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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. PMID:17572698

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

2007-01-01

2

Neuronal AChE splice variants and their non-hydrolytic functions: redefining a target of AChE inhibitors?  

PubMed Central

AChE enzymatic inhibition is a core focus of pharmacological intervention in Alzheimer's disease (AD). Yet, AChE has also been ascribed non-hydrolytic functions, which seem related to its appearance in various isoforms. Neuronal AChE presents as a tailed form (AChE-T) predominantly found on the neuronal synapse, and a facultatively expressed readthough form (AChE-R), which exerts short to medium-term protective effects. Notably, this latter form is also found in the periphery. While these non-hydrolytic functions of AChE are most controversially discussed, there is evidence for them being additional targets of AChE inhibitors. This review aims to provide clarification as to the role of these AChE splice variants and their interplay with other cholinergic parameters and their being targets of AChE inhibition: AChE-R is particularly involved in the mediation of (anti-)apoptotic events in cholinergic cells, involving adaptation of various cholinergic parameters and a time-dependent link to the expression of neuroprotective factors. The AChE-T C-terminus is central to AChE activity regulation, while isolated AChE-T C-terminal fragments mediate toxic effects via the ?7 nicotinic acetylcholine receptor. There is direct evidence for roles of AChE-T and AChE-R in neurodegeneration and neuroprotection, with these roles involving AChE as a key modulator of the cholinergic system: in vivo data further encourages the use of AChE inhibitors in the treatment of neurodegenerative conditions such as AD since effects on both enzymatic activity and the enzyme's non-hydrolytic functions can be postulated. It also suggests that novel AChE inhibitors should enhance protective AChE-R, while avoiding the concomitant up-regulation of AChE-T. PMID:23991627

Zimmermann, M

2013-01-01

3

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy  

PubMed Central

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

2013-01-01

4

Neurophysiological predictors of long term response to AChE inhibitors in AD patients  

PubMed Central

Background: In vivo evaluation of cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI). SAI is reduced in Alzheimer's disease (AD) and drugs enhancing cholinergic transmission increase SAI. Methods: We evaluated whether SAI testing, together with SAI test-retest, after a single dose of the acetylcholinesterase (AChE) inhibitor rivastigmine, might be useful in predicting the response after 1 year treatment with rivastigmine in 16 AD patients. Results: Fourteen AD patients had pathologically reduced SAI. SAI was increased after administration of a single oral dose of rivastigmine in AD patients with abnormal baseline SAI, but individual responses to rivastigmine varied widely, with SAI change ranging from an increase in inhibition of ?50% of test size to no change. Baseline SAI and the increase in SAI after a single dose of rivastigmine were correlated with response to long term treatment. A normal SAI in baseline conditions, or an abnormal SAI in baseline conditions that was not greatly increased by a single oral dose of rivastigmine, were invariably associated with poor response to long term treatment, while an abnormal SAI in baseline conditions in conjunction with a large increase in SAI after a single dose of rivastigmine was associated with good response to long term treatment in most of the patients. Conclusions: Evaluation of SAI may be useful for identifying AD patients likely to respond to treatment with AChE inhibitors. PMID:16024879

Di, L; Oliviero, A; Pilato, F; Saturno, E; Dileone, M; Marra, C; Ghirlanda, S; Ranieri, F; Gainotti, G; Tonali, P

2005-01-01

5

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

6

QSAR Models for the Reactivation of Sarin Inhibited AChE by Quaternary Pyridinium Oximes Based on Monte Carlo Method.  

PubMed

For three random splits, one-variable models of oximes reactivation of sarin inhibited acetylcholinesterase (logarithm of the AChE reactivation percentage by oximes with concentration of 0.001 M) have been calculated with CORAL software. The total number of considered oximes was 42. Simplified molecular input line entry system (SMILES) and hydrogen-suppressed graph (HSG) are used to represent the molecular structure. Using CORAL software by means of the calculation with Monte Carlo optimization of the so called correlation weights for the molecular fragments, optimal SMILES-based descriptors were defined, which are correlated with an endpoint for the training set. The predictability of these descriptors for an external test are estimated. In this study hybrid representation HSG together with SMILES was used. The "classic" scheme (i.e. split data into the training set and test set) of building up quantitative structure-activity relationships was employed. Computational experiments indicated that this approach can satisfactorily predict the desired endpoint. Best model had following statistical characteristics n=32, r2= 0.6012, s= 0.279, F= 45 for training and n=10, r2= 0.9301, s= 0.076, Rm2=0.9206 for test set. PMID:25479380

Veselinovi?, Aleksandar M; Veselinovi?, Jovana B; Toropov, Andrey A; Toropova, Alla P; Nikoli?, Goran M

2014-11-26

7

Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: synthesis, biological assessment, and molecular modeling.  

PubMed

The synthesis, biological assessment and molecular modeling of new pyridonepezils1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC(50) (hAChE) = 9.4 ± 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy. PMID:23078965

Samadi, Abdelouahid; Estrada, Martín; Pérez, Concepción; Rodríguez-Franco, María Isabel; Iriepa, Isabel; Moraleda, Ignacio; Chioua, Mourad; Marco-Contelles, José

2012-11-01

8

Design of multi-target compounds as AChE, BACE1, and amyloid-?(1-42) oligomerization inhibitors: in silico and in vitro studies.  

PubMed

Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-? (A?) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of A?, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, ?-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the A? monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 ?M) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit A? oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. PMID:24762947

Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

2014-01-01

9

Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease.  

PubMed

6-Chloro-pyridonepezils are chloropyridine-donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils1-8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine-3,5-dicarbonitrile (14)] with suitable 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 ± 0.08 ?M). 6-Chloro-pyridonepezils4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 ?M range. Particularly, 6-chloro-pyridonepezil8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils1-8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy. PMID:23838422

Samadi, Abdelouahid; de la Fuente Revenga, Mario; Pérez, Concepción; Iriepa, Isabel; Moraleda, Ignacio; Rodríguez-Franco, María Isabel; Marco-Contelles, José

2013-09-01

10

Synthesis, Biological Evaluation, and Computational Studies of Tri- and Tetracyclic Nitrogen-Bridgehead Compounds as Potent Dual-Acting AChE Inhibitors and hH3 Receptor Antagonists  

PubMed Central

Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer’s disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure–activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R. PMID:24422467

2014-01-01

11

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

12

Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE).  

PubMed

Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A-F (N = 47, q(2) = 0.736, r(2) = 0.860) and C-F (N = 47, q(2) = 0.753, r(2) = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC(50) for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor. PMID:21074294

Araújo, Jocley Queiroz; de Brito, Monique Araújo; Hoelz, Lucas Villas Bôas; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

2011-01-01

13

Muscle aches  

MedlinePLUS

... common cause of muscle aches and pain is fibromyalgia , a condition that includes tenderness in your muscles ... Electrolyte imbalances like too little potassium or calcium Fibromyalgia Infections, including influenza (the flu), Lyme disease , malaria , ...

14

Selection of a human butyrylcholinesterase-like antibody single-chain variable fragment resistant to AChE inhibitors from a phage library expressed in E. coli.  

PubMed

Organophosphates are potent poisoning agents that cause severe cholinergic toxicity. Current treatment has been reported to be unsatisfactory and novel antidotes are needed. In this study, we used a single-chain variable fragment (scFv) library to select a recombinant antibody fragment (WZ1-14.2.1) with butyrylcholinesterase-like catalytic activity by using an innovative method integrating genetic selection and the bait-and-switch strategy. Ellman assay demonstrated that WZ1-14.2.1 has Michaelis-Menten kinetics in the hydrolysis of all the three substrates used, acetylthiocholine, propionylthiocholine and butyrylthiocholine. Notably, the catalytic activity was resistant to the following acetylcholinesterase inhibitors: neostigmine, iso-OMPA, chlorpyrifos oxon, dichlorvos, and paraoxon ethyl. Otherwise, the enzymatic activity of WZ1-14.2.1 was inhibited by the selective butyrylcholinesterase inhibitor, ethopropazine, and by the Ser-blocking agent phenylmethanesuphonyl fluoride. A hypothetical 3D structure of the WZ1-14.2.1 catalytic site, compatible with functional results, is proposed on the basis of a molecular modeling analysis. PMID:24675419

Podestà, Adriano; Rossi, Serena; Massarelli, Ilaria; Carpi, Sara; Adinolfi, Barbara; Fogli, Stefano; Bianucci, Anna Maria; Nieri, Paola

2014-01-01

15

Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor.  

PubMed

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor. PMID:25562342

Fandrick, Keith R; Mulder, Jason A; Patel, Nitinchandra D; Gao, Joe; Konrad, Michael; Archer, Elizabeth; Buono, Frederic G; Duran, Adil; Schmid, Rolf; Daeubler, Juergen; Desrosiers, Jean-Nicolas; Zeng, Xingzhong; Rodriguez, Sonia; Ma, Shengli; Qu, Bo; Li, Zhibin; Fandrick, Daniel R; Grinberg, Nelu; Lee, Heewon; Bosanac, Todd; Takahashi, Hidenori; Chen, Zhidong; Bartolozzi, Alessandra; Nemoto, Peter; Busacca, Carl A; Song, Jinhua J; Yee, Nathan K; Mahaney, Paige E; Senanayake, Chris H

2015-02-01

16

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. PMID:21362439

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

17

Acetylcholinesterases of Rhipicephalus (Boophilus) microplus – Multiple gene expression presents an opportune model system for elucidation of multiple functions of AChEs.  

Technology Transfer Automated Retrieval System (TEKTRAN)

Acetylcholinesterase (AChE) is a key neural enzyme of both vertebrates and invertebrates, and is the biochemical target of organophosphate and carbamate pesticides for invertebrates, as well as vertebrate nerve agents, e.g., soman, tabun, VX, and others. AChE inhibitors are also key drugs among thos...

18

Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski's Rule of Five and ZINC Databank  

PubMed Central

Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47?µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms. PMID:25685814

Nogara, Pablo Andrei; Saraiva, Rogério de Aquino; Caeran Bueno, Diones; Lissner, Lílian Juliana; Lenz Dalla Corte, Cristiane; Braga, Marcos M.; Rosemberg, Denis Broock; Rocha, João Batista Teixeira

2015-01-01

19

Interactions of AChE with A? Aggregates in Alzheimer’s Brain: Therapeutic Relevance of IDN 5706  

PubMed Central

Acetylcholinesterase (AChE; EC 3.1.1.7) plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-? (A?) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the A? peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer’s patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10?weeks increases brain AChE activity in 7-month-old double transgenic mice (APPSWE–PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer’s model. We concluded that early treatment with IDN 5706 decreases AChE–A? interaction and this effect might be of therapeutic interest in the treatment of AD. PMID:21949501

Carvajal, Francisco J.; Inestrosa, Nibaldo C.

2011-01-01

20

[Pharmacophore identification of novel dual-target compounds targeting AChE and PARP-1].  

PubMed

Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases. In this study, a computer-assisted strategy was applied to search for multi-target compounds by the pharmacophore matching. This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1). Based on two pharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC50 value of (0.337 +/- 0.052) micromol x L(-1) and PARP-1 by 24.6% at 1 micromol x L(-1). PMID:25212026

Guan, Xin-Lei; Jiang, Feng-Chao; Wang, Yue; Wu, Peng-Fei; Wang, Fang; Chen, Jian-Guo

2014-06-01

21

Structural basis of femtomolar inhibitors for acetylcholinesterase subtype selectivity: insights from computational simulations.  

