of diterpenoid alkaloids, found in highly toxic plants of the genera Aconitum and Delphinium, act at neuronal nicotinic acetylcholine receptors (nAChRs) and exhibit potent N-cholinolytic activity. In the current study, GA-MLRA and GA-PLS approaches have been used to build QSAR models to predict N-cholinolytic activity measured in vivo (blockade of neuromuscular conductivity, BNMC and third eyelid relaxing activity, TYRA) and in vitro (suppression of frog's abdominal straight muscles on acetylcholine, SAM) for a series of diterpenoid alkaloids. Random splitting of a data set (five trials in total) produced QSAR models of a good level of correlation between experimental in vitro/in vivo and calculated N-cholinolytic activity expressed as log(1/ED(50)) with following average statistical parameters: log BNMC (r(2) = 0.87, s = 0.14, q(2) = 0.82), log TYRA (r(2) = 0.80, s = 0.29, q(2) = 0.67), log SAM (r(2) = 0.84, s = 29, q(2) = 0.64). QSAR results suggest descriptors accounting for H-bond capability of molecules influence all three type of N-cholinolytic activity with additional contribution of steric and reactivity features as identified for TYRA and SAM data, respectively. The alkaloid-receptor complexes were further analyzed by means of AutoDock Vina docking program using the binding site of MLA complexed with AChBP (homolog of the ligand binding domain of nAChRs) as template. All compounds were shown to be well fitted in the binding pocket of native MLA with good correlation exhibited between their ED(50) and AutoDock Vina binding free energy. An analysis of the possible factors significant for the ligand recognition has been enhanced by comparative docking studies performed for structurally related lycoctonine-type alkaloids (lappaconitine and aconitine) that are known to bind to voltage-gated Na(+) channel, but not to nAChRs. PMID:20594622

Turabekova, M A; Rasulev, B F; Dzhakhangirov, F N; Leszczynska, D; Leszczynski, J

2010-09-01

316

Toxicity assessments with Daphnia magna of Guadipyr, a new neonicotinoid insecticide and studies of its effect on acetylcholinesterase (AChE), glutathione S-transferase (GST), catalase (CAT) and chitobiase activities.  

PubMed

Guadipyr is a novel neonicotinoid insecticide, developed by the China Agricultural University. This work investigated its aquatic toxicity on Daphnia magna. The acute immobilization test showed that guadipyr was slightly toxic to daphnids, with a 48 h EC?? of 13.01 mg/L. In addition, guadipyr significantly enhanced the acetylcholinesterase (AChE) and glutathione S-transferase (GST) activity (per gram of protein), but had no obvious impact on catalase (CAT) activity within 48 h. The 21 d chronic exposure of D. magna to guadipyr induced a significant decrease in body growth and reproduction; both share the same lowest observed effect concentration (LOEC) at 0.10 mg/L. In the 14 d chronic test, a significant increase in chitobiase activity in test media was observed at day 8 (days to the first breeding), while a significant decrease was observed from days 10 to 14, which might be due to the endocrine imbalance resulting from guadipyr stress. These results demonstrated that guadipyr can induce notable negative ecotoxicological impacts on the aquatic system in long-term exposure at a sub-lethal dose. Further research in environmental behaviors is needed to regulate guadipyr use in the future. PMID:24075643

Qi, Suzhen; Wang, Chen; Chen, Xiaofeng; Qin, Zhaohai; Li, Xuefeng; Wang, Chengju

2013-12-01

317

Ternary and quaternary antimonide devices for thermophotovoltaic applications  

SciTech Connect

Thermophotovoltaic (TPV) devices have been fabricated using epitaxial ternary and quaternary layers grown on GaSb substrates. GaInSb ternary devices were grown by metalorganic vapor phase epitaxy (MOVPE) with buffer layers to accommodate the lattice mismatch, and GaInAsSb lattice-matched quaternaries were grown by MOVPE and by liquid phase epitaxy (LPE). Improved devices are obtained when optical absorption occurs in the p-layer due to the longer minority carrier diffusion length. Thick emitter p/n devices are limited by surface recombination, with highest quantum efficiency and lowest dark current being achieved with epitaxially grown surface passivation layers on lattice-matched MOVPE quaternaries. Thin emitter/thick base n/p devices are very promising, but require improved shallow high-quality n-type ohmic contacts.

Hitchcock, C.W.; Gutmann, R.J.; Ehsani, H.; Bhat, I.B. [Rensselaer Polytechnic Inst., Troy, NY (United States). Center for Integrated Electronics and Electronics Manufacturing; Wang, C.A. [Massachusetts Inst. of Tech., Lexington, MA (United States). Lincoln Lab.; Freeman, M.J.; Charache, G.W. [Lockheed Martin, Inc., Schenectady, NY (United States)

1998-06-01

318

[18F]ASEM, a radiolabeled antagonist for imaging the ?7-nicotinic acetylcholine receptor (?7-nAChR) with positron emission tomography (PET)  

PubMed Central

The ?7-nicotinic cholinergic receptor (?7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for ?7-nAChR are suitable for quantitative PET imaging, mostly due to insufficient specific binding. The goal of this study was to evaluate the potential of [18F]ASEM ([18F]JHU82132) as an ?7-nAChR radioligand for PET. Methods Inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of [18F]ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET). Results ASEM is an antagonist for the ?7-nAChR with high binding affinity (Ki = 0.3 nM). [18F]ASEM readily entered the baboon brain and specifically labeled ?7-nAChR. The in vivo specific binding of [18F]ASEM in the brain regions enriched with ?7-nAChRs was 80–90%. SSR180711, an ?7-nAChR selective partial agonist, blocked [18F]ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of [18F]ASEM was mediated by ?7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for [18F]ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus) and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential (BPND) values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of [18F]ASEM and ?7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous post-mortem human data. Conclusion [18F]ASEM holds promise as a radiotracer with suitable imaging properties for quantification of ?7-nAChR in the human brain.

Horti, Andrew G.; Gao, Yongjun; Kuwabara, Hiroto; Wang, Yuchuan; Abazyan, Sofya; Yasuda, Robert P.; Tran, Thao; Xiao, Yingxian; Sahibzada, Niaz; Holt, Daniel P.; Kellar, Kenneth J.; Pletnikov, Mikhail V.; Pomper, Martin G.; Wong, Dean F.; Dannals, Robert F.

2014-01-01

319

Characterization of Quaternary and suspected Quaternary faults, Amargosa area, Nevada and California  

SciTech Connect

This report presents the results of geologic studies that help define the Quaternary history of selected faults in the region around Yucca Mountain, Nevada. These results are relevant to the seismic-design basis of a potential nuclear waste repository at Yucca Mountain. The relevancy is based, in part, on a need for additional geologic data that became apparent in ongoing studies by S. Pezzopane (written commun., 1995) that resulted in the identification of 51 relevant and potentially relevant (see appendix A for definitions) individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. These structures were divided into local and regional categories by Pezzopane (1995); this report deals with selected regional structures. In this introduction, the authors outline the scope and strategy of the studies and the tectonic environment of the studied structures.

Anderson, R.E.; Crone, A.J.; Machette, M.N.; Bradley, L.A.; Diehl, S.F.

1995-12-31

320

GF(4) Based Synthesis of Quaternary Reversible\\/Quantum Logic Circuits  

Microsoft Academic Search

Galois field sum of products (GFSOP) has been found to be very promising for reversible\\/quantum implementation of multiple-valued logic. In this paper, we show ten quaternary Galois field expansions, using which quaternary Galois field decision diagrams (QGFDD) can be constructed. Flattening of the QGFDD generates quaternary GFSOP (QGFSOP). These QGFSOP can be implemented as cascade of quaternary 1-qudit gates and

Mozammel H. A. Khan; Marek A. Perkowski

2007-01-01

321

Ice Age Earth: Late Quaternary geology and climate  

SciTech Connect

This book is a concise and readable account of the most important geologic records of the late Quaternary. It provides a synopsis of the major environmental changes that took place from approximately 13,000 to 7,000 years ago, highlighting the complexity and rapidity of past climate changes and the environmental responses they produced. The text is well illustrated, though some figures are rough and need more explanation. Also needed is a critical appraisal of the geochronology which places the paleoenvironmental records into the temporal domain. However, as a whole the book reaches its objective of summarizing the most important scientific findings about the nature of the late Quaternary climate changes.

Dawson, A.G.

1992-01-01

322

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.  

PubMed

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic ?-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 ?M; MAO B (IC50 = 10.2 ± 0.9 ?M); AChE (IC50 = 1.8 ± 0.1 ?M); BuChE (IC50 = 1.6 ± 0.25 ?M)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice. PMID:24813882

Wang, Li; Esteban, Gerard; Ojima, Masaki; Bautista-Aguilera, Oscar M; Inokuchi, Tsutomu; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Youdim, Moussa B H; Romero, Alejandro; Soriano, Elena; Herrero, Raquel; Fernández Fernández, Ana Patricia; Ricardo-Martínez-Murillo; Marco-Contelles, José; Unzeta, Mercedes

2014-06-10

323

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).  

Code of Federal Regulations, 2010 CFR

...2010-07-01 2010-07-01 false Modified polymer of vinyl acetate and quaternary ammonium...Chemical Substances § 721.8658 Modified polymer of vinyl acetate and quaternary ammonium...substance identified generically as modified polymer of vinyl acetate and quaternary...