PubMed

Acetylcholinesterase (AChE) is a key enzyme of the cholinergic nervous system. More than one gene encodes the synaptic AChE target. As the most potent known AChE inhibitor, the syn1-TZ2PA6 isomer was recently shown to have higher affinity as a reversible organic inhibitor of acetylcholinesterase1 (AChE1) than the anti1-TZ2PA6 isomer. Opposite selectivity has been shown for acetylcholinesterase2 (AChE2). In an attempt to understand the selectivity of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2, six molecular dynamics (MD) simulations were carried out with mouse AChE (mAChE, type of AChE1), Torpedo californica AChE (TcAChE, type of AChE1), and Drosophila melanogaster AChE (DmAChE, type of AChE2) bound with syn1-TZ2PA6 and anti1-TZ2PA6 isomers. Within the structure of the inhibitor, the 3,8-diamino-6-phenylphenanthridinium subunit and 9-amino-1,2,3,4-tetrahydroacridine subunit, via ?-? interactions, made more favorable contributions to syn1-TZ2PA6 or anti1-TZ2PA6 isomer binding in the mAChE/TcAChE enzyme than the 1,2,3-triazole subunit. Compared to AChE1, the triazole subunit had increased binding energy with AChE2 due to a greater negative charge in the active site. The binding free energy calculated using the MM/PBSA method suggests that selectivity between AChE1 and AChE2 is mainly attributed to decreased binding affinity for the inhibitor. PMID:23500627

Zhu, Xiao-Lei; Yu, Ning-Xi; Hao, Ge-Fei; Yang, Wen-Chao; Yang, Guang-Fu

2013-04-01

22

Reaction Gorge Fluctuation in Acetylcholinesterase (AChE)  

NSDL National Science Digital Library

Scientists Huan-Xiang Zhou, Stanislaw Wlodek, and Andrew McCammon created this animation showing "the 'breathing' motions of the gorge or channel that leads from the region outside the enzyme Acetylcholinesterase (AChE), to the active site." The enzyme AChE controls the communication among nerve and muscle cells. This animation demonstrates, for the first time, the role of molecular dynamics in enzyme specificity. It is based on "a combination of computational models and theoretical calculations," which were published in the August 4, 1998 issue of the Proceedings of the National Academy of Sciences.

McCammon, J. Andrew.

1998-01-01

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

In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE  

PubMed Central

We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ?2.5 kcal/mol, which was ?5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O…H and N…H hydrogen bonding and C-H…? non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme. PMID:24312449

Lo, Rabindranath; Chandar, Nellore Bhanu; Kesharwani, Manoj K.; Jain, Aastha; Ganguly, Bishwajit

2013-01-01

25

Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions?  

PubMed Central

Proliferation, differentiation and death of ovarian cells ensure orderly functioning of the female gonad during the reproductive phase, which ultimately ends with menopause in women. These processes are regulated by several mechanisms, including local signaling via neurotransmitters. Previous studies showed that ovarian non-neuronal endocrine cells produce acetylcholine (ACh), which likely acts as a trophic factor within the ovarian follicle and the corpus luteum via muscarinic ACh receptors. How its actions are restricted was unknown. We identified enzymatically active acetylcholinesterase (AChE) in human ovarian follicular fluid as a product of human granulosa cells. AChE breaks down ACh and thereby attenuates its trophic functions. Blockage of AChE by huperzine A increased the trophic actions as seen in granulosa cells studies. Among ovarian AChE variants, the readthrough isoform AChE-R was identified, which has further, non-enzymatic roles. AChE-R was found in follicular fluid, granulosa and theca cells, as well as luteal cells, implying that such functions occur in vivo. A synthetic AChE-R peptide (ARP) was used to explore such actions and induced in primary, cultured human granulosa cells a caspase-independent form of cell death with a distinct balloon-like morphology and the release of lactate dehydrogenase. The RIPK1 inhibitor necrostatin-1 and the MLKL-blocker necrosulfonamide significantly reduced this form of cell death. Thus a novel non-enzymatic function of AChE-R is to stimulate RIPK1/MLKL-dependent regulated necrosis (necroptosis). The latter complements a cholinergic system in the ovary, which determines life and death of ovarian cells. Necroptosis likely occurs in the primate ovary, as granulosa and luteal cells were immunopositive for phospho-MLKL, and hence necroptosis may contribute to follicular atresia and luteolysis. The results suggest that interference with the enzymatic activities of AChE and/or interference with necroptosis may be novel approaches to influence ovarian functions. PMID:25766324

Blohberger, J; Kunz, L; Einwang, D; Berg, U; Berg, D; Ojeda, S R; Dissen, G A; Fröhlich, T; Arnold, G J; Soreq, H; Lara, H; Mayerhofer, A

2015-01-01

26

Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitors.  

PubMed

A new series of galanthamine derivatives have been designed, synthesized and evaluated as acetylcholinesterase inhibitors. All of the new compounds prepared showed high AChE inhibitory activities, with compound 3e that has an N-hexyl-benzyl piperidine substituent on the nitrogen atom reaching the best inhibitory activity for AChE (IC(50)=5.62 nM). The docking study performed with AutoDock demonstrated that 3e was nicely accommodated by AChE. PMID:18550228

Jia, Ping; Sheng, Rong; Zhang, Jing; Fang, Liang; He, Qiaojun; Yang, Bo; Hu, Yongzhou

2009-02-01

27

ACh Receptors Link Two Signaling Pathways to Neuroprotection against Glutamate-Induced Excitotoxicity in Isolated RGCs  

PubMed Central

Previous studies have reported that activation of nicotinic ACh receptors on cultured pig retinal ganglion cells (RGCs) has a neuroprotective effect against glutamate-induced excitotoxicity (Wehrwein et al., 2004; Thompson et al., 2006). However, the mechanism linking nAChRs to neuroprotection is unknown. Here we tested the hypothesis that signaling cascades involving p38 MAP kinase and PI3 kinase ? Akt are involved in linking activation of nAChRs to neuroprotection in isolated pig RGCs. In ELISA studies, regulation of phosphorylated p38 MAP kinase and Akt were analyzed after inducing excitotoxicity or neuroprotection in the presence and absence of specific inhibitors for p38 MAP kinase and PI3 kinase. ELISA results demonstrated that ACh significantly increased phosphorylated Akt and decreased p38 MAP kinase. Glutamate increased phosphorylated p38 MAP kinase but had no significant effect on phosphorylated Akt. Other ELISA studies using p38 MAP kinase and PI3 kinase inhibitors also supported the hypothesis that ACh up-regulated Bcl-2 levels downstream from PI3 kinase and Akt, whereas glutamate down-regulated Bcl-2 levels downstream from p38 MAP kinase. RGC survival was subsequently assessed by culturing RGCs in conditions to induce excitotoxicity or neuroprotection in the presence or absence of specific inhibitors of p38 MAP kinase or PI3 kinase. The p38 MAP kinase inhibitor significantly decreased the number of RGCs that died by glutamate-induced excitotoxicity but had no effect on the number of cells that survived due to ACh-induced neuroprotection. PI3 kinase inhibitors significantly decreased cell survival caused by ACh-induced neuroprotection but had no effect on cell death caused by glutamate-induced excitotoxicity. These results demonstrate that glutamate mediates excitotoxicity through the p38 MAP kinase signaling pathway and that ACh provides neuroprotection by stimulating the PI3 kinase ? Akt ? Bcl-2 signaling pathway and inhibiting the p38 MAP kinase ? Bcl-2 pathway. PMID:19845831

Asomugha, C.O.; Linn, D.M.; Linn, C.L.

2009-01-01

28

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

29

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.

30

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

31

Modulated dye retention for the signal-on fluorometric determination of acetylcholinesterase inhibitor.  

PubMed

A novel fluorometric assay method based on target-induced signal on was developed for acetylcholinesterase (AChE) inhibitor with obviously improved detection sensitivity. In this method, the AChE molecules catalyzed the hydrolysis of acetylthiocholine (ATCl) to form thiocholine, which in turn can specifically react with fluorescent squaraine derivative, a specific chemodosimeter for thiol-containing compounds, resulting in fluorescence quenching and offering a low fluorometric background for the further detection of AChE inhibitor. In the presence of AChE inhibitor, the catalytic hydrolysis of ATCl is blocked, and then the squaraine derivative remains intact and shows signal-on fluorescence. The amount of the remaining fluorescent squaraine derivative is positively correlated with that of the AChE inhibitor in solution. This new designed sensing system shows an obviously improved sensitivity toward target with a detection limit of 5 pg mL(-1) (0.018 nM) for the AChE inhibitor, comparing favorably with previously reported fluorometric methods. To our best knowledge, this new method is the first example of fluorometric enzymatic assay for AChE inhibitors based on such a signal-on principle and using a specific reaction, which has potential to offer an effective strategy for the detection of AChE inhibitors. PMID:23597308

Liao, Shuzhen; Han, Wenting; Ding, Huazhi; Xie, Dexun; Tan, Hui; Yang, Shengyuan; Wu, Zhaoyang; Shen, Guoli; Yu, Ruqin

2013-05-21

32

Toxic effects of HgCl2 on activities of SOD, AchE and relative expression of SOD, AChE, CYP1A1 of zebrafish.  

PubMed

In order to explore the impact of mercury on fish, zebrafish were exposed in various levels of HgCl2 and the superoxide dismutase (SOD), acetylcholinesterase (AChE) activities were measured after 1 and 7 days exposure. Muscle RNA was also extracted for semi-quantitative RT-PCR determination of the expression of AChE, CYP1A1, Cu/Zn-SOD. It indicated that 96 h-LC50 of HgCl2 to zebrafish is 244.06 µg L(-1). The AChE activity was decreased on 1st day and 7th day. The SOD activity was almost unchanged on 1st day, it showed a dose-response effect on 7th day. The expression of AChE was down-regulated on 1st day, it is consistent with the AChE activity, but the expression was showed a significant difference between exposed group and the control group on 7th day. The expression of CYP1A1 was decreased compared with the control group on 1st day. After 7 day exposure, the expression of CYP1A1 was up-regulated in 0.1LC(50) group, and down-regulated in 0.4LC(50) group, 0.8LC(50) group, showing a stimulation effect at low concentration and inhibition at high concentration. The expression of Cu/Zn-SOD was down-regulated on 1st day, also showing an effect of stimulation at low concentration and inhibition at high concentrations. Thus HgCl2 was highly toxic to zebrafish, both the enzymatic activities and the gene transcription were changed significantly. But the change of gene transcription is earlier than enzymes activities. It indicates that gene transcript can be used as an early warning for environmental risk assessment. PMID:25240424

Zhen, He; Wen, Mu; Yang, Yang; Can, Zhang; Hui, Geng; Li, Xiong; Deli, Liu

2014-12-01

33

Inhibitors  

MedlinePLUS

... Hemophilia Related Pages Hemophilia Treatment Center Directory Universal Data Collection (UDC) System Blood Disorders Homepage Von Willebrand Disease ... Required) Data & Statistics Training & Education Research CHAMP Universal Data Collection Blood Safety Inhibitors Articles & Key Findings Free Materials ...

34

Vasoactive intestinal polypeptide modulation of nicotinic ACh receptor channels in rat intracardiac neurones.  

PubMed Central

1. The effects of vasoactive intestinal polypeptide (VIP) on isolated parasympathetic neurones of rat intracardiac ganglia were examined under voltage clamp using dialysed and perforated patch whole-cell and excised outside-out membrane patch recording configurations. 2. VIP reversibly potentiated nicotinic ACh-evoked whole-cell currents, with half-maximal potentiation (EC50) obtained with 260 pM VIP. However, VIP had no effect on muscarinic ACh-evoked currents, ATP-evoked currents, or depolarization-activated ionic currents in these neurones. 3. VIP-induced potentiation of nicotinic ACh-evoked whole-cell currents was observed following cell dialysis, and was inhibited reversibly by bath application of the VIP receptor-binding inhibitor L-8-K (5 microM) or the neuronal nicotinic receptor antagonist mecamylamine (3 microM). 4. The signal transduction pathway mediating VIP-induced potentiation of nicotinic ACh-evoked currents involves a guanine nucleotide-binding protein (G-protein) but not cyclic AMP. Intracellular application of 100 microM GDP-beta-S, or pre-incubation of neurones with pertussis toxin, inhibited VIP-induced potentiation of ACh-evoked whole-cell currents. 5. In outside-out membrane patches, co-application of ACh (4 microM) and VIP (4 nM) decreased the duration of closings between bursts and clusters of bursts of ACh single-channel activity relative to control (4 microM, ACh alone). VIP, however, did not alter single ACh receptor channel current amplitude, duration of closings and openings within a burst, or mean burst duration. 6. VIP-induced modification of nicotinic ACh receptor channel kinetics results in an increase in the open-channel probability which is sufficient to account for the VIP-mediated potentiation of nicotinic ACh-evoked whole-cell currents. 7. The potentiation of nicotinic ACh-evoked currents by VIP is likely to account for the altered neuronal activity observed in the mammalian intracardiac ganglia in vivo and consequent changes in heart rate and cardiac contractility. Images Figure 5 Figure 6 PMID:8782112

Cuevas, J; Adams, D J

1996-01-01

35

Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis.  

PubMed

Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with ?-? interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89?kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH. PMID:24805972

Chadha, Nidhi; Tiwari, Anjani K; Kumar, Vikas; Lal, Sangeeta; Milton, Marilyn D; Mishra, Anil K

2015-05-01

36

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study  

PubMed Central

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

37

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

2014-04-01

38

Impaired formation of the inner retina in an AChE knockout mouse results in degeneration of all photoreceptors  

Microsoft Academic Search

Blinding diseases can be assigned predominantly to genetic defects of the photoreceptor ?pigmented epithelium complex. As an alternative, we show here for an acetylcholinesterase (AChE) knockout mouse that photoreceptor degeneration follows an impaired development of the inner retina. During the first 15 postnatal days of the AChE- ? - retina, three major calretinin sublaminae of the inner plexiform layer (IPL)

Afrim H. Bytyqi; Oksana Lockridge; Ellen Duysen; Yuxia Wang; Uwe Wolfrum; Paul G. Layer

2004-01-01

39

The acetylcholinesterase (AChE) inhibition analysis of medaka (Oryzias latipes) in the exposure of three insecticides.  

PubMed

The continuous effects on Acetylcholinesterase (AChE) activity of medaka (Oryzias latipes) caused by dichlorvos, methomyl and deltamethrin in vivo were investigated, and the trends of AChE activity inhibition due to the influence of these insecticides were discussed. The LC50-24h of dichlorvos, methomyl and deltamethrin on medaka were 2.3 mg/L, 0.2 mg/L, and 2.9×10(-3) mg/L respectively. The result suggested that at the beginning of the exposure, the AChE activity might increase, and the AChE activity in dead individuals was obviously lower than the live individuals. Though the de novo synthesis of AChE in medaka might help the AChE activity recover, the trends during the exposure in different treatments were downward, and it showed both exposure time and concentration dependent. Meanwhile, higher temperature might cause the AChE inhibition earlier due to the higher metabolic rate. Therefore, as a specific biomarker for organophosphate, carbamate pesticides and pyrethroids, the degree of the AChE inhibition with in vivo conditions is a good tool in continuous monitoring of insecticides, which may induce the nerve conduction disorders. PMID:25796143

Zhu, Jianping; Huan, Cheng; Si, Guiyun; Yang, Haitang; Yin, Li; Ren, Qing; Ren, Baixiang; Fu, Rongshu; Miao, Mingsheng; Ren, Zongming

2015-03-01

40

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.

41

Irish Quaternary Association (IQUA)  

NSDL National Science Digital Library

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." Visitors can learn about the importance of quaternary studies, find out the latest news and upcoming meetings, and find links to Quaternary studies journals.

42

Molecular docking of fisetin with AD associated AChE, ABAD and BACE1 proteins  

PubMed Central

Alzheimer?s disease (AD) is one of the most common dementias showing slow progressive cognitive decline. Progression of intracerebral accumulation of beta amyloid (A?) peptides by the action of amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme and ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the degradation of Acetylcholinesterase (AChE) the main pathological characteristics of AD. Therefore, it is of interest to evaluate the importance of fisetin (a flavonol that belongs to the flavonoid group of polyphenols) binding with AChE, ABAD and BACE1 proteins. Docking experiment of fisetin with these proteins using two different tools namely iGEMDOCK and FlexX show significant binding with acceptable binding values. Thus, the potential inhibitory role of fisetin with AD associated proteins is documented. PMID:25352723

Dash, Raju; Emran, Talha Bin; Uddin, Mir Muhammad Nasir; Islam, Ashekul; Junaid, Md

2014-01-01

43

Lycopodiaceae from Panama: A new source of acetylcholinesterase inhibitors  

Microsoft Academic Search

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,

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

2012-01-01

44

Cholinesterase inhibitors from botanicals  

PubMed Central

Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

2013-01-01

45

Decorative a-C:H coatings  

NASA Astrophysics Data System (ADS)

a-C:H coatings on stainless steel sheets were prepared for decorative purposes by RF PACVD method. The silicon and nitrogen were introduced into coatings for improving adhesion. Adhesion was tested by scratchtest and by static indentation. Hardness was investigated by nanoindentation. Chemical composition of coatings was measured by ERDA. Coatings with thickness 1.3 ?m have approximately the same morphology as the substrate.

?erný, F.; Jech, V.; Št?pánek, I.; Macková, A.; Konvi?ková, S.

2009-11-01

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

Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors.  

PubMed

Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-? peptide (A?) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced A? aggregation, most likely by competing with the A? peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between A? and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders. PMID:24217282

Darreh-Shori, Taher; Hosseini, Sharokh Makvand; Nordberg, Agneta

2014-01-01

48

Baculovirus expression, biochemical characterization and organophosphate sensitivity of rBmAChE1, rBmAChE2, and rBmAChE3 of Rhipicephalus (Boophilus) microplus  

Technology Transfer Automated Retrieval System (TEKTRAN)

Rhipicephalus (Boophilus) microplus cDNAs, BmAChE1, BmAChE2, and BmAChE3,were previously identified as presumptively encoding acetylcholinesterases, but biochemical identity was confirmed only for recombinant BmAChE3. In the present study, four recombinant BmAChE1 constructs and single recombinant c...

49

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

50

Selected properties of a-C:H PACVD coatings  

NASA Astrophysics Data System (ADS)

a-C:H films were deposited by rf PACVD from methane and their growth rate, thermal treatment, morphology, adhesion and electrical passivation properties were investigated. Deposition at room temperature gave the highest film growth rates. The Raman spectra obtained for a-C:H films indicated that the D peak becomes more pronounced as the annealing temperature grows higher. The rf plasma produced a-C:H passivation films which are sufficiently insulating at voltages up to ca. 2200 V.

Cerny, F.; Jech, V.; Konvickova, S.; Suchanek, J.

2009-11-01

51

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. PMID:22216416

Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

2012-01-01

52

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

53

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

54

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

55

Synthesis, biological activity and molecular modeling studies on 1H-benzimidazole derivatives as acetylcholinesterase inhibitors.  

PubMed

A series of N-{2-[4-(1H-benzimidazole-2-yl)phenoxy]ethyl}substituted amine derivatives were designed to assess cholinesterase inhibitor activities. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor activities were evaluated in vitro by using Ellman's method. It was discovered that most of the compounds displayed AChE and/or BuChE inhibitor activity and few compounds were selective against AChE/BuChE. Compound 3c and 3e were the most active compounds in the series against eeAChE and hAChE, respectively. Molecular docking studies and molecular dynamics simulations were also carried out. PMID:23891231

Alpan, Ay?e Selcen; Parlar, Sülünay; Carlino, Luca; Tarikogullari, Ayse Hande; Alptüzün, Vildan; Güne?, Hasan Semih

2013-09-01

56

Nonlinear mixed effects pharmacokinetic\\/pharmacodynamic analysis of the cholinesterase inhibitor pyridostigmine bromide in Chinese males  

Microsoft Academic Search

Pyridostigmine is a reversible inhibitor of acetylcholinesterase (AChE). The objective of the present analysis was to characterise the population pharmacokinetics \\/ pharmacodynamics (PK\\/PD) of pyridostigmine given as pyridostigmine bromide. Fifty healthy Chinese males received 7 doses of 30 mg of pyridostigmine bromide each every 8 hours orally. Plasma concentrations of pyridostigmine and red blood cell (RBC) AChE activity were determined

Seng Kok Yong; Loke Weng Keong; Moochhala Shabbir; Jon Deoon Lee

2009-01-01

57

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.

58

Quantifying Equilibrium Network Externalities in the ACH Banking Industry  

Microsoft Academic Search

We seek to determine the causes and magnitudes of network externalities for the automated clearinghouse (ACH) electronic payments system. We construct an equilibrium model of customer and bank adoption of ACH. We structurally estimate the parameters of the model using an indirect inference procedure and panel data. The parameters are identified from exogenous variation in the adoption decisions of banks

Daniel A. Ackerberg; Gautam Gowrisankaran

2006-01-01

59

Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies.  

PubMed

Garcinia mangostana is a well-known tropical plant found mostly in South East Asia. The present study investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of G. mangostana extract and its chemical constituents using Ellman's colorimetric method. Cholinesterase inhibitory-guided approach led to identification of six bioactive prenylated xanthones showing moderate to potent cholinesterases inhibition with IC50 values of lower than 20.5 ?M. The most potent inhibitor of AChE was garcinone C while ?-mangostin was the most potent inhibitor of BChE with IC50 values of 1.24 and 1.78 ?M, respectively. Among the xanthones, mangostanol, 3-isomangostin, garcinone C and ?-mangostin are AChE selective inhibitors, 8-deoxygartanin is a BChE selective inhibitor while ?-mangostin is a dual inhibitor. Preliminary structure-activity relationship suggests the importance of the C-8 prenyl and C-7 hydroxy groups for good AChE and BChE inhibitory activities. The enzyme kinetic studies indicate that both ?-mangostin and garcinone C are mixed-mode inhibitors, while ?-mangostin is a non-competitive inhibitor of AChE. In contrast, both ?-mangostin and garcinone C are uncompetitive inhibitors, while ?-mangostin is a mixed-mode inhibitor of BChE. Molecular docking studies revealed that ?-mangostin, ?-mangostin and garcinone C interacts differently with the five important regions of AChE and BChE. The nature of protein-ligand interactions is mainly hydrophobic and hydrogen bonding. These bioactive prenylated xanthones are worthy for further investigations. PMID:25172794

Khaw, K Y; Choi, S B; Tan, S C; Wahab, H A; Chan, K L; Murugaiyah, V

2014-09-25

60

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

61

Novel tacrine analogs as potential cholinesterase inhibitors in Alzheimer's disease.  

PubMed

Acetylcholinesterase inhibitors (AChEIs) are used for the treatment of Alzheimer's disease (AD). The increase in ACh levels ameliorates the symptoms of the disease. Tacrine is the first clinically approved drug as AChEI used in the treatment of AD. In this paper, we synthesized new tacrine analogs to act on catalytic and peripheral sites of AChE. Their inhibitory activity was evaluated. All novel compounds except 7a showed promising results toward AChE. Two compounds, 10b and 11b, are more potent than tacrine. Furthermore, molecular-modeling studies were performed for these two compounds to rationalize the obtained pharmacological activity. Moreover, various drug-likeness properties of the new compounds were predicted. PMID:24343873

El-Malah, Afaf; Gedawy, Ehab M; Kassab, Asmaa E; Salam, Rania M Abdel

2014-02-01

62

Novel multipotent AChEI-CCB attenuates hyperhomocysteinemia-induced memory deficits and Neuropathologies in rats.  

PubMed

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3?. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD. PMID:25024319

Xia, Yiyuan; Liu, Rong; Chen, Rong; Tian, Qing; Zeng, Kuan; Hu, Jichang; Liu, Xinghua; Wang, Qun; Wang, Peng; Wang, Xiao-Chuan; Wang, Jian-Zhi

2014-01-01

63

Human acetylcholinesterase inhibitors: electronic-topological and neural network approaches to the structure-activity relationships study.  

PubMed

The Electronic-Topological (ETM) and Neural Network methods were applied to the study of the "structure-acetylcholinesterase (AChE) inhibitor activity" relationships for a series of physostigmine and N-benzylpiperidine derivatives. Molecular fragments specific for active compounds and breaks of activity were calculated for human AChE by applying the ETM and Neural Network methods. Requirements necessary for a compound to be active were formulated; they are the result of detailed analysis of all compounds under study. A comparative study of the activity features found for human AChE was performed. PMID:15892689

Kandemirli, F; Saraçoglu, M; Kovalishyn, V

2005-05-01

64

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

PubMed

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. PMID:24187393

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

2013-07-01

65

Screening of acetylcholinesterase inhibitors by CE after enzymatic reaction at capillary inlet.  