2010-07-01

324

An investigation of amorphous hydrogenated carbon (a-C:H) coatings using x-ray reflectivity and scratch testing  

NASA Astrophysics Data System (ADS)

X-ray reflectivity was used to differentiate between two hydrogenated amorphous carbon (a-C:H) coatings with distinct Raman signatures proving that they are layered, with the top-layer characterized by a density that is either higher or lower than the averaged film density of the coating. The density of the upper-layer was found to be 1.3 g/cm3 for the coating with the greater intensity ratio Id/Ig [the intensity ratio of the raman D-band (1350 cm-1) and the G-band (1530 cm-1)], as compared with 2.2 g/cm3 for the ``typical'' a-C:H. The coating with the lower-density 8 nm top-layer was manufactured under conditions that allow for the trapping of physisorbed hydrogen. It is likely that this polymeric top-layer was necessary in trapping unbound hydrogen. This coating was also distinguished by a higher surface roughness of 0.98 nm as compared with 0.68 nm for the denser coating. A very low coefficient of friction, 0.02-0.04, was recorded during scratch testing using progressive loading. The critical load to failure was in the range of 28-40 N and the failure mode was brittle as determined by the Si substrate.

Rabbani, F.; Staakman, R.; Ettema, A. R. H. F.

2004-09-01

325

Diamond-like a-C:H coatings deposited in a non-self-sustained discharge with plasma cathode  

NASA Astrophysics Data System (ADS)

Hydrogenated amorphous carbon (a-C:H) coatings have been obtained by means of acetylene decomposition in a non-self-sustained periodic pulse discharge (2A, 50 kHz, 10 ?s) with hollow cathode. The discharge operation was maintained by plasma cathode emission with grid stabilization based on dc glow discharge. Using the proposed method, it is possible to control the deposition conditions (total pressure of the Ar + C2H2 mixture, partial pressure of C2H2, ion current density, carbon ion energy) within broad limits, to apply a-C:H coatings onto large-area articles, and to perform deposition in one technological cycle with ion etching and ion implantation treatments aimed at improving the adhesion of coatings to substrates (Ti, Al, stainless steel, VK8 hard alloy) at temperatures below 150°C. Results of determining the deposition rate (1-8 ?m), the nanohardness of coatings (up to 70 GPa), and the fraction of sp 3 bonds (25-70%) in the diamond-like coating material are presented.

Gavrilov, N. V.; Mamaev, A. S.; Ka?igorodov, A. S.

2009-01-01

326

Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes  

PubMed Central

Nicotinic acetylcholine receptors (nAChR) mediate fast synaptic transmission in ganglia of the autonomic nervous system. Here, we have determined the subunit composition of hetero-pentameric nAChRs in the mouse superior cervical ganglion (SCG), the function of distinct receptors (obtained by deletions of nAChR subunit genes), and mechanisms at the level of nAChRs that might compensate for the loss of subunits. As shown by immunoprecipitation and Western blots, wild type (WT) mice expressed (%): ?3?4 (55), ?3?4?5 (24), and ?3?4?2 (21) nAChRs. nAChRs in ?4 knockout (KO) mice were reduced to less than 15 % of controls and no longer contained the ?5 subunit. Compound action potentials, recorded from the postganglionic (internal carotid) nerve and induced by preganglionic nerve stimulation, did not differ between ?5?4 KO and WT, suggesting that the reduced number of receptors in the KO did not impair transganglionic transmission. Deletions of ?5 or ?2 did not affect the overall number of receptors and we found no evidence that the two subunits substitute for each other. In addition, dual KOs allowed us to study the functional properties of distinct ?3?4 and ?3?2 receptors that have previously only been investigated in heterologous expression systems. The two receptors strikingly differed in the decay of macroscopic currents, the efficacy of cytisine, and their responses to the ?-conotoxins AuIB and MII. Our data - based on biochemical and functional experiments and several mouse KO models - clarifies and significantly extends previous observations on the function of nAChRs in heterologous system and the SCG.

David, Reinhard; Ciuraszkiewicz, Anna; Simeone, Xenia; Orr-Urtreger, Avi; Papke, Roger L.; McIntosh, J. Michael; Huck, Sigismund; Scholze, Petra

2010-01-01

327

CC4, a dimer of cytisine, is a selective partial agonist at ?4?2/?6?2 nAChR with improved selectivity for tobacco smoking cessation  

PubMed Central

Background and Purpose Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. Key Results When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal ?4?2, ?3?4, ?7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through ?4?2 and ?6?2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the ?3?4 and ?7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose–response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions. Conclusion and Implications Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for ?2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.

Sala, Mariaelvina; Braida, Daniela; Pucci, Luca; Manfredi, Irene; Marks, Michael J; Wageman, Charles R; Grady, Sharon R; Loi, Barbara; Fucile, Sergio; Fasoli, Francesca; Zoli, Michele; Tasso, Bruno; Sparatore, Fabio; Clementi, Francesco; Gotti, Cecilia

2013-01-01

328

Population variation and differences in serum leptin independent of adiposity: a comparison of Ache Amerindian men of Paraguay and lean American male distance runners  

PubMed Central

Background Serum leptin variation is commonly associated with fat percentage (%), body mass index (BMI), and activity. In this investigation, we report population differences in mean leptin levels in healthy men as well as associations with fat % and BMI that are independent of these factors and reflect likely variation resulting from chronic environmental conditions. Methods Serum leptin levels, fat %, and BMI were compared between lean American distance runners and healthy Ache Native Americans of Paraguay. Mean levels were compared as were the regressions between fat %, BMI, and leptin. Comparisons were performed between male American distance runners (n = 13, mean age 32.2 ± 9.2 SD) and highly active male New World indigenous population (Ache of Paraguay, n = 20, mean age 32.8 ± 9.2) in order to determine whether significant population variation in leptin is evident in physically active populations living under different ecological circumstances independent of adiposity and BMI. Results While the Ache were hypothesized to exhibit higher leptin due to significantly greater adiposity (fat %, Ache 17.9 ± 1.8 SD; runners 9.7 ± 3.2, p < 0.0001), leptin levels were nonetheless significantly higher in American runners (Ache 1.13 ng/ml ± 0.38 SD; runners 2.19 ± 1.15; p < 0.007). Significant differences in the association between leptin and fat % was also evident between Ache and runner men. Although fat % was significantly related with leptin in runners (r = 0.90, p < 0.0001) fat % was negatively related in Ache men (r = -0.50, p < 0.03). Conclusion These results illustrate that chronic ecological conditions in addition to activity are likely factors that contribute to population variation in leptin levels and physiology. Population variation independent of adiposity should be considered to be an important source of variation, especially in light of ethnic and population differences in the incidence and etiology of obesity, diabetes, and other metabolic conditions.

Bribiescas, Richard G; Hickey, Matthew S

2006-01-01

329

In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles.  

PubMed

The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD. PMID:20092557

Härtig, Wolfgang; Kacza, Johannes; Paulke, Bernd-Reiner; Grosche, Jens; Bauer, Ute; Hoffmann, Anke; Elsinghorst, Paul W; Gütschow, Michael

2010-01-01

330

A PKG inhibitor increases Ca(2+)-regulated exocytosis in guinea pig antral mucous cells: cAMP accumulation via PDE2A inhibition.  

PubMed

In antral mucous cells, acetylcholine (ACh, 1 ?M) activates Ca(2+)-regulated exocytosis, consisting of an initial peak that declines rapidly (initial transient phase) followed by a second slower decline (late phase) lasting during ACh stimulation. The addition of 8-bromo-cGMP (8-BrcGMP) enhanced the initial phase, which was inhibited by the protein kinase G (PKG) inhibitor guanosine 3',5'-cyclic monophosphorothoiate, ?-phenyl-1,N(2)-etheno-8-bromo, Rp-isomer, sodium salt (Rp-8-BrPETcGMPS, 100 nM). However, Rp-8-BrPETcGMPS produced a delayed, but transient, increase in the exocytotic frequency during the late phase that was abolished by a protein kinase A (PKA) inhibitor (PKI-amide), suggesting that Rp-8-BrPETcGMPS accumulates cAMP. The cGMP-dependent phosphodiesterase 2 (PDE2), which degrades cAMP, may exist in antral mucous cells. The PDE2 inhibitor BAY-60-7550 (250 nM) mimicked the effect of Rp-8-BrPETcGMPS on ACh-stimulated exocytosis. Measurement of the cGMP and cAMP contents in antral mucosae revealed that ACh stimulates the accumulation of cGMP and that BAY-60-7550 accumulates cAMP similarly to Rp-8-BrPETcGMPS during ACh stimulation. Analyses of Western blot and immunohistochemistry demonstrated that PDE2A exists in antral mucous cells. In conclusion, Rp-8-BrPETcGMPS accumulates cAMP by inhibiting PDE2 in ACh-stimulated antral mucous cells, leading to the delayed, but transient, increase in the frequency of Ca(2+)-regulated exocytosis. PDE2 may prevent antral mucous cells from excessive mucin secretion caused by the cAMP accumulation. PMID:23449671

Tanaka, Saori; Tanaka, Rina; Harada, Saeko; Kohda, Yuka; Matsumura, Hitoshi; Shimamoto, Chikao; Sawabe, Yukinori; Marunaka, Yoshinori; Kuwabara, Hiroko; Takahashi, Yuko; Ito, Shigenori; Nakahari, Takashi

2013-05-01

331

Application of quaternary phase diagrams to compound semiconductor processing  

SciTech Connect

Isobaric, isothermal phase diagrams are a molar representation of condensed phases in equilibrium with each other at a fixed temperature, pressure, and composition. Since three or four elements are usually involved at a fabricated interface in a semiconductor device, knowledge of the appropriate ternary or quaternary phase diagram is important for optimizing the processing parameters and designing long term stability of devices. While the use of phase diagrams is well-established in the fields of metallurgy, ceramics and mineralogy, only recently have phase diagrams been employed to provide a framework for understanding thin film reactions on a substrate, encountered in semiconductor processing. Even though there are many examples of applications of ternary phase diagrams in the semiconductor literature (for instance, metallization of GaAs, the use of refractory metal silicides for metallization layers in VLSI devices and oxidation of III-V compounds), the same is not true for quaternary phase diagrams. To date, the only application is oxidation of mercury cadmium telluride. This lack of examples is not warranted, as four elements are often involved at a critical interface in compound semiconductor processing and devices. This paper reports on the progress made to remedy this situation by considering the application of quaternary phase diagrams to understanding and predicting the behavior of II-VI thin film interfaces in photovoltaic devices under annealing conditions. Moreover, for the first time, solid solubility is taken into account for quaternary phase diagrams of semiconductor systems.

Sinclair, R.

1994-10-01

332

Pliocene and Quaternary geology of Mana Island (Note)  

Microsoft Academic Search

Mana Island, off the south-west coast of the North Island, is capped by the Mana Surface which dips south-east at about 2. This dip is considered to be tectonic in origin. The surface, considered to be a marine abrasion platform, has no overlying deposits except late Quaternary loesses. No continuity with mainland surfaces can be demonstrated, but correlation with the

D. N. Williams

1978-01-01

333

Double-Chain Surfactants with Two Quaternary Ammonium Head Groups.  

National Technical Information Service (NTIS)

Double-chain surfactants with two quaternary ammonium head groups were prepared: 2-(7-trimethylammo nioheptyl)-2-decyl-4-(8-trimethyla mmoniooctyl)-5-octyl-1- 3-dioxolane dibromide (3) and 2-(3- trimethylammoniopropyl) -2-tetradecyl-4-(8-trimethylammo nio...

D. A. Jaeger S. G. Russell H. Shinozaki

1994-01-01

334

Quaternary Paleoecology and Climate Change, Bladen County, NC  

NSDL National Science Digital Library

Students analyze a Quaternary pollen diagram from lakes in Bladen County, NC. This diagram contains (from the top down) the current deglaciation, the last glacial, and the previous interglacial. Students These lakes occur in Carolina Bays and students also evaluate a proposal that meteorite impact created the Bays.

Farley, Martin

335

European quaternary refugia: a factor in large carnivore extinction?  

Microsoft Academic Search

The extinction of large carnivores in Europe during the Quaternary is reviewed and the potential role of glacial refugia in these extinctions is investigated using the VORTEX model for population viability analysis. A model was built for a medium sized big cat similar to the extinct Panthera gombaszoegensis utilising life history data from the modern jaguar Panthera onca. This approach

Hannah J. O'Regan; Alan Turner; David M. Wilkinson

2002-01-01

336

Quaternary deformation in the Eastern Pamirs, Tadzhikistan and Kyrgyzstan  

Microsoft Academic Search

Active deformation in the eastern Pamir of Central Asia is concentrated on the margins of the orogen with minor deformation within the high terrain. Along the Trans-Alai mountain front at the northern perimeter of the orogen, Quaternary thrusting is documented by uplifted pediments, now at >500 m above the piedmont, Holocene fault scarps, and large earthquakes with N to NW

M. R. Strecker; W. Frisch; M. W. Hamburger; L. Ratschbacher; S. Semiletkin; A. Zamoruyev; N. Sturchio

1995-01-01

337

Seismic stratigraphy of Late Quaternary deposits in the eastern Skagerrak  

Microsoft Academic Search

High-resolution seismic profiles from the Swedish west coast divide Quaternary deposits into six seismic sequences, containing 13 different seismic facies. Documentation of these sequences and facies and their stratigraphic and geographic variability is the first step in a basin-fill analysis to interpret depositional environments and major controlling processes. The deposits are attributed to one deglaciation cycle. The seismic sequences are:

Olof Larsson; Rodney L. Stevens

2008-01-01

338

Pliocene - Quaternary Faults and Potential Seismic Hazards in Southern Nevada  

Microsoft Academic Search

Known Quaternary faults in the Central Basin & Range Province (CBR) have a southern limit at about 35 degrees 30' N latitude, south of Las Vegas, NV. The boundary is generally aligned with the southern end of the Sierra Nevada and strike-slip faults, such as those in Death Valley, that accommodate the right-lateral motion transferred from the plate boundary to

W. J. Taylor; J. Wagoner; C. M. Depolo; B. Luke; J. Louie

2005-01-01

339

Enhanced energy transfer in quasi-quaternary nanocrystal superlattices.  

PubMed

Quasi-quaternary nanocrystal superlattices are assembled by using exclusively core-shell particles as building blocks. The assemblies show an enhancement of energy-transfer from cadmium selenide-based core-shell quantum dots to gold-iron oxide core-shell nanocrystals compared to random mixtures of the same components. PMID:24357329

Cargnello, Matteo; Diroll, Benjamin T; Gaulding, E Ashley; Murray, Christopher B

2014-04-16

340

Quaternary geology of the Channeled Scabland and adjacent areas  

Microsoft Academic Search

The quaternary history of the channeled scabland is characterized by discrete episodes of catastrophic flooding and prolonged periods of loess accumulation and soil formation. The loess sequence was correlated with Richmond's Rocky Mountain glacial chronology. At least five major catastrophic flood events occurred in the general vicinity of the channeled scabland. The earliest episode occurred prior to the extensive deposition

V. R. Baker

1978-01-01

341

Quaternary fossil fish from the Kibish Formation, Omo Valley, Ethiopia  

Microsoft Academic Search

The late Quaternary Kibish Formation of the Omo Valley, southwestern Ethiopia, preserves environments reflecting a history of fluctuations in the level of nearby Lake Turkana over the past 200,000 years. The Kibish Formation has yielded a diverse mammalian fauna (as well as birds and crocodiles), stone tools, and the oldest anatomically modern Homo sapiens. Fish, the most common vertebrate fossils

Josh Trapani

2008-01-01

342

Late Quaternary paleohydrologic and paleotemperature change in southern Nevada  

Microsoft Academic Search

Paleo-spring discharge activity in the southern Great Basin responded to changes in recharge, hence climate changes, in high mountain areas during the late Quaternary. In our study, we examined four stratigraphic sections in southern Nevada in order to reconstruct paleohydrologic change spanning the last two major discharge cycles. The largest discharge event in those sections is expressed as extensive wetland

Jay Quade; Richard M. Forester; Joseph F. Whelan

343

Quaternary history and contemporary patterns in a currently expanding species  

Microsoft Academic Search

BACKGROUND: Quaternary climatic oscillations had dramatic effects on species evolution. In northern latitudes, populations had to survive the coldest periods in refugial areas and recurrently colonized northern regions during interglacials. Such a history usually results in a loss of genetic diversity. Populations that did not experience glaciations, in contrast, probably maintained most of their ancestral genetic diversity. These characteristics dramatically

Carole Kerdelhué; Lorenzo Zane; Mauro Simonato; Paola Salvato; Jérôme Rousselet; Alain Roques; Andrea Battisti

2009-01-01

344

Quaternary glacial history of NW Garhwal, Central himalayas  

Microsoft Academic Search

A first account of the Quaternary glacial history is presented for northwest Garhwal, Central Himalaya. On the basis of sediments and landforms, one glacial stage has been recognised. This is called the Bhagirathi Glacial Stage, when extensive valley glaciers advanced down the Bhagirathi valley to Jhala, 40.5 km from the snout of Gangotri Glacier. The ELA depression during this stage

Milap Chand Sharma; Lewis A. Owen

1996-01-01

345

Landscape paleoecology and late Quaternary extinctions in the Hudson Valley  

Microsoft Academic Search

Stratigraphic palynological analyses of four late Quaternary deposits comprise a landscape-level study of the patterns and processes of megafaunal extinction in the southeastern New York region. Distinctive spores of the dung fungus Sporormiella are used as a proxy for megafaunal biomass and charcoal particle analysis as a proxy for fire history. A decline in spore values at all sites is

Guy Schuyler Robinson

2003-01-01

346

Transport phenomena in a reactive quaternary gas mixture  

Microsoft Academic Search

Quaternary gas mixtures which undergo a binary and reversible chemical reaction of the type A+B?C+D are analyzed within the framework of Boltzmann equation in order to investigate the effects caused by the reactions on the transport coefficients. The gas system is considered close to chemical equilibrium, a state in which the affinity has a small value characterizing the final stage

Adriano W. Silva; Giselle M. Alves; Gilberto M. Kremer

2007-01-01

347

Impact of Quaternary Structure Dynamics on Allosteric Drug Discovery  

PubMed Central

The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131–143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor ?. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.

Jaffe, Eileen K.

2013-01-01

348

Influence of surgical and chemical orchidectomy on weight and distribution of AChE-nerve fibres in thymuses of adult rats  

PubMed Central

The thymus is a crossroad between the immune and neuroendocrine systems. As such, it is innervated by acetylcholinesterase (AChE)-positive fibres of the vagus, the recurrent laryngeal and the phrenic nerves. It is well know, that the innervations density of the thymus increases with age. In our study, adult rats were orchidectomized (surgically and chemically by the application of a luteinizing hormone-releasing hormone). The density of AChE-positive nerve fibres in thymuses, as well as the weight of thymuses was examined. The authors found that both surgical and chemical orchidectomy result in macroscopic and microscopic regeneration of the atrophied thymuses. In regenerated rat’s thymuses after orchidectomy the density of AChE-positive nerve fibres was markedly higher in comparison with the control animals. The distribution, as well as the density of AChE-positive nerve fibres in regenerated thymuses after orchidectomy evokes the images of its innervations like in young animals before age-related involution. The authors also found a markedly higher weight of thymuses of orchidectomized rats in comparison with the control groups. In recent study the authors proved that after 8 weeks surgical orchidectomy leads to the regeneration of thymic AChE-positive innervation and chemical orchidectomy by administration of luteinizing hormone-releasing hormone after 4 weeks of adult rats.