PubMed

In this study the development of a procedure based on capillary electrophoresis after enzymatic reaction at capillary inlet methodology for the screening and in vitro evaluation of the biological activity of acetylcholinesterase (AChE) inhibitors is presented. The progress of the enzymatic reaction of the hydrolysis of acetylthiocholine at pH 8 in the presence of AChE and the inhibitor studied is determined by measuring at 230 nm the peak area of the reaction product thiocholine (TCh). In the method employed the capillary was first filled with 30 mM borate-phosphate buffer (pH 8.0) and subsequently, plugs of: (i) water, (ii) AChE solution, (iii) substrate solution with or without inhibitor, (iv) AChE solution, and (v) water, were hydrodynamically injected into the capillary, and were allowed to stand (and react) during a waiting period of 2 min. The applicability of the proposed methodology to estimate different kinetic parameters of interest such as inhibition constants K(i), identification of inhibitory action mechanism and IC(50), is evaluated using compounds with known activity, tacrine edrophonium, and neostigmine. The results obtained are compared with bibliographic values and confirm the effectiveness of the methodology proposed. Finally a method for AChE Inhibitor screening is proposed. PMID:19472276

Martín-Biosca, Yolanda; Asensi-Bernardi, Lucia; Villanueva-Camañas, Rosa M; Sagrado, Salvador; Medina-Hernández, Maria J

2009-05-01

66

Toxicological and Biochemical Characterizations of AChE in Phosalone-Susceptible and Resistant Populations of the Common Pistachio Psyllid, Agonoscena pistaciae  

PubMed Central

The toxicological and biochemical characteristics of acetylcholinesterases (AChE) in nine populations of the common pistachio psyllid, Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Psyllidae), were investigated in Kerman Province, Iran. Nine A. pistaciae populations were collected from pistachio orchards, Pistacia vera L. (Sapindales: Anacardiaceae), located in Rafsanjan, Anar, Bam, Kerman, Shahrbabak, Herat, Sirjan, Pariz, and Paghaleh regions of Kerman province. The previous bioassay results showed these populations were susceptible or resistant to phosalone, and the Rafsanjan population was most resistant, with a resistance ratio of 11.3. The specific activity of AChE in the Rafsanjan population was significantly higher than in the susceptible population (Bam). The affinity (KM) and hydrolyzing efficiency (Vmax) of AChE on acetylthiocholine iodide, butyrylthiocholine iodide, and propionylthiocholine odide as artificial substrates were clearly lower in the Bam population than that in the Rafsanjan population. These results indicated that the AChE of the Rafsanjan population had lower affinity to these substrates than that of the susceptible population. The higher Vmax value in the Rafsanjan population compared to the susceptible population suggests a possible over expression of AChE in the Rafsanjan population. The in vitro inhibitory effect of several organophosphates and carbamates on AChE of the Rafsanjan and Bam populations was determined. Based on I50, the results showed that the ratios of AChE insensitivity of the resistant to susceptible populations were 23 and 21.7-fold to monocrotophos and phosphamidon, respectively. Whereas, the insensitivity ratios for Rafsanjan population were 0.86, 0.8, 0.78, 0.46, and 0.43 for carbaryl, eserine, propoxur, m-tolyl methyl carbamate, and carbofuran, respectively, suggesting negatively correlated sensitivity to organophosphate-insensitive AChE. Therefore, AChE from the Rafsanjan population showed negatively correlated sensitivity, being insensitive to phosphamidon and monocrotophos and sensitive to N-methyl carbamates. PMID:25373165

Alizadeh, Ali; Talebi-Jahromi, Khalil; Hosseininaveh, Vahid; Ghadamyari, Mohammad

2014-01-01

67

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

68

Pharmacophore Modeling, virtual and in vitro screening for acetylcholinesterase inhibitors and their effects on amyloid-? self- assembly.  

PubMed

One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloid? (A?) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer's disease. PMID:22734711

Bag, Seema; Tulsan, Rekha; Sood, Abha; Datta, Silpi; Török, Marianna

2013-03-01

69

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

70

Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors.  

PubMed

Alzheimer's disease (AD), a progressive and neurodegenerative disorder of the brain, is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, aurone derivatives were designed and synthesized as AChE inhibitors based on the lead structure of sulfuretin. Of those synthesized, compound 10d showed ca. 1700-fold and 6-fold higher AChE inhibitory activity than sulfuretin and galantamine, respectively. This compound also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2mg/kg. PMID:25468034

Lee, Young Hun; Shin, Min Cheol; Yun, Yong Don; Shin, Seo Young; Kim, Jong Min; Seo, Jeong Moo; Kim, Nam-Jung; Ryu, Jong Hoon; Lee, Yong Sup

2015-01-01

71

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

72

Isolation, Identification and Characterization of a Antidementia Acetylcholinesterase Inhibitor-Producing Yarrowia lipolytica S-3  

PubMed Central

This report describes the isolation and identification of a potent acetylcholinesterase (AChE) inhibitor-producing yeasts. Of 731 species of yeast strain, the S-3 strain was selected as a potent producer of AChE inhibitor. The selected S-3 strain was investigated for its microbiological characteristics. The S-3 strain was found to be short-oval yeast that did not form an ascospore. The strain formed a pseudomycelium and grew in yeast malt medium containing 50% glucose and 10% ethanol. Finally, the S-3 strain was identified by its physiological characteristics and 26S ribosomal DNA sequences as Yarrowia lipolytica S-3. PMID:22783133

Kang, Min-Gu; Yoon, Min-Ho; Choi, Young-Jun

2012-01-01

73

In vitro effect of H2O 2, some transition metals and hydroxyl radical produced via fenton and fenton-like reactions, on the catalytic activity of AChE and the hydrolysis of ACh.  

PubMed

It is well known that the principal biomolecules involved in Alzheimer's disease (AD) are acetylcholinesterase (AChE), acetylcholine (ACh) and the amyloid beta peptide of 42 amino acid residues (A?42). ACh plays an important role in human memory and learning, but it is susceptible to hydrolysis by AChE, while the aggregation of A?42 forms oligomers and fibrils, which form senile plaques in the brain. The A?42 oligomers are able to produce hydrogen peroxide (H2O2), which reacts with metals (Fe(2+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)) present at high concentrations in the brain of AD patients, generating the hydroxyl radical ((·)OH) via Fenton (FR) and Fenton-like (FLR) reactions. This mechanism generates high levels of free radicals and, hence, oxidative stress, which has been correlated with the generation and progression of AD. Therefore, we have studied in vitro how AChE catalytic activity and ACh levels are affected by the presence of metals (Fe(3+), Cu(2+), Cr(3+), Zn(2+), and Cd(2+)), H2O2 (without A?42), and (·) OH radicals produced from FR and FLR. The results showed that the H2O2 and the metals do not modify the AChE catalytic activity, but the (·)OH radical causes a decrease in it. On the other hand, metals, H2O2 and (·)OH radicals, increase the ACh hydrolysis. This finding suggests that when H2O2, the metals and the (·)OH radicals are present, both, the AChE catalytic activity and ACh levels diminish. Furthermore, in the future it may be interesting to study whether these effects are observed when H2O2 is produced directly from A?42. PMID:25096900

Méndez-Garrido, Armando; Hernández-Rodríguez, Maricarmen; Zamorano-Ulloa, Rafael; Correa-Basurto, José; Mendieta-Wejebe, Jessica Elena; Ramírez-Rosales, Daniel; Rosales-Hernández, Martha Cecilia

2014-11-01

74

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro.  

PubMed

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity. PMID:11256231

Ogura, H; Kosasa, T; Kuriya, Y; Yamanishi, Y

2000-10-01

75

AChE and EROD activities in two echinoderms, Holothuria leucospilota and Holoturia atra (Holothuroidea), in a coral reef (Reunion Island, South-western Indian Ocean)  

Microsoft Academic Search

AChE and EROD activities were investigated in two holothurian species, Holothuria leucospilota and Holoturia atra, from a tropical coral reef. These organisms were collected from 3 back-reef stations, where temperature and salinity were homogeneous. The activity levels of both AChE and EROD varied significantly between the two species, but were in the range of values determined in other echinoderm species.

Joanna Kolasinski; Dorothée Taddei; Pascale Cuet; Patrick Frouin

2010-01-01

76

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. PMID:23386834

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

2013-01-01

77

AChE and EROD activities in two echinoderms, Holothuria leucospilota and Holoturia atra (Holothuroidea), in a coral reef (Reunion Island, South-western Indian Ocean).  

PubMed

AChE and EROD activities were investigated in two holothurian species, Holothuria leucospilota and Holoturia atra, from a tropical coral reef. These organisms were collected from 3 back-reef stations, where temperature and salinity were homogeneous. The activity levels of both AChE and EROD varied significantly between the two species, but were in the range of values determined in other echinoderm species. AChE activity levels were higher in the longitudinal muscle than in the tentacle tegument. Among the several tissues tested, the digestive tract wall exhibited higher EROD activity levels. Sex did not influence AChE and EROD activity levels in both species. Animal biomass and EROD activity levels were only correlated in the tegument tissue of H. atra, and we hypothesize a possible influence of age. EROD activity did not show intraspecific variability. A significant relationship was found between AChE activity and Cuvierian tubules time of expulsion in Holothuria leucospilota. Individuals collected at the southern site presented both lower AChE activity levels and Cuvierian tubules time of expulsion, indicating possible neural disturbance. More information on holothurians biology and physiology is needed to further assess biomarkers in these key species. This study is the first of its kind performed in the coastal waters of Reunion Island and data obtained represent reference values. PMID:20390918

Kolasinski, Joanna; Taddei, Dorothée; Cuet, Pascale; Frouin, Patrick

2010-01-01

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.

Christopher Hill

79

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

80

The rationale for E2020 as a potent acetylcholinesterase inhibitor.  

PubMed

The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements of optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information. PMID:8894101

Kawakami, Y; Inoue, A; Kawai, T; Wakita, M; Sugimoto, H; Hopfinger, A J

1996-09-01

81

Novel coumarin-3-carboxamides bearing N-benzylpiperidine moiety as potent acetylcholinesterase inhibitors.  

PubMed

Some novel coumarin-3-carboxamide derivatives linked to N-benzylpiperidine scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The screening results showed that most of compounds exhibited potent anti-AChE activity in the range of nM concentrations. Among them, compound 10c bearing an N-ethylcarboxamide linker and a 6-nitro substituent showed the most potent activity (IC?? = 0.3 nM) and the highest selectivity (SI = 26,300). Compound 10c was 46-fold more potent than standard drug donepezil against AChE. The kinetic study revealed that compound 10c exhibited mixed-type inhibition against AChE. Protein-ligand docking study demonstrated that the target compounds have dual binding site interaction mode and these results are in agreement with kinetic study. PMID:24211638

Asadipour, Ali; Alipour, Masoumeh; Jafari, Mona; Khoobi, Mehdi; Emami, Saeed; Nadri, Hamid; Sakhteman, Amirhossein; Moradi, Alireza; Sheibani, Vahid; Homayouni Moghadam, Farshad; Shafiee, Abbas; Foroumadi, Alireza

2013-01-01

82

Gripped by Gout: Avoiding the Ache and Agony  

MedlinePLUS

... Ache and Agony Sudden, painful swelling at the base of the big toe is often the first warning sign of gout. It can affect other joints as well. Without treatment, gout can lead to severe joint damage and make it hard for you to move. The good news is, ...

83

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

84

Screening of ?-secretase and acetylcholinesterase inhibitors from plant resources.  

PubMed

The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of ?-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened ?-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit ?-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of ?-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, ?- and ?-caryophyllene, ?-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine ?- and ?-caryophyllene, ?-caryophyllene oxide, and piperine as ?-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low. PMID:25119528

Murata, Kazuya; Matsumura, Shinichi; Yoshioka, Yuri; Ueno, Yoshihiro; Matsuda, Hideaki

2015-01-01

85

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. PMID:23379636

2013-01-01

86

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. PMID:23440963

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

2013-01-01

87

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. PMID:22148173

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

2012-01-01

88

[Capacitative Ca²? entry is involved in ACh-induced distal colon smooth muscle contraction in rats].  