Dorko, F.; Kluchova, D.; Bolekova, A.; Spakovska, T.; Borosova, T.; Lovasova, K.

2011-01-01

349

In situ analysis of corrosion inhibitors using a portable mass spectrometer with paper spray ionization.  

PubMed

Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (<1 ng ?L(-1)) and over a dynamic range of ?5 pg ?L(-1) to 500 pg ?L(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng ?L(-1). PMID:23675580

Jjunju, Fred P M; Li, Anyin; Badu-Tawiah, Abraham; Wei, Pu; Li, Linfan; Ouyang, Zheng; Roqan, Iman S; Cooks, R Graham

2013-07-01

350

Synthesis and biological evaluation of a series of dithiocarbamates as new cholinesterase inhibitors.  

PubMed

In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4-(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by (1) H NMR, mass spectral data, and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The most potent AChE inhibitor was found as compound 2g (IC50 ?=?0.53?±?0.001?µM) followed by compounds 2f (IC50 ?=?0.74?±?0.001?µM) and 2j (IC50 ?=?0.89?±?0.002?µM) when compared with donepezil (IC50 ?=?0.048?±?0.001?µM). Compounds 2f and 2g were more effective than donepezil (IC50 ?=?7.88?±?0.52?µM) on BuChE inhibition. Compounds 2f and 2g exhibited the inhibitory effect on BuChE with IC50 values of 1.39?±?0.041 and 3.64?±?0.072?µM, respectively. PMID:23881696

Alt?ntop, Mehlika D; Gurkan-Alp, A Selen; Ozkay, Yusuf; Kaplanc?kl?, Zafer A

2013-08-01

351

Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease  

Microsoft Academic Search

The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22–25. Compounds of type II

Abdelouahid Samadi; Mourad Chioua; Irene Bolea; Cristóbal de los Ríos; Isabel Iriepa; Ignacio Moraleda; Agatha Bastida; Gerard Esteban; Mercedes Unzeta; Enrique Gálvez; José Marco-Contelles

2011-01-01

352

No significant effects of single intravenous, single oral and subchronic oral administration of acetylcholinesterase inhibitors on striatal [ 123 I]FP-CIT binding in rats  

Microsoft Academic Search

Purpose  [123I]FP-CIT SPECT is a valuable diagnostic tool to discriminate Lewy body dementia from Alzheimer’s dementia. To date, however,\\u000a it is uncertain whether the frequently used acetylcholinesterase inhibitors (AChEIs) by demented patients, have an effect\\u000a on [123I]FP-CIT binding to dopamine transporters (DATs). Earlier animal studies showed a decline of DAT availability after acute\\u000a intravenous injection of AChEIs. The aim of this

R. J. J. Knol; K. de Bruin; B. L. F. van Eck-Smit; J. Booij

2008-01-01

353

Discovery of Isoxazole Analogs of Sazetidine-A as Selective ?4?2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression  

PubMed Central

Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with ?4?2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the ?4?2 subtype of nAChR over ?3?4-nAChRs are partial agonists at the ?4?2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

Liu, Jianhua; Yu, Li-Fang; Eaton, J. Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A.; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

2011-01-01

354

In vivo pharmacological interactions between a type II positive allosteric modulator of ?7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model  

PubMed Central

Background and Purpose The ?7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that ?7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the ?7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II ?7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. Experimental Approach We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective ?7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. Key Results We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and ?7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of ?7 nAChRs. Conclusions and Implications Our results demonstrate that type II ?7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous ?7 agonist choline.

Freitas, K; Negus, SS; Carroll, FI; Damaj, MI

2013-01-01

355

Acetylcholinesterase of Schistosoma mansoni--functional correlates. Contributed in honor of Professor Hans Neurath's 90th birthday.  

PubMed Central

Acetylcholinesterase (AChE) is an enzyme broadly distributed in many species, including parasites. It occurs in multiple molecular forms that differ in their quaternary structure and mode of anchoring to the cell surface. This review summarizes biochemical and immunological investigations carried out in our laboratories on AChE of the helmint, Schistosoma mansoni. AChE appears in S. mansoni in two principal molecular forms, both globular, with sedimentation coefficients of approximately 6.5 and 8 S. On the basis of their substrate specificity and sensitivity to inhibitors, both are "true" acetylcholinesterases. Approximately half of the AChE activity of S. mansoni is located on the outer surface of the parasite, attached to the tegumental membrane via a covalently attached glycosylphosphatidylinositol anchor. The remainder is located within the parasite, mainly associated with muscle tissue. Whereas the internal enzyme is most likely involved in termination of neurotransmission at cholinergic synapses, the role of the surface enzyme remains to be established; there are, however, indications that it is involved in signal transduction. The two forms of AChE differ in their heparin-binding properties, only the internal 8 S form of the AChE being retained on a heparin column. The two forms differ also in their immunological specificity, since they are selectively recognized by different monoclonal antibodies. Polyclonal antibodies raised against S. mansoni AChE purified by affinity chromatography are specific for the parasite AChE, reacting with both molecular forms, but do not recognize AChE from other species. They interact with the surface-localized enzyme on the intact organism, and produce almost total complement-dependent killing of the parasite. S. mansoni AChE is thus demonstrated to be a functional protein, involved in multifaceted activities, which can serve as a suitable candidate for diagnostic purposes, vaccine development, and drug design.

Arnon, R.; Silman, I.; Tarrab-Hazdai, R.

1999-01-01

356

Hepatitis C virus NS5A inhibitors and drug resistance mutations.  

PubMed

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for "difficult-to-treat" HCV-infected patients. "First generation" HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. "Second generation" NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants. PMID:24659881

Nakamoto, Shingo; Kanda, Tatsuo; Wu, Shuang; Shirasawa, Hiroshi; Yokosuka, Osamu

2014-03-21

357

Mapping a buried Quaternary valley and pre-Quaternary faults through seismic methods in Copenhagen, Denmark.  

NASA Astrophysics Data System (ADS)

Limited knowledge of the subsurface geology motivates the use of geophysical techniques before large engineering projects are conducted. These applications are normally restricted to satisfy the project aims, like mapping the near surface sediments, unconsolidated rocks and/or geological structures that may affect the construction locally. However, the applications can also contribute to the general knowledge of the regional geology around the location of interest. This report highlights the mapping of a buried Quaternary valley and identification of regional faults by a reflection and refraction seismic survey performed in Copenhagen. A 13.9 Km seismic survey was carried out at Copenhagen city along six crooked lines in order to determine the velocity fields in the near subsurface segment of a planned metro line and reflection patterns in deeper levels. The aim of the survey was to collect information needed for designing the underground metro. In particular it was sought to map the interface between Quaternary sedimentary layers of clay, till and sand, and the underlying layers of Palaeogene limestone found between 7 and 40 m below the ground surface. The data acquisition was carried out using a 192 channels array, receiver groups with 5 m spacing and a Vibroseis as a source at 5 m spacing following a roll along technique to complete the survey spreads. The urban environment demanded extensive survey planning including traffic control, notifications to residents and a fluent coordination with municipal authorities in order to minimize disturbances and ensure data acquisition. The reflection data was processed under a conventional scheme and the refraction data was interpreted using a non-linear traveltime tomography algorithm. The reflection results indicate the presence of faults oriented NW-SE to NNW-SSE affecting the limestone sequences. The faults may be associated to the Sorgenfrei-Tornquist Zone at the transition between the Danish Basin and the Baltic Shield. The refraction interpretation allowed the mapping of the velocity distribution in the upper sediments and their interface with the underlying limestone sequences. In this work two sections along the northern part of the survey are presented and discussed. The cases show the ability of the seismic results to image the presence of a buried valley that has been previously reported but was geophysically mapped for the first time under these investigations. The results delineate the sediments-limestone interface as the depth to the limestone increases. These results are validated through borehole data from locations along the surveyed lines. Other minor lateral variations are also observed and compared to a geological model. The location of the buried valley corresponds to a fault zone observed in the reflection seismic investigation. Accordingly, the location of the valley may in part have been controlled by the faults. The overall results of the seismic investigations are currently being used as part of the design basis for the construction of the metro line and may be useful for future engineering projects in the area. In general, the investigation results demonstrated that in addition to meet specific project objectives near surface geophysics has the potential to provide insights to the general understanding of geological processes. The authors wish to acknowledge Metroselskabet I/S for permission in presenting the results, and the Cityringen Joint Venture partners COWI, Arup and Systra.

Martinez, Kerim; Alfredo Mendoza, Jose; Henrik, Olsen

2010-05-01

358

Matrix Metalloproteinase Inhibitor Peptides.  

National Technical Information Service (NTIS)

The objects of the invention are: to provide means of purifying natural inhibitors of metalloproteinases; to provide matrix metalloproteinase inhibitors and derivatives thereof. The inhibitors may be obtained from natural sources, may be produced by synth...

W. G. Stetler-Stevenson L. A. Liotta H. C. Krutzsch

1990-01-01

359

Quaternary sedimentation of the principal deltas of Vietnam  

NASA Astrophysics Data System (ADS)

Quaternary depressions in Vietnam (namely the Cuulong River, the Red River, and coastal depressions in the central part of the country) were filled mainly by continental deposits in five cycles as follows: (V) Upper Holocene (Thaibinh and Dongkhoi formations); (IV) Lower to Middle Holocene (Haihung and Tanthanh Binh-chanh formations); (III) Upper Pleistocene (Vinhphuc formation); (II) Middle to Upper Pleistocene (Hanoi and Thuduc formations); (I) Lower Pleistocene (Lechi, Trangbom, and Hoanghoa formations). Each cycle starts with a regression and ends with a transgression. Within the Quaternary the maximum regressive phase was in the Middle to Upper Pleistocene (beginning of cycle II) and the maximum transgressive phase in the Middle Holocene (end of cycle IV).

Nghi, Tran; Ngo Quang Toan; Do Thi Van Thanh; Nguyen Dinh Minh; Nguyen Van Vuong

360

Helix Bundle Quaternary Structure from [alpha]/[beta]-Peptide Foldamers  

SciTech Connect

The function of a protein generally depends on adoption of a specific folding pattern, which in turn is determined by the side chain sequence along the polypeptide backbone. Here we show that the sequence-encoded structural information in peptides derived from yeast transcriptional activator GCN4 can be used to prepare hybrid {alpha}/{beta}-peptide foldamers that adopt helix bundle quaternary structures. Crystal structures of two hybrid {alpha}/{beta}-peptides are reported along with detailed structural comparison to {alpha}-peptides of analogous side chain sequence. There is considerable homology between {alpha}- and {alpha}/{beta}-peptides at the level of helical secondary structure, with modest but significant differences in the association geometry of helices in the quaternary structure.

Horne, W. Seth; Price, Joshua L.; Keck, James L.; Gellman, Samuel H. (UW-MED)

2008-11-18

361

Quaternary Fault and Fold Database of the United States  

NSDL National Science Digital Library

This database summarizes geologic, geomorphic, and geographic information for about 2,000 Quaternary faults and folds in the United States. These structures are believed to be sources of magnitude 6 or greater earthquakes during the Quaternary Period (the past 1,600,000 years). Maps of these geologic structures are linked to detailed descriptions, including geologic setting, fault orientation, fault type, sense of movement, slip rate, recurrence (repeat) interval, and the time of the most recent surface-faulting event. The database is searchable by using an interactive map viewer, a state/regional interactive map, or a text-based search. There is also a link to a fact sheet that provides information about the database.

362

Organic non-quaternary clathrate salts for petroleum separation  

SciTech Connect

A method is described for separating hydrocarbon feed streams containing mixtures of aromatic hydrocarbons and non-aromatic hydrocarbons into aromatics lean raffinate streams and aromatics rich extract streams by contacting the hydrocarbon feed streams with an organic non-quaternary clathrate salt having less than 16 carbon atoms in the cation, whereby the clathrate salt selectively interacts with the aromatic component of the hydrocarbon feed mixture producing a raffinate phase of reduced aromatic content a hydrocarbon - salt clathrate and an extract phase of increased aromatic content containing the clathrate salt and combined aromatic hydrocarbon, separating the raffinate phase from the extract phase and releasing the aromatic hydrocarbon from the clathrate salt of the extract phase to recover an aromatics rich stream and the organic non-quaternary salt which is recycled for contact with fresh hydrocarbon feed.

Boate, D.R.; Zaworotko, M.J.

1993-06-15

363

Unexpected primitive rodents in the Quaternary of Argentina  

NASA Astrophysics Data System (ADS)

This article describes the first fossils recorded in the Hernandarias Formation (Pleistocene) in Entre Ríos province (eastern Argentina). They are represented by three teeth assigned to the caviomorph rodents (Rodentia, Mammalia) Aenigmys diamantensis gen. et sp. nov. and Eumysops. To establish the phylogenetic affinities of the two most enigmatic teeth, their enamel microstructure was studied. Aenigmys diamantensis is considered the most primitive taxon of a clade formed by Dinomyidae-Neoepiblemidae-Heptaxodontidae. Evidence of the close relationships among these families also is presented herein. The new fossils reinforce previous hypotheses about the survival of primitive Brazilian taxa after their extinction in the Pampas and Patagonia of southern South America. They also show that the diversity of caviomorph rodents during the Quaternary was greater than supposed and that an important Quaternary extinction, not previously detected, affected several lineages. With the available evidence, it is not possible to determine if these rodents indicate a warm pulse or a particular biogeographic situation in Entre Ríos.

Vucetich, María G.; Vieytes, Emma C.; Verzi, Diego H.; Noriega, Jorge I.; Tonni, Eduardo P.

2005-10-01

364

?-CD assisted dissolution of quaternary ammonium permanganates in aqueous medium.  

PubMed

The non-polar internal cavity of ?-cyclodextrin (?-CD) has been exploited for the entrapment of the hydrophobic tails of two water insoluble quaternary ammonium permanganates (QAPs): cetyltrimethylammonium permanganate (CTAP) and tetrabutylammonium permanganate (TBAP), for solubilization in aqueous medium. The solubilization and organizational behavior of the QAPs in aqueous ?-CD solution have been determined from the comparison of their rates of self-oxidation in presence and in absence of ?-CD. Effect of QAP concentration on their observed rate constants (kobs) at a fixed ?-CD concentration, phase solubility analysis in varying ?-CD concentration, impact of quaternary ammonium bromides (QABs) on the kobs values of CTAP and TBAP at fixed QAP and ?-CD concentrations, and the temperature effect have been reported. A scheme to explain the solvation of QAPs in aqueous ?-CD has been proposed based on dynamic light scattering (DLS) analysis of the samples. PMID:25037419

Bank, Suraj Prakash; Guru, Partha Sarathi; Dash, Sukalyan

2014-10-13

365

The impact of Quaternary Ice Ages on mammalian evolution.  

PubMed

The Quaternary was a time of extensive evolution among mammals. Most living species arose at this time, and many of them show adaptations to peculiarly Quaternary environments. The latter include continental northern steppe and tundra, and the formation of lakes and offshore islands. Although some species evolved fixed adaptations to specialist habitats, others developed flexible adaptations enabling them to inhabit broad niches and to survive major environmental changes. Adaptation to short-term (migratory and seasonal) habitat change probably played a part in pre-adapting mammal species to the longer-term cyclical changes of the Quaternary. Fossil evidence indicates that environmental changes of the order of thousands of years have been sufficient to produce subspeciation, but speciation has typically required one hundred thousand to a few hundred thousand years, although there are both shorter and longer exceptions. The persistence of taxa in environments imposing strong selective regimes may have been important in forcing major adaptive change. Individual Milankovitch cycles are not necessarily implicated in this process, but nor did they generally inhibit evolutionary change among mammals: many evolutionary divergences built over multiple climatic cycles. Deduction of speciation timing requires input from fossils and modern phenotypic and breeding data, to complement and constrain mitochondrial DNA coalescence dates which appear commonly to overestimate taxic divergence dates and durations of speciation. Migrational and evolutionary responses to climate change are not mutually exclusive but, on the contrary, may be synergistic. Finally, preliminary analysis suggests that faunal turnover, including an important element of speciation, was elevated in the Quaternary compared with the Neogene, at least in some biomes. Macroevolutionary species selection or sorting has apparently resulted in a modern mammalian fauna enriched with fast-reproducing and/or adaptively generalist species. PMID:15101579

Lister, Adrian M

2004-02-29

366

Fractionation of Serum Proteins with a Quaternary Ammonium Detergent  

Microsoft Academic Search

THE fractionation of serum proteins with the aid of quaternary ammonium compounds has met with difficulties, because the detergent\\/protein ratio must be maintained at a very constant level1. We have shown that this is no longer necessary if `Desogen' (methylphenyl dodecyltrimethyl-ammonium-methosulphate, Geigy S.A., Basle) is used. Separation into at least four components can be performed by the following method.

F. J. Loomeijer

1950-01-01

367

Sorption of quaternary ammonium compounds to municipal sludge  

Microsoft Academic Search

The sorptive behavior of four quaternary ammonium compounds (QACs) – hexadecyl trimethyl ammonium chloride (C16TMA), dodecyl trimethyl ammonium chloride (C12TMA), hexadecyl benzyl dimethyl ammonium chloride (C16BDMA), and dodecyl benzyl dimethyl ammonium chloride (C12BDMA) – to municipal primary, waste activated, mesophilic digested, and thermophilic digested sludges was assessed at 22°C. Batch adsorption of all four separately tested QACs to primary sludge

Zainab Z. Ismail; Ulas Tezel; Spyros G. Pavlostathis

2010-01-01

368

Sorption of Polymeric Quaternary Ammonium Compounds to Humic Acid  

Microsoft Academic Search

Polymeric quaternary ammonium salts or polyquaterniums are used not only in the water and wastewater industry but also in\\u000a cosmetics. The former have been extensively studied with sorption to wastewater treatment plant (WWTP) biosolids an important\\u000a factor in their fate, mitigating release to the environment. Compounds of cosmetic origin have not received the same scrutiny\\u000a as those used in other

Janet Cumming; Darryl William Hawker; Heather Chapman; Kerry Nugent

2011-01-01

369

Ternary and quaternary mixed electrolytes for lithium cells  

Microsoft Academic Search

This paper reports the influence of composition of mixed solvent electrolyte composition on the discharge capacity and charge–discharge cycle life of lithium metal\\/amorphous V2O5–P2O5 (95:5 in molar ratio) cells. The solvents used were ethylene carbonate (EC), propylene carbonate (PC), 2-methyltetrahydrofuran (2MeTHF) and THF. LiAsF6 was used as the solute. The electrolyte solutions examined here contain ternary and quaternary mixed systems.