PubMed

Contraction of smooth muscle cells is triggered by an increase in cytosolic Ca(2+) upon agonist stimulation. Ca(2+) influx across the plasma membrane constitutes a major component of the agonist-induced response in smooth muscle cells. Traditionally, voltage-operated Ca(2+) channel (VOCC) is considered as the channel mediating the Ca(2+) entry. However, this view has been challenged by recent discoveries, which demonstrated that other types of ion channels, such as store-operated and/or receptor-operated Ca(2+) channels (SOCC and/or ROCC), also participate in Ca(2+) response induced by agonists in smooth muscle cells. SOCC is defined as the channel activated in response to the depletion of the internal Ca(2+) stores, an event secondary to G protein coupled receptor or receptor tyrosine kinase stimulation. The Ca(2+) flow mediated by SOCC is termed as capacitative Ca(2+) entry (CCE). Previous study from other group has demonstrated that VOCC played a predominant role in ACh-induced contraction of distal colon smooth muscle in guinea pig. However, whether SOCC participates in the agonist-induced contractile response in this particular tissue is unknown. The present study was performed to investigate the role of CCE in ACh-induced mechanical activity of distal colon smooth muscle in rats. The contractile function of the smooth muscle was assessed by measuring isometric force of isolated rat distal colon rings. We showed that both high extracellular K(+) (40 mmol/L) and ACh (5 mumol/L) evoked striking contraction of the smooth muscle. The contractile responses were almost abolished by removal of extracellular Ca(2+) with ethylene glycol-bis(2-aminoethylether)-N,N,N',N' tetraacetic acid (EGTA), suggesting a critical contribution of extracellular source of Ca(2+) to the contraction. Verapamil (5 mumol/L), an L-type VOCC blocker, significantly attenuated, but didn't completely eliminate the high K(+)- and ACh-induced contraction (74% and 41% for high K(+) and ACh, respectively), indicating that additional channels might be involved in the contractile mechanism. Furthermore, ACh only induced transient contractions in the absence of extracellular Ca(2+). Readmission of Ca(2+) into the extracellular compartment resulted in a significant and sustained increase in the tension of the smooth muscle. This response was not affected by verapamil (5 mumol/L) and Cd(2+) (5 mumol/L), both of which efficiently block VOCC at the doses. However, La(3+), a known inhibitor of SOCC, significantly suppressed the Ca(2+) readdition-induced contraction in a dose-dependent manner. On the basis of these results, we conclude that contraction of smooth muscle in the distal colon is regulated by multiple Ca(2+) channels. In addition to VOCC-mediated Ca(2+) influx, SOCC-mediated CCE participates in agonist-induced contractile response of distal colon smooth muscle in rats. PMID:16628362

Kong, De-Hu; Zhou, Hua; Song, Jie; Ke, Dao-Ping; Hu, Jin-Lan; Li, Zhong-Wen; Ma, Rong

2006-04-25

89

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. PMID:23936743

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

2013-01-01

90

Variability of AChE, BChE, and ChAT genes in the late-onset form of Alzheimer's disease and relationships with response to treatment with Donepezil and Rivastigmine.  

PubMed

Several factors are believed to give rise to the late onset sporadic form of Alzheimer's disease (LOAD). We have studied the variation at the genes of three enzymes of the cholinergic system: acetylcholinesterase, butyrylcholinesterase, and choline acetyltransferase. The single nucleotide polymorphisms (SNPs) examined were: AChE rs2571598, BChE rs1355534, BChE rs1803274, and ChAT rs2177369. The sample for the case-control study was 471 LOAD patients aged 60 years or older, and 254 subjects with no neurodegenerative disorders as the control group. A significant difference in the genotype distribution between patients and controls was observed only for ChAT rs2177369, showing that the G/G genotype was to be considered a risk factor with respect to the G/A + A/A genotypes (odds ratio = 1.56; 95% Confidence Interval = 1.10-2.22; P = 0.01). Though indicating a significant association with AD onset, our results are far from definitive since contrast with the ones reported by other authors in a previous case-control study, and call for further investigations. Among patients, 171 took part in an observational study concerning the possible role of the genetic composition on the efficacy of treatment with Donepezil and Rivastigmine. We related the SNPs of the above cited genes with cognitive status measured by MMSE. Carrying an allele or a genotype of these SNPs does not seem to play a relevant role in the response to treatment with the two cholinesterase inhibitors, though some significant results were found associated with the AChE A/A genotype that had the best response when treated with Rivastigmine. PMID:18780301

Scacchi, Renato; Gambina, Giuseppe; Moretto, Giuseppe; Corbo, Rosa Maria

2009-06-01

91

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. PMID:24294601

Mishra, Nibha; Basu, Arijit

2013-01-01

92

Low Back Ache Treatment with Botulinum Neurotoxin Type A  

Microsoft Academic Search

Objective: To investigate the efficacy, safety and tolerability of paraspinal administration of botulinum neurotoxin type A (BoNT-A) in patients with chronic low back ache (LBA). Subjects and Methods: Eight patients with chronic LBA were injected with BoNT-A at three sites on either side of lumbar paraspinal muscles. The patients rated their pain intensity using a visual analogue scale (VAS) from

Venkatesan Nagarajan; Asmahan Al-Shubaili; Yasser M. Ayad; John Alexander; Khadijah Al-Ramezi

2007-01-01

93

Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors.  

PubMed

A series of benzofuran-based N-benzylpyridinium derivatives 5a-o were designed and synthesized as novel AChE inhibitors. The synthetic pathway of the compounds involved the preparation of 4-(benzofuran-2-yl)pyridine intermediates via the reaction of different salicylaldehyde derivatives and 4-(bromomethyl)pyridine, followed by intramolecular cyclization. Subsequently, the 4-(benzofuran-2-yl)pyridines were N-benzylated by using appropriate benzyl bromide to afford the final product 5a-o. The results of in vitro AChE activity evaluation of synthesized compounds revealed that all compound had potent anti-AChE activity comparable or more potent than standard drug donepezil. The N-(3,5-dimethylbenzyl) derivative 5e with IC50 value of 4.1 nM was the most active compound, being 7-fold more potent than donepezil. PMID:25681712

Baharloo, Farzaneh; Moslemin, Mohammad Hossein; Nadri, Hamid; Asadipour, Ali; Mahdavi, Mohammad; Emami, Saeed; Firoozpour, Loghman; Mohebat, Razieh; Shafiee, Abbas; Foroumadi, Alireza

2015-03-26

94

Real Time Ligand-Induced Motion Mappings of AChBP and nAChR Using X-ray Single Molecule Tracking  

PubMed Central

We observed the dynamic three-dimensional (3D) single molecule behaviour of acetylcholine-binding protein (AChBP) and nicotinic acetylcholine receptor (nAChR) using a single molecule tracking technique, diffracted X-ray tracking (DXT) with atomic scale and 100??s time resolution. We found that the combined tilting and twisting motions of the proteins were enhanced upon acetylcholine (ACh) binding. We present the internal motion maps of AChBP and nAChR in the presence of either ACh or ?-bungarotoxin (?Btx), with views from two rotational axes. Our findings indicate that specific motion patterns represented as biaxial angular motion maps are associated with channel function in real time and on an atomic scale. PMID:25223459

Sekiguchi, Hiroshi; Suzuki, Yasuhito; Nishino, Yuri; Kobayashi, Suzuko; Shimoyama, Yoshiko; Cai, Weiyan; Nagata, Kenji; Okada, Masato; Ichiyanagi, Kouhei; Ohta, Noboru; Yagi, Naoto; Miyazawa, Atsuo; Kubo, Tai; Sasaki, Yuji C.

2014-01-01

95

Naturally Occurring Mutations at the Acetylcholine Receptor Binding Site Independently Alter ACh Binding and Channel Gating  

Microsoft Academic Search

By defining functional defects in a congenital myasthenic syndrome (CMS), we show that two mutant residues, located in a binding site region of the acetylcholine receptor (AChR) epsilon subunit, exert opposite ef- fects on ACh binding and suppress channel gating. Single channel kinetic analysis reveals that the first mutation, ? N182Y, increases ACh affinity for receptors in the resting closed

Steven M. Sine; Xing-Ming Shen; Hai-Long Wang; Kinji Ohno; Won-Yong Lee; Akira Tsujino; Joan Brengmann; Nina Bren; Jiri Vajsar; Andrew G. Engel

2002-01-01

96

Acetylcholinesterase complexes with the natural product inhibitors dihydrotanshinone I and territrem B: binding site assignment from inhibitor competition and validation through crystal structure determination.  

PubMed

Acetylcholinesterase (AChE) is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and organophosphate (OP) chemical warfare agents that cripple the nervous system and cause death through paralysis. We are exploring a strategy to design compounds that bind tightly at or near a peripheral or P-site near the mouth of the AChE active site gorge and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. Here, we review our recent reports on two uncharged, natural product inhibitors of AChE, dihydrotanshinone I and territrem B, that have relatively high affinities for the enzyme. We describe an inhibitor competition assay and comment on the structures of these inhibitors in complex with recombinant human acetylcholinesterase as determined by X-ray crystallography. Our results reveal that dihydrotanshinone I binding is specific to only the P-site, while territrem B binding spans the P-site and extends into the acylation or A-site at the base of the gorge. PMID:24573600

Cheung, Jonah; Beri, Veena; Shiomi, Kazuro; Rosenberry, Terrone L

2014-07-01

97

WblAch, a pivotal activator of natamycin biosynthesis and morphological differentiation in Streptomyces chattanoogensis L10, is positively regulated by AdpAch.  

PubMed

Detailed mechanisms of WhiB-like (Wbl) proteins involved in antibiotic biosynthesis and morphological differentiation are poorly understood. Here, we characterize the role of WblAch, a Streptomyces chattanoogensis L10 protein belonging to this superfamily. Based on DNA microarray data and verified by real-time quantitative PCR (qRT-PCR), the expression of wblAch was shown to be positively regulated by AdpAch. Gel retardation assays and DNase I footprinting experiments showed that AdpAch has specific DNA-binding activity for the promoter region of wblAch. Gene disruption and genetic complementation revealed that WblAch acts in a positive manner to regulate natamycin production. When wblAch was overexpressed in the wild-type strain, the natamycin yield was increased by ?30%. This provides a strategy to generate improved strains for natamycin production. Moreover, transcriptional analysis showed that the expression levels of whi genes (including whiA, whiB, whiH, and whiI) were severely depressed in the ?wblAch mutant, suggesting that WblAch plays a part in morphological differentiation by influencing the expression of the whi genes. PMID:25172865

Yu, Pin; Liu, Shui-Ping; Bu, Qing-Ting; Zhou, Zhen-Xing; Zhu, Zhen-Hong; Huang, Fang-Liang; Li, Yong-Quan

2014-11-01

98

Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons.  

PubMed

The three most common Cys-loop receptors expressed by myenteric neurons are nACh, 5-HT3 and GABAA . To investigate the function of these proteins researchers have used channel inhibitors such as hexamethonium (antagonist of nACh receptors), ondansetron (antagonist of 5-HT3 receptors), picrotoxin and bicuculline (both antagonists of GABAA receptors). The aim of this study was to investigate the specificity of these inhibitors on Cys-loop receptors of primary cultured neurons obtained from the guinea-pig small intestine. The whole-cell configuration of the patch clamp techniques was used to record membrane currents induced by ACh (IACh ), 5-HT (I5-HT ) and GABA (IGABA ) in the absence and the presence of various concentrations of hexamethonium, ondansetron, picrotoxin or bicuculline. The three Cys-loop receptors present in enteric neurons are expressed independently and they do not cross-desensitized. Hexamethonium inhibited IACh without affecting I5-HT and IGABA . Ondansetron inhibited I5-HT and also IACh but did not affect IGABA . Picrotoxin and bicuculline inhibited I5-HT , IACh and IGABA with different potency, being the lowest potency on 5-HT3 receptors. All these inhibitory effects were concentration dependent and reversible. Our observations showed that except for hexamethonium, all other inhibitors used here show different degrees of selectivity, which has to be considered when these antagonists are used in experimental studies aimed to investigate the functions of these receptors. In particular, in tissues expressing nACh receptors because these are the targets of all other inhibitors used here. The low potency of picrotoxin and bicuculline to inhibit 5-HT3 receptors suggests that these receptors are heteromeric proteins. PMID:24151989

Juárez, E H; Ochoa-Cortés, F; Miranda-Morales, M; Espinosa-Luna, R; Montaño, L M; Barajas-López, C

2014-01-01

99

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

100

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. PMID:24893223

Pohanka, Miroslav

2014-01-01

101

Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease  

PubMed Central

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection. PMID:23307081

2013-01-01

102

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

103

[Design, synthesis and activity of N-acyl-thiochromenothiazol-2-amine as acetylcholinesterase inhibitors].  