S. I. Tobishima; K. Hayashi; Y. Nemoto; S. Sugihara; J. I. Yamaki

1999-01-01

370

Low Sensitivity of Listeria monocytogenes to Quaternary Ammonium Compounds  

Microsoft Academic Search

Ninety-seven epidemiologically unrelated strains of Listeria monocytogenes were investigated for their sen- sitivities to quaternary ammonium compounds (benzalkonium chloride and cetrimide). The MICs for seven serogroup 1\\/2 strains were high. Three came from the environment and four came from food; none were isolated from human or animal samples. All 97 strains carried the mdrL gene, which encodes a multidrug efflux

L. Mereghetti; R. Quentin; N. Marquet-Van Der Mee; A. Audurier

2000-01-01

371

Design of quaternary Ir-Nb-Ni-Al refractory superalloys  

SciTech Connect

The authors propose a method for developing new quaternary Ir-Nb-Ni-Al refractory superalloys for ultra-high-temperature uses, by mixing two types of binary alloys, Ir-20 at. pct Nb and Ni-16.8 at. pct Al, which contain fcc/L1{sub 2} two-phase coherent structures. For alloys of various Ir-Nb/Ni-Al compositions, the authors analyzed the microstructure and measured the compressive strengths. Phase analysis indicated that three-phase equilibria--fcc, Ir{sub 3}Nb-L1{sub 2}, and Ni{sub 3}Al-L1{sub 2}--existed in Ir-5Nb-62.4Ni-12.6A1(at.pct) (alloy A), Ir-10Nb-41.6Ni-8.4Al(at.pct)(alloy B), and Ir-15Nb-20.8Ni-4.2Al(at.pct)(alloy C) at 1,400 C; at 1,300 C, three phase equilibria--fcc, Ir{sub 3}Nb, and Ni{sub 3}Al--existed in alloys A and C and four-phase equilibria--fcc, Ir{sub 3}Nb, Ni{sub 3}Al, and IrAl-B2--existed in alloy B. The fcc/L1{sub 2} coherent structure was examined by using transmission electron microscopy (TEM). At a temperature of 1,200 C, the compressive strength of these quaternary alloys was between 130 and 350 MPa, which was higher than that of commercial Ni-based superalloys, such as MarM247 (50 MPa), and lower than that of Ir-based binary alloys (500 MPa). Compared to Ir-based alloys, the compressive strain of these quaternary alloys was greatly improved. The potential of the quaternary alloys for ultra-high-temperature use is also discussed.

Yu, X.H.; Yamabe-Mitarai, Y.; Ro, Y.; Harada, H.

2000-01-01

372

Humidity sensor using epoxy resin containing quaternary ammonium salts  

Microsoft Academic Search

Humidity-sensitive epoxy monomer, glycidyl trimethyl ammonium chloride (GTMAC) was selected as the humidity-sensing resin. Polypropylene glycol diglycidyl ether (PPGDGE) and methyl tetrahydrophthalic anhydride (MTPHA) were used as a comonomer and a curing agent, respectively. The humidity-sensitive membranes were composed of GTMAC, PPGDGE and MTPHA. When impedance characteristics of the epoxy resins containing quaternary ammonium salts were measured, the impedance decreased

Chil-Won Lee; Hee-Woo Rhee; Myoung-Seon Gong

2001-01-01

373

Quaternary Constant-Amplitude Codes for Multicode CDMA  

Microsoft Academic Search

A constant-amplitude code is a code that reduces the peak-to-average power ratio (PAPR) in multicode code-division multiple access (MC-CDMA) systems to the favorable value 1. In this paper, quaternary constant-amplitude codes (codes over Z 4) of length 2 m with error-correction capabilities are studied. These codes exist for every positive integer m, while binary constant-amplitude codes cannot exist if m

Kai-Uwe Schmidt

2009-01-01

374

Methane Hydrates in Quaternary Climate Change: The Clathrate Gun Hypothesis  

NASA Astrophysics Data System (ADS)

A new AGU title, Methane Hydrates in Quaternary Climate Change: The Clathrate Gun Hypothesis, by James P. Kennett, Kevin G. Cannariato, Ingrid L. Hendy and Richard J. Behl, presents an alternate hypothesis to explain climate behavior, including abrupt warming over the past 800,000 years. According to the Clathrate Gun Hypothesis, periodic releases of atmospheric methane from melting methane hydrate amplified a pattern of temperature fluctuations and triggered "greenhouse" warming that led to an increase in global temperatures.

375

Quaternary Benzo[C]Phenanthridine Alkaloids — Biological Activities  

Microsoft Academic Search

\\u000a Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolated from Caprifoliaceae, Fumariaceae,\\u000a Meliacea, Papaveraceae and Rutaceae plants. QBA belong to the elicitor-inducible secondary metabolites and are considered\\u000a phytoalexines because of their antifungal and nematocidal activities. Quaternary benzo[c]phenanthridine alkaloids whose most\\u000a studied representatives are sanguinarine (SA), chelerythrine (CHE), and fagaronine (FA) (Fig. 1) display a wide spectrum of

V. Šimánek; R. Vespalec; A. Šedo; J. Ulrichová; J. Vi?ar

376

Quaternary subsidence zones in Albania: some case studies  

Microsoft Academic Search

The Neotectonic evolution of Albania, from the Middle Pleistocene to the present day, is characterised by a general uplift\\u000a that began after the Pliocene. Subsidence took place locally and led to the formation of graben-shaped Quaternary lakes and\\u000a plains. During this period, graben lakes were formed at Shkodra, Ohrid, Prespa and Butrinti, whereas at Korça, Elbasani, Zadrima,\\u000a Tirana, Myzeqe, etc.,

Sh. Aliaj; G. Baldassarre; D. Shkupi

2001-01-01

377

Transport phenomena in a reactive quaternary gas mixture  

Microsoft Academic Search

Quaternary gas mixtures which undergo a binary and reversible chemical reaction of the type A+B&rlhar2;C+D are analyzed within the framework of Boltzmann equation in order to investigate the effects caused by the reactions on the transport coefficients. The gas system is considered close to chemical equilibrium, a state in which the affinity has a small value characterizing the final stage

Adriano W. Silva; Giselle M. Alves; Gilberto M. Kremer

2007-01-01

378

Targeting cholinesterase inhibitor poisoning with a novel blocker against both nicotinic and muscarinic receptors.  

PubMed

Clinicians have been treating poisoning by acetylcholinesterase inhibitors (ChEI) for more than half a century. However, the current atropine-centered therapy still cannot protect completely against all ChEIs, and poisoning by ChEIs is fatal in more than 20% of cases. Various solutions that try to enhance atropine's antimuscarinic effects have been used, but these fail to increase the antidotal effect, and their too potent muscarinic antagonism may produce incapacitating side effects. We hypothesized that, in the treatment of ChEI poisoning, the high death rate may not be attributed to the insufficient muscarinic antagonism but to the lack of nicotinic antagonism. To test this hypothesis, we designed and synthesized benthiactzine, a drug that blocks both muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs). A specific [(3)H]quinuclidinyl benzilate-binding assay showed that benthiactzine was much weaker than atropine in binding to five different mAChR subtypes or to mAChRs expressed in 14 different tissues. Electrophysiological measures were used to identify and characterize benthiactzine's antinicotinic effect on three typical neuronal nAChRs subtypes, alpha4beta2, alpha4beta4, and alpha7, which are expressed heterogenously in SH-EP1 cells. Finally, benthiactzine afforded better protection than atropine against the most lethal ChEI, VX or sarin, in a mouse model. These results indicate that the antidotal effect may not be directly related to the antidote's antimuscarinic effect and that the antinicotinic effect may provide additional protection against ChEI poisoning. This new drug may benefit future antidote discovery. PMID:19830505

Luo, Wangqian; Ge, Xulin; Cui, Wenyu; Wang, Hai

2010-08-01

379

Protein Flexibility Facilitates Quaternary Structure Assembly and Evolution  

PubMed Central

The intrinsic flexibility of proteins allows them to undergo large conformational fluctuations in solution or upon interaction with other molecules. Proteins also commonly assemble into complexes with diverse quaternary structure arrangements. Here we investigate how the flexibility of individual protein chains influences the assembly and evolution of protein complexes. We find that flexibility appears to be particularly conducive to the formation of heterologous (i.e., asymmetric) intersubunit interfaces. This leads to a strong association between subunit flexibility and homomeric complexes with cyclic and asymmetric quaternary structure topologies. Similarly, we also observe that the more nonhomologous subunits that assemble together within a complex, the more flexible those subunits tend to be. Importantly, these findings suggest that subunit flexibility should be closely related to the evolutionary history of a complex. We confirm this by showing that evolutionarily more recent subunits are generally more flexible than evolutionarily older subunits. Finally, we investigate the very different explorations of quaternary structure space that have occurred in different evolutionary lineages. In particular, the increased flexibility of eukaryotic proteins appears to enable the assembly of heteromeric complexes with more unique components.

Marsh, Joseph A.; Teichmann, Sarah A.

2014-01-01

380

Microstructure development in Al-Cu-Ag-Mg quaternary alloy  

NASA Astrophysics Data System (ADS)

The solidification behaviour of multi-component and multi-phase systems has been largely investigated in binary and ternary alloys. In the present study, a quaternary model system is proposed based on the well known Al-Cu-Ag and Al-Cu-Mg ternary eutectic alloys. The quaternary eutectic composition and temperature were determined by EDS (Energy Dispersive Spectrometry) and DSC (Differential Scanning Calorimetry) analysis, respectively. The microstructure was then characterised by SEM (Scanning Electron Microscope). In the DSC experiments, two types of quaternary eutectics were determined according to their phase composition. For each type of eutectic, various microstructures were observed, which result in different eutectic compositions. Only one of the determined eutectic compositions was further studied by the controlled growth technique in a vertical Bridgeman type furnace. In the initial part of the directionally solidified sample, competing growth between two-phase dendrites and three-phase eutectics was obtained, which was later transformed to competing growth between three-phase and four-phase eutectics. Moreover, silver enrichment was measured at the solidification front, which is possibly caused by Ag sedimentation due to gravity and Ag rejection from dendritic and three-phase eutectic growth, and its accumulation at the solidification front.

Zhou, Bin; Froyen, L.

2012-01-01

381

Ecological impacts of the late Quaternary megaherbivore extinctions.  

PubMed

As a result of the late Quaternary megafaunal extinctions (50,000-10,000 before present (BP)), most continents today are depauperate of megaherbivores. These extinctions were time-transgressive, size- and taxonomically selective, and were caused by climate change, human hunting, or both. The surviving megaherbivores often act as ecological keystones, which was likely true in the past. In spite of this and extensive research on the causes of the Late Quaternary Extinctions, the long-term ecological consequences of the loss of the Pleistocene megafauna remained unknown until recently, due to difficulties in linking changes in flora and fauna in paleorecords. The quantification of Sporormiella and other dung fungi have recently allowed for explicit tests of the ecological consequences of megafaunal extirpations in the fossil pollen record. In this paper, I review the impacts of the loss of keystone megaherbivores on vegetation in several paleorecords. A growing number of studies support the hypothesis that the loss of the Pleistocene megafauna resulted in cascading effects on plant community composition, vegetation structure and ecosystem function, including increased fire activity, novel communities and shifts in biomes. Holocene biota thus exist outside the broader evolutionary context of the Cenozoic, and the Late Quaternary Extinctions represent a regime shift for surviving plant and animal species. PMID:24649488

Gill, Jacquelyn L

2014-03-01

382

Quaternary salts containing the pentafluorosulfanyl (SF5) group.  

PubMed

The first quaternary salts of pyridine (2), N-methyl imidazole (3), N-propyl triazole (4), and pyridazine (5) that contain the pentafluorosulfanyl (SF(5)) group were prepared and characterized. Neat reactions of the aromatic nitrogen compounds with SF(5)(CF(2))(n)(CH(2))(m)I (n = 2 or 4, m = 2 or 4) gave quaternary iodides 6a-c, 7a-c, 8a, and 9a,b, which were metathesized with LiN(SO(2)CF(3))(2) to form the bis(trifluoromethylsulfonyl)amides 10a-c, 11a-c, 12a, and 13a,b, in high yields. With the exception of the pyridine bis(trifluoromethylsulfonyl)amide salts, the compounds melted or exhibited a T(g) at <0 degrees C. The methylimidazolium, pyridinium, and pyridazinium salts exhibited densities of approximately 2 g/cm(3). Particularly striking was the density of CF(3)(CF(2))(5)(CH(2))(2)-pyridazinium N(CF(3)SO(2))(2) measured at 2.13 g/cm(3); however, an atypically high density for the 1-CF(3)(CF(2))(5)(CH(2))(2)-3-methyl imidazolium amide (14) was also observed at 1.77 g/cm(3). All quaternary salts were characterized via IR, (19)F, (1)H, and (13)C NMR spectra and elemental analyses. PMID:12971788

Singh, Rajendra P; Winter, Rolf W; Gard, Gary L; Gao, Ye; Shreeve, Jean'ne M

2003-09-22

383

Quaternary diversification in European alpine plants: pattern and process.  

PubMed Central

Molecular clock approaches applied previously to European alpine plants suggest that Primula sect. Auricula, Gentiana sect. Ciminalis and Soldanella diversified at the beginning of the Quaternary or well within this period, whereas Globularia had already started diversifying in the (Late-)Tertiary. In the first part of this paper we present evidence that, in contrast to Globularia and Soldanella, the branching patterns of the molecular internal transcribed spacer phylogenies of both Primula and Gentiana are incompatible with a constant-rates birth-death model. In both of these last two taxa, speciation probably decreased through Quaternary times, perhaps because of some niche-filling process and/or a decrease in specific range size. In the second part, we apply nonlinear regression analyses to the lineage-through-time plots of P. sect. Auricula to test a range of capacity-dependent models of diversification, and the effect of Quaternary climatic oscillations on diversification and extinction. At least for one major clade of sect. Auricula there is firm evidence that both diversification and extinction are a function of temperature. Intriguingly, temperature appears to be correlated positively with extinction, but negatively with diversification. This suggests that diversification did not take place, as previously assumed, in geographical isolation in high-altitude interglacial refugia, but rather at low altitudes in geographically isolated glacial refugia.

Kadereit, Joachim W; Griebeler, Eva Maria; Comes, Hans Peter

2004-01-01

384

Simulation of Quaternary glacial cycles with fully interactive carbon cycle  

NASA Astrophysics Data System (ADS)

Although it is generally accepted that, as postulated by the Milankovitch theory, Earth's orbital variations play an important role in Quaternary climate dynamics, the mechanism of glacial cycles still not fully understood. Among major scientific challenges remains the understanding of the nature of 100 kyr cycles that dominated climate variability over the late part of Quaternary and a strong link between ice volume and atmospheric CO2 concentration. Here using the Earth system model of intermediate complexity CLIMBER-2 which includes all major components of the Earth system - atmosphere, ocean, land surface, northern hemisphere ice sheets, terrestrial biota and soil carbon, aeolian dust and marine biogeochemistry - we performed simulations of the Quaternary climate cycles using variations in the Earth's orbital parameters as the only prescribed climate forcing. Thanks to high computational efficiency of the CLIMBER-2 model we performed a large suite of model simulations aimed on better understanding the role of individual processes. We found that the main drivers of atmospheric CO2 evolve with time: changes in sea surface temperature and volume of bottom water of southern origin exert CO2 control during glacial inception and deglaciation, while changes in carbonate chemistry and marine biology are dominant during the first and second parts of the glacial cycles, respectively. Changes in terrestrial carbon pool play significant role during deglaciation. We also discus how paleoclimate records, such as atmospheric and deep oceanic d13C, can help to constrain model parameters and test hypotheses on the mechanism of glacial-interglacial CO2 variations.

Ganopolski, Andrey; Brovkin, Victor

2014-05-01

385

Sharing the Vision, Leading the Way: Continuing Educators in the New Millennium. ACHE Proceedings (62nd, Myrtle Beach, South Carolina, October 14-17, 2000).  

ERIC Educational Resources Information Center

This document presents the proceedings of the 2000 annual meeting of the Association for Continuing Higher Education (ACHE). Part 1 contains the text of the presidential address, "Building Solid Communities within Higher Education" (Nancy Thomason), as well as summaries of the following addresses: "Riding the Rapids of Change: Survival Tactics for…

Barrineau, Irene T., Ed.

386

Cigarette smoking during pregnancy regulates the expression of specific nicotinic acetylcholine receptor (nAChR) subunits in the human placenta.  

PubMed

Smoking during pregnancy is associated with low birth weight, premature delivery, and neonatal morbidity and mortality. Nicotine, a major pathogenic compound of cigarette smoke, binds to the nicotinic acetylcholine receptors (nAChRs). A total of 16 nAChR subunits have been identified in mammals (9 ?, 4 ?, and 1 ?, ? and ? subunits). The effect of cigarette smoking on the expression of these subunits in the placenta has not yet been determined, thus constituting the aim of this study. Using RT-qPCR and western blotting, this study investigated all 16 mammalian nAChR subunits in the normal healthy human placenta, and compared mRNA and protein expressions in the placentas from smokers (n = 8) to controls (n = 8). Our data show that all 16 subunit mRNAs are expressed in the normal, non-diseased human placenta and that the expression of ?2, ?3, ?4, ?9, ?2 and ?4 subunits is greater than the other subunits. For mRNA, cigarette smoke exposure was associated with increased expression of the ?9 subunit, and decreased expression of the ? subunit. At the protein level, expression of both ?9 and ? was increased. Thus, cigarette smoking in pregnancy is sufficient to regulate nAChR subunits in the placenta, specifically ?9 and ? subunits, and could contribute to the adverse effects of vasoconstriction and decreased re-epithelialisation (?9), and increased calcification and apoptosis (?), seen in the placentas of smoking women. PMID:24607864

Machaalani, R; Ghazavi, E; Hinton, T; Waters, K A; Hennessy, A

2014-05-01

387

[Facilitatory actions of the cognitive enhancer nefiracetam on neuronal Ca2+ channels and nicotinic ACh receptors: their intracellular signal transduction pathways].  

PubMed

Nootropics are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. We have attempted to assess the intracellular signal transduction pathways mediating the action of nefiracetam, a nootropic agent, on neuronal Ca2+ channels and nicotinic ACh receptors. In NG108-15 cells, nefiracetam (1 microM) enhanced the activities of N/L-type Ca2+ channels without affecting T-type The nefiracetam action was mimicked by dibutyryl cAMP (1 mM), or blocked by pertussis toxin (PTX), indicating that PTX-sensitive inhibitory G-proteins and cAMP-dependent pathways mediate the drug action. Nefiracetam also exerted a dose-dependent biphasic effect on Torpedo nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes, in which the drug induced a short-term depression of ACh-evoked currents at submicromolar concentrations (0.01-0.1 microM) and a long-term enhancement of the currents at micromolar concentrations (1-10 microM). The depression was caused by activation of PTX-sensitive G-protein-regulated cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enhancement was caused by activation of Ca(2+)-dependent protein kinase C (PKC) and the ensuing PKC phosphorylation of the receptors. It is concluded that nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognitive enhancers. PMID:10190131

Yoshii, M; Nishizaki, T; Watabe, S

1998-10-01

388

Effects of lithium-implantation on the hydrogen retention in both a-C:H and a-Si C:H materials submitted to deuterium bombardment.  

National Technical Information Service (NTIS)

The hydrogen release in plasma facing materials is a challenging problem for the hydrogen recycling. The hydrogen desorption from a-C:H and a-SiC:H materials induced by deuterium bombardment has been investigated. Prior to the deuterium bombardment, both ...