PubMed

A series of novel N-acyl-thiochromenothiazol-2-amine derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase was investigated. N-Acyl-thiochromenothiazol-2-amines were prepared from thiophenol by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 10a was the best in them. The IC50 of 10a to AChE is 7.92 ?mol x L(-1), and the value is better than that of rivastigmine. N-Acyl-thiochromenothiazol-2-amine derivatives showed a certain bioactivity in vitro, which were worth further investigation. PMID:25518328

Ma, Zheng-Yue; Zhang, Yuan-Gong; Yang, Qi; Li, Jun-Jie; Yang, Geng-Liang

2014-09-01

104

Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases  

PubMed Central

We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (kinact/KI) of 3,604–458,597?M?1sec?1 but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with kinact/KI values of 1,915 and 1,507?M?1sec?1, respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases. PMID:23323211

Dou, Dengfeng; Park, Jewn Giew; Rana, Sandeep; Madden, Benjamin J.; Jiang, Haobo; Pang, Yuan-Ping

2013-01-01

105

Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases  

NASA Astrophysics Data System (ADS)

We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (kinact/KI) of 3,604-458,597 M-1sec-1 but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with kinact/KI values of 1,915 and 1,507 M-1sec-1, respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.

Dou, Dengfeng; Park, Jewn Giew; Rana, Sandeep; Madden, Benjamin J.; Jiang, Haobo; Pang, Yuan-Ping

2013-01-01

106

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.

107

Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.  

PubMed

T-superfamily conotoxins have a typical cysteine pattern of "CC-CC", and are known to mainly target calcium or sodium ion channels. Recently, we screened the targets of a series of T-superfamily conotoxins and found that a new T-superfamily conotoxin TxVC (KPCCSIHDNSCCGL-NH2) from the venom of Conus textile. It selectively targeted the neuronal nicotinic acetylcholine receptor (nAChR) subtypes ?4?2 and ?3?2, with IC50 values of 343.4 and 1047.2nM, respectively, but did not exhibit obvious pharmacological effects on voltage-gated potassium, sodium or calcium channel in DRG cells, the BK channels expressed in HEK293 cells, or the Kv channels in L?T2 cells. The changes in the inhibitory activities of its Ala mutants, the NMR structure, and molecular simulation results based on other conotoxins targeting nAChR ?4?2, all demonstrated that the residues Ile(6) and Leu(14) were the main hydrophobic pharmacophores. To our best knowledge, this is the first T-superfamily conotoxin that inhibits neuronal nAChRs and possesses high binding affinity to ?4?2. This finding will expand the knowledge of the targets of T-superfamily conotoxins and the motif information could help the design of new nAChR inhibitors. PMID:25450372

Wang, Shuo; Du, Tianpeng; Liu, Zhuguo; Wang, Sheng; Wu, Ying; Ding, Jiuping; Jiang, Ling; Dai, Qiuyun

2014-11-01

108

Pretreatment for acute exposure to diisopropylfluorophosphate: in vivo efficacy of various acetylcholinesterase inhibitors.  

PubMed

Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors before exposure to organophosphorus compounds (OPCs) can reduce OPC-induced mortality. Pyridostigmine is the only FDA-approved substance for such use. The AChE-inhibitory activity of known AChE inhibitors was quantified in vitro and their in vivo mortality-reducing efficacy was compared, when given prophylactically before the exposure to the OPC diisopropylfluorophosphate (DFP). The IC50 was measured in vitro for the known AChE inhibitors pyridostigmine, physostigmine, ranitidine, tiapride, tacrine, 7-methoxytacrine, amiloride, metoclopramide, methylene blue and the experimental oxime K-27. Their in vivo efficacy, when given as pretreatment, to protect rats from DFP-induced mortality was quantified by determining the relative risk of death (RR) by Cox analysis, with RR = 1 for animals given only DFP, but no pretreatment. Physostigmine was the strongest in vitro AChE-inhibitor (IC50 = 0.012 µ m), followed by 7-methoxytacrine, tacrine, pyridostigmine and methylene blue. Ranitidine (IC50 = 2.5 µ m), metoclopramide and amiloride were in the mid-range. Tiapride (IC50 = 256 µ m) and K-27 (IC50 = 414 µ m) only weakly inhibited RBC AChE activity. Best in vivo protection from DFP-induced mortality was achieved when physostigmine (RR = 0.02) or tacrine (RR = 0.05) was given before DFP exposure, which was significantly superior to the pretreatment with all other tested compounds, except K-27 (RR = 0.18). The mortality-reducing effect of pyridostigmine, ranitidine and 7-methoxytacrine was inferior, but still significant. Tiapride, methylene blue, metoclopramide and amiloride did not significantly improve DFP-induced mortality. K-27 may be a more efficacious alternative to pyridostigmine, when passage into the brain precludes administration of physostigmine or tacrine. PMID:20981864

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

2011-08-01

109

The ?7 nAChR selective agonists as drug candidates for Alzheimer's disease.  

PubMed

The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the ?7 nAChR is one of the most abundant subtypes in the brain. The ?7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the A? amyloid. A? amyloid is co-localized with ?7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the ?7 nAChR expression. Treatment with ?7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the ?7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the ?7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab. PMID:25387975

Fan, Huaimeng; Gu, Ruoxu; Wei, Dongqing

2015-01-01

110

Insect-specific irreversible inhibitors of acetylcholinesterase in pests including the bed bug, the eastern yellowjacket, German and American cockroaches, and the confused flour beetle.  

PubMed

Insecticides directed against acetylcholinesterase (AChE) are facing increased resistance among target species as well as increasing concerns for human toxicity. The result has been a resurgence of disease vectors, insects destructive to agriculture, and residential pests. We previously reported a free cysteine (Cys) residue at the entrance to the AChE active site in some insects but not higher vertebrates. We also reported Cys-targeting methanethiosulfonate molecules (AMTSn), which, under conditions that spared human AChE, caused total irreversible inhibition of aphid AChE, 95% inhibition of AChE from the malaria vector mosquito (Anopheles gambia), and >80% inhibition of activity from the yellow fever mosquito (Aedes aegypti) and northern house mosquito (Culex pipiens). We now find the same compounds inhibit AChE from cockroaches (Blattella germanica and Periplaneta americana), the flour beetle (Tribolium confusum), the multi-colored Asian ladybird beetle (Harmonia axyridis), the bed bug (Cimex lectularius), and a wasp (Vespula maculifrons), with IC(50) values of approximately 1-11muM. Our results support further study of Cys-targeting inhibitors as conceptually novel insecticides that may be free of resistance in a range of insect pests and disease vectors and, compared with current compounds, should demonstrate much lower toxicity to mammals, birds, and fish. PMID:20109441

Polsinelli, Gregory A; Singh, Sanjay K; Mishra, Rajesh K; Suranyi, Robert; Ragsdale, David W; Pang, Yuan-Ping; Brimijoin, Stephen

2010-09-01

111

A study of the suitability of amorphous, hydrogenated carbon (aC:H) for photovoltaic devices  

Microsoft Academic Search

Amorphous, hydrogenated carbon (a-C:H) is a prospective material for photovoltaic energy conversion because its electronic bandgap can be varied over an unusually wide range (0.4-4.1 eV). Therefore, the suitability of a-C:H for photovoltaic devices has been investigated. Two vacuum deposition techniques, electric arc evaporation and DC magnetron sputtering, were used to deposit a-C:H films. These films were analyzed with respect

Michael Maldei

1997-01-01

112

Liquid-crystal alignment on aC:H films by nitrogen plasma beam scanning  

Microsoft Academic Search

A plasma beam scanning treatment has been developed to modify the surface of the hydrogenated amorphous carbon (a-C:H) film on the indium tin oxide glass. The plasma beam scanning treatment makes the a-C:H film an excellent layer for liquid-crystal alignment. The qualities of a-C:H films were characterized by using atomic force microscope, micro-Raman spectroscopy, and field-emission scanning electron microscope. The

K. Y. Wu; C.-H. Chen; C.-M. Yeh; J. Hwang; P.-C. Liu; C.-Y. Lee; C.-W. Chen; H. K. Wei; C. S. Kou; C.-D. Lee

2005-01-01

113

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. PMID:24260568

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

2013-01-01

114

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

PubMed

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

115

Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors.  

PubMed

The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168 nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment. PMID:23200223

Xie, Ruliang; Zhao, Qianfei; Zhang, Tao; Fang, Jing; Mei, Xiangdong; Ning, Jun; Tang, Yun

2013-01-01

116

Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques.  

PubMed

Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the ?-amyloid (A?) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 ?M) and Spec2 (IC(50)=5.986 ?M) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity. PMID:21273074

Gupta, Shikhar; Fallarero, Adyary; Järvinen, Päivi; Karlsson, Daniela; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

2011-02-15

117

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors  

PubMed Central

Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies. PMID:19578388

Shi, Yu-fang; Zhang, Hai-yan; Wang, Wei; Fu, Yan; Xia, Yu; Tang, Xi-can; Bai, Dong-lu; He, Xu-chang

2009-01-01

118

Additive Effects of Numbness and Muscle Aches on Fatigue Occurrence in Individuals with HIV/AIDS Who are Taking Antiretroviral Medications  

PubMed Central

Context Muscle aches, numbness in the feet/toes (neuropathy), and fatigue are often reported concurrently and are among the symptoms most frequently reported by individuals with HIV/AIDS, whether or not they are taking antiretroviral medications (ARVs). Objectives This study used a longitudinal analytical methodology to analyze these symptoms together to determine whether symptom clusters are maintained over time and to determine whether there is a temporal relationship between fatigue and reports of neuropathic pain and muscle aches. Methods This was a secondary analysis of a subset of data from a six-month, longitudinal, randomized, controlled trial of 243 HIV-positive individuals taking ARVs. Self-reported symptom frequency and intensity were recorded using the Revised Sign and Symptom Checklist for Persons with HIV Disease at baseline (month 0), one month, three months, and six months. Multilevel, logistic regression models were used to analyze time-lagged effects of muscle aches, numbness of the feet/toes, and fatigue to estimate any predictive and interactive effects that the symptoms have upon one another. Results A significant relationship between muscle aches and fatigue intercepts was noted (odds ratio [OR] =1.80, P ? 0.05). Significant relationships between numbness and fatigue were also noted for the entire measurement period (OR=2.70, P ? 0.05). Time-lagged models showed persons reporting neuropathic-related numbness in one period were nearly twice as likely to report fatigue in subsequent periods (OR=1.89, P ? 0.05). The final model revealed that the addition of muscle aches and numbness explained 28% of the random variance in the occurrence of fatigue. Between-person descriptive variables including years living with HIV, age, having an AIDS diagnosis, ethnicity, and nucleoside reverse transcriptase inhibitor (NRTI) treatment regimens with stavudine, zalactabine, or didanosine did not significantly explain any additional model variation. Conclusion These findings are consistent with physiological research and provide evidence that analyzing multiple symptom change over time can provide a more accurate representation of an individual’s symptom experience. When evaluating patients with muscle aches or numbness, particularly when both symptoms are present, an evaluation of fatigue should be considered. Similarly, if fatigue is reported, underlying physiological assessments for neuropathic symptoms and muscle aches may be considered. PMID:21232913

Wantland, Dean J.; Mullan, Joseph P.; Holzemer, William L.; Portillo, Carmen J.; McGhee, Eva M.