G. Barbier N. Chevarier A. Chevarier G. G. Ross M. A. El Khakani

1996-01-01

389

Involvement of ?7 nAChR signaling cascade in epigallocatechin gallate suppression of ?-amyloid-induced apoptotic cortical neuronal insults.  

PubMed

Excessive generation and accumulation of the ?-amyloid (A?) peptide in selectively vulnerable brain regions is a key pathogenic event in the Alzheimer's disease (AD), while epigallocatechin gallate (EGCG) is a very promising chemical to suppress a variety of A?-induced neurodegenerative disorders. However, the precise molecular mechanism of EGCG responsible for protection against neurotoxicity still remains elusive. To validate and further investigate the possible mechanism involved, we explored whether EGCG neuroprotection against neurotoxicity of A? is mediated through the ?7 nicotinic acetylcholine receptor (?7 nAChR) signaling cascade. It was shown in rat primary cortical neurons that short-term treatment with EGCG significantly attenuated the neurotoxicity of A?1-42, as demonstrated by increased cell viability, reduced number of apoptotic cells, decreased reactive oxygen species (ROS) generation, and downregulated caspase-3 levels after treatment with 25-?M A?1-42. In addition, EGCG markedly strengthened activation of ?7nAChR as well as its downstream pathway signaling molecules phosphatidylinositol 3-kinase (PI3K) and Akt, subsequently leading to suppression of Bcl-2 downregulation in A?-treated neurons. Conversely, administration of ?7nAChR antagonist methyllycaconitine (MLA; 20 ?M) to neuronal cultures significantly attenuated the neuroprotection of EGCG against A?-induced neurototoxicity, thus presenting new evidence that the ?7nAChR activity together with PI3K/Akt transduction signaling may contribute to the molecular mechanism underlying the neuroprotective effects of EGCG against A?-induced cell death. PMID:23807728

Zhang, Xijing; Wu, Mingmei; Lu, Fan; Luo, Na; He, Zu-Ping; Yang, Hao

2014-02-01

390

Activation of the alpha-7 nicotinic acetylcholine receptor (?7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.  

PubMed

In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (?7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective ?7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective ?7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using ?7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases. PMID:22722030

Costa, Robson; Motta, Emerson M; Manjavachi, Marianne N; Cola, Maíra; Calixto, João B

2012-10-01

391

Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors  

PubMed Central

Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell survival. SphK phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has been implicated in cancer growth and survival. SphK exists as two different isotypes, namely SphK1 and SphK2, which play different roles inside the cell. In this report, we describe SphK inhibitors based on the immunomodulatory drug, FTY720, which is phosphorylated by SphK2 to generate a S1P mimic. Structural modification of FTY720 provided a template for synthesizing new inhibitors. A diversity-oriented synthesis generated a library of SphK inhibitors with a novel scaffold and headgroup. We have discovered subtype selective inhibitors with Ki’s in the low micromolar range. This is the first report describing quaternary ammonium salts as SphK inhibitors.

Raje, Mithun R.; Knott, Kenneth; Kharel, Yugesh; Bissel, Philippe; Lynch, Kevin R.; Santos, Webster L.

2013-01-01

392

Effect of a nicotine vaccine on nicotine binding to the beta2-nAChRs in vivo in human tobacco smokers  

PubMed Central

Objective Nicotine acts in the brain to promote smoking in part by binding to the beta2-containing nicotinic acetylcholine receptors (?2*-nAChRs) and acting in the mesolimbic reward pathway. The effects of nicotine from smoking one tobacco cigarette are significant (80% of ?2*-nAChRs occupied for >6h). This likely contributes to the maintenance of smoking dependence and low cessation outcomes. Development of nicotine vaccines provides potential for alternative treatments. We used [123I]5IA-85380 SPECT to evaluate the effect of 3?-AmNic-rEPA on the amount of nicotine that binds to the ?2*-nAChRs in the cortical and subcortical regions in smokers. Method Eleven smokers (36years (SD=13); 19cig/day (SD=11) for 10years (SD=7) who were dependent on nicotine (Fagerström Test of Nicotine Dependence score =5.5 (SD=3); plasma nicotine 9.1 ng/mL (SD=5)) participated in 2 SPECT scan days: before and after immunization with 4–400?g doses of 3?-AmNic-rEPA. On SPECT scan days, 3 30-min baseline emission scans were obtained, followed by administration of IV nicotine (1.5mg/70kg) and up to 9 30-min emission scans. Results ?2*-nAChR availability was quantified as VT/fP and nicotine binding was derived using the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding (F=5.19, df=1,10, p=0.05). Significant positive correlations were observed between nicotine bound to ?2*-nAChRs and nicotine injected before but not after vaccination (p=0.05 vs. p=0.98). There was a significant reduction in the daily number of cigarettes and desire for a cigarette (p=.01 and p=.04, respectively). Conclusions This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ?2*-nAChRs and disrupt the relationship between nicotine administered vs. nicotine available to occupy ?2*-nAChRs.

Esterlis, Irina; Hannestad, Jonas O.; Perkins, Evgenia; Bois, Frederic; D'Souza, D. Cyril; Tyndale, Rachel F.; Seibyl, John P.; Hatsukami, Dorothy M.; Cosgrove, Kelly P.; O'Malley, Stephanie S.

2013-01-01

393

Electrical coupling and release of K+ from endothelial cells co-mediate ACh-induced smooth muscle hyperpolarization in guinea-pig inner ear artery.  

PubMed

The physiological basis of ACh-elicited hyperpolarization in guinea-pig in vitro cochlear spiral modiolar artery (SMA) was investigated by intracellular recording combined with dye labelling of recorded cells and immunocytochemistry. We found the following. (1) The ACh-hyperpolarization was prominent only in cells that had a low resting potential (less negative than -60 mV). ACh-hyperpolarization was reversibly blocked by 4-DAMP, charybdotoxin or BAPTA-AM, but not by N(omega)-nitro-L-arginine methyl ester, glipizide, indomethacin or 17-octadecynoic acid. (2) Ba(2)(+) (100 microm) and ouabain (1 microm) each attenuated ACh-hyperpolarization by approximately 30% in smooth muscle cells (SMCs) but had only slight or no inhibition in endothelial cells (ECs). A combination of Ba(2)(+) and 18beta-glycyrrhetinic acid near completely blocked the ACh-hyperpolarization in SMCs. (3) High K(+) (10 mm) induced a smaller hyperpolarization in ECs than in SMCs, with an amplitude ratio of 0.49 : 1. Ba(2)(+) blocked the K(+)-induced hyperpolarization by approximately 85% in both cell types, whereas ouabain inhibited K(+)-hyperpolarization differently in SMCs (19%) and ECs (35%) and increased input resistance. 18beta-Glycyrrhetinic acid blocked the high K(+)-hyperpolarization in ECs only. (4) Weak myoendothelial dye coupling was detected by confocal microscopy in cells recorded with a propidium iodide-containing electrode for longer than 30 min. A sparse plexus of choline acetyltransferase-immunoreactive (ChAT) fibres was observed around the SMA and its up-stream arteries. (5) Evoked excitatory junction potentials (EJP) were partially blocked by 4-DAMP in half of the cells tested. We conclude that ACh-induced hyperpolarization originates from ECs via activation of Ca(2)(+)-activated potassium channels, and is independent of the release of NO, cyclo-oxygenase or cytochrome P450 products. ACh-induced hyperpolarization in smooth muscle cells involves two mechanisms: (a) electrical spread of the hyperpolarization from the endothelium, and (b) activation of inward rectifier K(+) channels (K(ir)) and Na(+)-K(+) pump current by elevated interstitial K(+) released from the endothelial cells, these being responsible for about 60% and 40% of the hyperpolarization, respectively. The role ratio of K(ir) and pump current activation is at 8 : 1 or less. PMID:15731195

Jiang, Zhi-Gen; Nuttall, Alfred L; Zhao, Hui; Dai, Chun-Fu; Guan, Bing-Cai; Si, Jun-Qiang; Yang, Yu-Qin

2005-04-15

394

Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors.  

PubMed

This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity. PMID:24186541

de Aquino, Roney Anderson Nascimento; Modolo, Luzia Valentina; Alves, Rosemeire Brondi; de Fátima, Ângelo

2013-12-28

395

Automated Docking with Protein Flexibility in the Design of Femtomolar "Click Chemistry" Inhibitors of Acetylcholinesterase  

PubMed Central

The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.1 Here we describe the application of the program AutoDock2 to the design of a focused library that was used in the “click chemistry in-situ” generation of the most potent non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~100 fM).3 AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein.

Morris, Garrett M.; Green, Luke G.; Radic, Zoran; Taylor, Palmer; Sharpless, K. Barry; Olson, Arthur J.; Grynszpan, Flavio

2013-01-01

396

Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase.  

PubMed

Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 ?M. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 ?M. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 ?M. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD. PMID:24794747

Hong, Chen; Luo, Wen; Yao, Dong; Su, Ya-Bin; Zhang, Xin; Tian, Run-Guo; Wang, Chao-Jie

2014-06-15

397

Anti-Allergic Role of Cholinergic Neuronal Pathway via ?7 Nicotinic ACh Receptors on Mucosal Mast Cells in a Murine Food Allergy Model  

PubMed Central

The prevalence of food allergy (FA) has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs) in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2) cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85? disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR) agonists (nicotine and ?7 nAChR agonist GTS-21) alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by ?7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via ?7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.

Yamamoto, Takeshi; Kodama, Toshihisa; Lee, Jaemin; Utsunomiya, Naho; Hayashi, Shusaku; Sakamoto, Hiroshi; Kuramoto, Hirofumi; Kadowaki, Makoto

2014-01-01