2011-01-01

119

Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties  

PubMed Central

Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits. PMID:18541221

Hornick, Ariane; Schwaiger, Stefan; Rollinger, Judith M.; Vo, Nguyen Phung; Prast, Helmut; Stuppner, Hermann

2012-01-01

120

Evidence for a role for ?6(?) nAChRs in l-dopa-induced dyskinesias using parkinsonian ?6(?) nAChR gain-of-function mice.  

PubMed

l-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of ?6?2(?) nAChRs in LIDs, we used gain-of-function ?6(?) nAChR (?6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and ?6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3?g/ml) into the medial forebrain bundle. Three to 4wk later, they were administered l-dopa (3mg/kg) plus benserazide (15mg/kg) until stably dyskinetic. l-dopa-induced abnormal involuntary movements (AIMs) were similar in ?6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300?g/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in ?6L9S mice at a maximally tolerated nicotine dose of 20?g/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min before l-dopa) reduced l-dopa-induced AIMs in both ?6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in ?6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive ?6?2(?) nAChRs may desensitize less readily. The present data show that ?6?2(?) nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. PMID:25813704

Bordia, T; McGregor, M; McIntosh, J M; Drenan, R M; Quik, M

2015-06-01

121

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

122

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

PubMed

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 (5-14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity. PMID:20926161

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

2010-12-01

123

Differential regulation of neuronal nicotinic ACh receptor subunit genes in cultured neonatal rat sympathetic neurons: specific induction of alpha 7 by membrane depolarization through a Ca2+/calmodulin-dependent kinase pathway.  

PubMed

We have examined the regulation of neuronal nicotinic ACh receptor (nAChR) genes and ACh-evoked currents by neonatal rat sympathetic neurons developing in culture. These neurons contain 5 nAChR transcripts: alpha 3, alpha 5, alpha 7, beta 2, and beta 4. When developing in culture, the neurons express 4 of these transcripts, alpha 3, alpha 5, beta 2, and beta 4, at levels similar to those in neurons developing in vivo: alpha 3 mRNA levels increase two- to threefold over the first week, whereas the levels for alpha 5, beta 2, and beta 4 remain essentially constant. In contrast, alpha 7 mRNA levels drop by 60-75% within the first 48 hr and remain low. We show that during the first week, the ACh-evoked current densities on these cultured neurons increase twofold and correlate well with the increase in alpha 3 mRNA levels. Depolarizing the neurons with 40 mM KCl for 1-2 d upregulates the alpha 7 gene; this specific change in alpha 7 mRNA level correlates with an increase in alpha-bungarotoxin (alpha-BTX) binding on the surface of the neurons. Depolarization has little effect on the expression of the other four transcripts, or on the magnitude or kinetics of the ACh-evoked currents. Furthermore, activators or inhibitors of protein kinase A (PKA), protein kinase C (PKC), or tyrosine kinase do not affect nAChR transcript levels in these cultured neurons. The effect of membrane depolarization on alpha 7 expression is a result of Ca2+ influx through L-type Ca2+ channels, and we show that alpha 7 is upregulated through a Ca2+/calmodulin-dependent protein kinase (CaM kinase) pathway. The identification of CaM kinase as a link between activity and neurotransmitter receptor expression may indicate a novel mechanism that underlies some forms of synaptic plasticity. PMID:8613734

De Koninck, P; Cooper, E

1995-12-01

124

Lithium Inhibits a Late Step in Agrin-Induced AChR Aggregation  

E-print Network

Lithium Inhibits a Late Step in Agrin-Induced AChR Aggregation S. K. Sharma,* B. G. Wallace 1. Here we report that treating chick myotubes with lithium prevented any detectable agrin-induced change phosphorylation and detergent extractabil- ity. Lithium treatment also increased the rate at which AChR aggregates

Sharma, Shiv K.

125

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

126

Two Distinct Channels Mediated by m2mAChR and ?9nAChR Co-Exist in Type II Vestibular Hair Cells of Guinea Pig  

PubMed Central

Acetylcholine (ACh) is the principal vestibular efferent neurotransmitter among mammalians. Pharmacologic studies prove that ACh activates a small conductance Ca2+-activated K+ channels (KCa) current (SK2), mediated by ?9-containing nicotinic ACh receptor (?9nAChR) in mammalian type II vestibular hair cells (VHCs II). However, our studies demonstrate that the m2 muscarinic ACh receptor (m2mAChR) mediates a big conductance KCa current (BK) in VHCs II. To better elucidate the correlation between these two distinct channels in VHCs II of guinea pig, this study was designed to verify whether these two channels and their corresponding AChR subtypes co-exist in the same VHCs II by whole-cell patch clamp recordings. We found that m2mAChR sensitive BK currents were activated in VHCs II isolated by collagenase IA, while ?9nAChR sensitive SK2 currents were activated in VHCs II isolated by trypsin. Interestingly, after exposing the patched cells isolated by trypsin to collagenase IA for 3 min, the ?9nAChR sensitive SK2 current was abolished, while m2mAChR-sensitive BK current was activated. Therefore, our findings provide evidence that the two distinct channels and their corresponding AChR subtypes may co-exist in the same VHCs II, and the alternative presence of these two ACh receptors-sensitive currents depended on isolating preparation with different enzymes. PMID:23615472

Zhou, Tao; Wang, Yi; Guo, Chang-Kai; Zhang, Wen-Juan; Yu, Hong; Zhang, Kun; Kong, Wei-Jia

2013-01-01

127

Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors.  

PubMed

A series of 4-hydroxycoumarin derivatives were designed and synthesized as new acetylcholinesterase (AChE) inhibitors which could be considered for Alzheimer's disease therapeutics. Among the 19 coumarin-derived compounds tested toward Electrophorus electricus acetylcholinesterase (eelAChE) and horse serum butyrylcholinesterase (eqBChE), N-(1-benzylpiperidin-4-yl)acetamide derivative 4m displayed highest AChE inhibitory activity (IC50 = 1.2 ?M) and good selectivity (37 times). The docking study of the most potent compound 4m, indicated that Phe330 is responsible for ligand recognition and trafficking by forming ?-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional ?-? interaction between coumarin moiety and Trp279 of peripheral anionic site could stabilize the ligand in the active site resulting in more potent inhibition of the enzyme. PMID:23644208

Razavi, Seyyede Faeze; Khoobi, Mehdi; Nadri, Hamid; Sakhteman, Amirhossein; Moradi, Alireza; Emami, Saeed; Foroumadi, Alireza; Shafiee, Abbas

2013-06-01

128

Quaternary Glaciers of New Zealand  

Microsoft Academic Search

Located in the southwestern Pacific Ocean, New Zealand's record of Quaternary glaciations, preserved in landforms and near-surface deposits, begins at the margins of modern glaciers and extends outwards geographically and backwards in time, to the last glaciation and beyond. The record becomes increasingly fragmentary into the Middle and Early Pleistocene.

D. J. A. Barrell

2011-01-01

129

Quaternary uplift of southern Italy  

Microsoft Academic Search

Dramatic coastline changes demonstrate rapid Quaternary uplift of Calabria in southern Italy. Because most of the west (Tyrrhenian Sea) coast is normal fault bounded, previous work has asserted that its uplift is local footwall uplift related to extension. However, the east (Ionian Sea) coast is also uplifting but is not normal fault bounded. This reanalysis, based on original field work

Rob Westaway

1993-01-01

130

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. PMID:19218367

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

2009-01-01

131

Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase.  

PubMed

A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease. PMID:8064800

Villalobos, A; Blake, J F; Biggers, C K; Butler, T W; Chapin, D S; Chen, Y L; Ives, J L; Jones, S B; Liston, D R; Nagel, A A

1994-08-19

132

3'-R/S-hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata.  

PubMed

Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory. The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1)H and (13)C NMR spectra is reported. The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7.00±1.99 ?M. An HPLC method was developed for the quantitative analysis of the AChE inhibitor. It suggested that there was 12.4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem. PMID:23375813

Chaiyana, Wantida; Schripsema, Jan; Ingkaninan, Kornkanok; Okonogi, Siriporn

2013-04-15

133

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

134

Local anaesthetic blockade of neuronal nicotinic ACh receptor-channels in rat parasympathetic ganglion cells.  

PubMed Central

1 The effects of the local anaesthetics QX-222 and procaine on nicotinic acetylcholine (ACh)-evoked currents in cultured parasympathetic cardiac neurones of the rat were investigated by use of the whole-cell, perforated-patch, and outside-out recording configurations of the patch clamp method. 2 QX-222 and procaine, applied to the extracellular surface, reversibly inhibited the peak amplitude of the whole-cell nicotinic ACh-evoked current in a concentration-dependent manner, with half-maximal inhibitory concentrations (IC50) of 28 microM and 2.8 microM, respectively, at -80 mV. In these neurones, the sustained inward current mediated by M1 muscarinic receptor activation was unaltered by QX-222, and neither local anaesthetic affected the adenosine 5'-triphosphate (ATP)-evoked current. 3 QX-222 and procaine block of nicotinic ACh-evoked inward current was voltage-dependent and enhanced by hyperpolarization. An e-fold change in their dissociation equilibrium constants (Kd) resulted from a 62 mV and a 122 mV change in membrane potential, respectively. 4 Both local anaesthetics produce a concentration-dependent increase in the half-time of decay of the nicotinic ACh-evoked inward current. 5 Measurements of unitary currents in outside-out patches showed that QX-222 reversibly increased the mean burst duration and closed time and reduced the mean channel open time and open-state probability of the nicotinic ACh receptor-channel (AChR) in a concentration-dependent manner. 6 The Kd and voltage sensitivity of local anaesthetic block of the nicotinic AChR in rat intracardiac neurones suggests that the pore-forming region of this channel differs from that of the AChR in frog and rat skeletal muscle and from the neuronal alpha 4 beta 2 ACh receptor-channel. PMID:7517326

Cuevas, J.; Adams, D. J.

1994-01-01

135

Anti-amnesic effect of neurosteroid PREGS in A?25-35-injected mice through ?1 receptor- and ?7nAChR-mediated neuroprotection.  

PubMed

A single intracerebroventricular injection of ?-amyloid 25-35 peptide (A?(25-35)) (9 nmol/mouse) induces the spatial cognitive deterioration and approximately 50% loss of pyramidal cells in hippocampal CA1 region within 1 week. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (?(1)R) and ?7 nicotinic acetylcholine receptor (?7nAChR), on the cognitive deficits and the death of pyramidal cells in A?(25-35)-mice. Herein, we reported that the administration of PREGS (1-100 mg/kg) for 7 days after A?(25-35)-injection could dose-dependently ameliorate the cognitive deficits and attenuate the apoptosis of pyramidal cells. Either the ?(1)R antagonist NE100 or the ?7nAChR antagonist MLA could block the neuroprotection of PREGS in A?(25-35)-mice. Both the ?(1)R agonist PRE084 and the ?7nAChR agonist DMXB could mimic the PREGS-neuroprotection against the A?(25-35)-neurotoxicity. The neuroprotection of PRE084 was attenuated by MLA, but the DMXB-action was insensitive to NE100. The neuroprotection of PREGS, PRE084 or DMXB was blocked by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, whereas only the effect of PREGS or PRE084 was sensitive to the MAPK/ERK kinase (MEK) inhibitor U0126. PREGS prevented A?(25-35)-inhibited Akt (Serine/threonine kinase) phosphorylation leading to increase in caspase-3 activity, which was ?(1)R- and ?7nAChR-dependent. By contrast, PREGS-rescued reduction of extracellular signal-related kinase-2 (ERK2) phosphorylation in A?(25-35)-mice only required the activation of ?(1)R. Blockage of PREGS-neuroprotection by LY294002 significantly attenuated its anti-amnesic effect in A?(25-35)-mice. The findings indicate that the anti-amnesic effects of PREGS in A?(25-35)-mice depend on the ?(1)R- and ?7nAChR-mediated neuroprotection. PMID:22884465

Yang, Rong; Chen, Lei; Wang, Haofei; Xu, Bingzhong; Tomimoto, Hidekazu; Chen, Ling

2012-11-01

136

[(125)I]Iodo-ASEM, a specific in vivo radioligand for ?7-nAChR.  

PubMed

[(125)I]Iodo-ASEM, a new radioligand with high affinity and selectivity for ?7-nAChRs (Ki=0.5nM; ?7/?4?2=3414), has been synthesized in radiochemical yield of 33±6% from the corresponding di-butyltriazene derivative and at high specific radioactivity (1600Ci/mmol; 59.2MBq/?mol). [(125)I]Iodo-ASEM readily entered the brains of normal CD-1 mice and specifically and selectively labeled cerebral ?7-nAChRs. [(125)I]iodo-ASEM is a new useful tool for studying ?7-nAChR. PMID:25687449

Gao, Yongjun; Mease, Ronnie C; Olson, Thao T; Kellar, Kenneth J; Dannals, Robert F; Pomper, Martin G; Horti, Andrew G

2015-05-01

137

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

138

Design, synthesis, and structure-activity relationships of a series of 3-[2-(1-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors.  

PubMed

Starting from the 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine 1, we performed the design, the synthesis, and the structure-activity relationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound 1 and led to the following observations: (i) introduction of a lipophilic environment in the C-5 position of the pyridazine ring is favorable for the AChE-inhibitory activity and the AChE/BuChE selectivity; (ii) substitution and various replacements of the C-6 phenyl group are possible and led to equivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the activity. Among all derivatives prepared, the indenopyridazine derivative 4g was found to be the more potent inhibitor with an IC(50) of 10 nM on electric eel AChE. Compared to compound 1, this represents a 12-fold increase in potency. Moreover, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-5-methyl-6-phenylpyridazine 4c, which showed an IC(50) of 21 nM, is 100-times more selective for human AChE (human BuChE/AChE ratio of 24) than the reference compound tacrine. PMID:11495583

Contreras, J M; Parrot, I; Sippl, W; Rival, Y M; Wermuth, C G

2001-08-16

139

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

140

Sequence polymorphism in acetylcholinesterase transcripts and genotyping survey of BmAChE1 in laboratory and Mexican strains of Rhipicephalus (Boophilus) microplus  

Technology Transfer Automated Retrieval System (TEKTRAN)

BmAChE1, BmAChE2, and BmAChE3 cDNAs of Rhipicephalus (Boophilus) microplus were sequenced and found to exhibit significant polymorphism. A portion of the predicted amino acid substitutions in BmAChE1, BmAChE2 and BmAChE3 were found predominantly in organophosphate-resistant (OP-R) strains, but most ...

141

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

142

Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl.  

PubMed

Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01 ) 30?min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR?=?1). The most efficacious prophylactic agents were K-27 (RR?=?0.15) and physostigmine (RR?=?0.21), being significantly more efficacious than ranitidine (RR?=?0.62) and pyridostigmine (RR?=?0.37). Pre-treatment with tacrine (RR?=?0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25186309

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

2015-05-01

143

ach year across the US, mesoscale weather events--flash floods, tornadoes, hail,  

E-print Network

E ach year across the US, mesoscale weather events--flash floods, tornadoes, hail, strong winds, lightning, and localized winter storms--cause hundreds of deaths, routinely disrupt transportation and com

Plale, Beth

144

Design, synthesis, and biological evaluation of coumarin derivatives tethered to an edrophonium-like fragment as highly potent and selective dual binding site acetylcholinesterase inhibitors.  

PubMed

A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC(50)=0.236 nM) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N-trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of pi-pi stacking interactions in the AChE peripheral binding site. PMID:20677317

Pisani, Leonardo; Catto, Marco; Giangreco, Ilenia; Leonetti, Francesco; Nicolotti, Orazio; Stefanachi, Angela; Cellamare, Saverio; Carotti, Angelo

2010-09-01

145

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae.  

PubMed

To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification. PMID:25684426

Verma, Astha; Wong, Dawn M; Islam, Rafique; Tong, Fan; Ghavami, Maryam; Mutunga, James M; Slebodnick, Carla; Li, Jianyong; Viayna, Elisabet; Lam, Polo C-H; Totrov, Maxim M; Bloomquist, Jeffrey R; Carlier, Paul R

2015-03-15

146

21 CFR 172.165 - Quaternary ammonium chloride combination.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 true Quaternary ammonium chloride combination. 172.165 ...Preservatives § 172.165 Quaternary ammonium chloride combination. The food additive, quaternary ammonium chloride combination, may be...

2010-04-01

147

40 CFR 721.10511 - Quaternary ammonium salts (generic).  

Code of Federal Regulations, 2014 CFR

...2014-07-01 false Quaternary ammonium salts (generic). 721.10511 Section 721...Substances § 721.10511 Quaternary ammonium salts (generic). (a) Chemical substance...identified generically as quaternary ammonium salts (PMNs P-07-320,...

2014-07-01

148

Both endogenous and exogenous ACh plays antinociceptive role in the hippocampus CA1 of rats.  

PubMed

The present study examines the effect of acetylcholine (ACh), muscarinic acetylcholine receptors (mAChRs) agonist pilocarpine and mAChRs antagonist atropine on the pain-evoked response of pain-excited neurons (PEN) and pain-inhibited neurons (PIN) in the hippocampal CA1 of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The discharges of PEN and PIN in the hippocampal CA1 were recorded by glass microelectrode. The results showed that intrahippocampal microinjection of ACh (2 microg/1 microl) or pilocarpine (2 microg/1 microl) decreased the frequency of discharge of PEN, and increased the frequency of discharge of PIN evoked by the noxious stimulation in the hippocampal CA1, while intrahippocampal administration of atropine (0.5 microg/1 microl) produced opposite response. On the basis of the above findings, we can deduce that ACh and mAChRs are involved in the modulation of nociceptive information transmission in the hippocampal CA1. PMID:17851635

Yang, X F; Xiao, Y; Xu, M-Y

2008-01-01

149

Donepezil: an anticholinesterase inhibitor for Alzheimer's disease.  

PubMed

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of donepezil are reviewed. Donepezil is a synthetic noncovalent reversible inhibitor of acetylcholinesterase (AChE) for the treatment of mild to moderate dementia associated with Alzheimer's disease. In contrast to tacrine hydrochloride, the only comparable agent currently approved by FDA, donepezil exhibits a relatively high degree of selectivity for neuronal AChE as opposed to butyrylcholinesterase. It has a half-life of 60 hours in young adults and 104 hours in elderly patients. In clinical trials, donepezil has been associated with significant improvements in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Interview-Based Impression of Change scores. The most common adverse effects associated with donepezil are nausea, diarrhea, anorexia, and vomiting, which are most likely to occur during dose initiation or adjustment. Hepatotoxicity, a dose-limiting adverse effect that sometimes requires discontinuation of tacrine, has not been reported with donepezil. Donepezil does not appear to interact with theophylline, cimetidine, warfarin, or digoxin. Ketoconazole and quinidine inhibit the metabolism of donepezil in vitro, but there is a lack of clinical data showing that these drugs decrease the clearance of donepezil. The initial recommended dosage is 5 mg daily before bedtime, with a dosage increase to 10 mg after four to six weeks according to the patient's response and tolerance. Donepezil appears to be preferable to tacrine as the initial agent for patients with mild to moderate dementia associated with Alzheimer's disease. PMID:9428950

Shintani, E Y; Uchida, K M

1997-12-15

150

Immigrant background and medicine use for aches: national representative study of adolescents  

PubMed Central

Objectives The aims of the study were to examine the association between immigrant background and medicine use for headache and stomach-ache among adolescents, and whether symptoms of headache and stomach-ache could explain the differences in medicine use. Methods We used data from the Danish contribution to the WHO-affiliated international cross-sectional survey Health Behaviour in School-aged Children (HBSC) in 2006. Among boys, a total of 4170 ethnic Danes, 244 descendants of immigrants, and 224 immigrants participated. Among girls, 4310 ethnic Danes, 264 descendants of immigrants, and 232 immigrants were included. The associations between migrant background and medicine use for headache and stomach-ache by means of multilevel multivariate logistic regression analyses adjusted for age group, symptoms and the clustering effect of school and stratified by sex due to interactions. Results Among boys, the risk of medicine use for stomach-ache was higher for immigrants (odds ratio (OR), 1.54; 95% confidence intervals (CI), 0.99-2.44)) and descendants (OR, 1.97 (1.33-2.94)) compared to ethnic Danes. Similar associations were found for use of medicine for stomach-ache for immigrant girls (OR, 1.55 (1.12-2.15) and use of medicine for headache among boys (immigrants (OR, 1.36 (1.02-1.97 and descendants (1.48 (1.12-1.97)). Symptoms of aches were all independently associated with medicine use. After adjusting for these factors the association between immigrant background and medicine use attenuated slightly. Conclusion Among adolescents in Denmark, the risk of medicine use for headache and stomach-ache was higher for immigrants and descendants as compared to ethnic Danes, with the exception of medicine use for headache among girls.

2014-01-01

151

Congo red modulates ACh-induced Ca2+ oscillations in single pancreatic acinar cells of mice  

PubMed Central

Aim: Congo red, a secondary diazo dye, is usually used as an indicator for the presence of amyloid fibrils. Recent studies show that congo red exerts neuroprotective effects in a variety of models of neurodegenerative diseases. However, its pharmacological profile remains unknown. In this study, we investigated the effects of congo red on ACh-induced Ca2+ oscillations in mouse pancreatic acinar cells in vitro. Methods: Acutely dissociated pancreatic acinar cells of mice were prepared. A U-tube drug application system was used to deliver drugs into the bath. Intracellular Ca2+ oscillations were monitored by whole-cell recording of Ca2+-activated Cl? currents and by using confocal Ca2+ imaging. For intracellular drug application, the drug was added in pipette solution and diffused into cell after the whole-cell configuration was established. Results: Bath application of ACh (10 nmol/L) induced typical Ca2+ oscillations in dissociated pancreatic acinar cells. Addition of congo red (1, 10, 100 ?mol/L) dose-dependently enhanced Ach-induced Ca2+ oscillations, but congo red alone did not induce any detectable response. Furthermore, this enhancement depended on the concentrations of ACh: congo red markedly enhanced the Ca2+ oscillations induced by ACh (10–30 nmol/L), but did not alter the Ca2+ oscillations induced by ACh (100–10000 nmol/L). Congo red also enhanced the Ca2+ oscillations induced by bath application of IP3 (30 ?mol/L). Intracellular application of congo red failed to alter ACh-induced Ca2+ oscillations. Conclusion: Congo red significantly modulates intracellular Ca2+ signaling in pancreatic acinar cells, and this pharmacological effect should be fully considered when developing congo red as a novel therapeutic drug. PMID:25345744

Huang, Ze-bing; Wang, Hai-yan; Sun, Na-na; Wang, Jing-ke; Zhao, Meng-qin; Shen, Jian-xin; Gao, Ming; Hammer, Ronald P; Fan, Xue-gong; Wu, Jie

2014-01-01

152

Stereoselective Synthesis of Quaternary Proline Analogues  

PubMed Central

This review describes available methods for the diastereoselective and asymmetric synthesis of quaternary prolines. The focus is on the preparation of ?-functionalized prolines with the pyrrolidine moiety not embedded in a polycyclic frame. The diverse synthetic approaches are classified according to the bond which is formed to complete the quaternary skeleton. PMID:19655047

Calaza, M. Isabel

2009-01-01

153

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. PMID:23638015

Kuryatov, Alexander; Mukherjee, Jayanta; Lindstrom, Jon

2013-01-01

154

Axonal regeneration in early stages of sciatic nerve crush injury is enhanced by ?7nAChR in rats.  

PubMed

This study investigated the role of alpha 7 nicotinic acetylcholine receptor (?7nAChR) in axonal regeneration after crush injury to the rat sciatic nerve. The time course of ?7nAChR expression following injury was assessed by immunohistochemistry and western blotting, and local inflammation, as indicated by the expression of tumor necrosis factor (TNF)-?, was detected by enzyme-linked immunosorbent assay. Axonal regeneration was evaluated by the pinch-test, morphometric analysis, and by measuring growth-associated protein 43 expressions. Local ?7nAChR expression increased on day 1, peaked on day 3, and remained elevated on day 5 following nerve injuries. Prominent ?7nAChR immunoreactivity was observed in Schwann cells, endothelial cells of the capillaries, and a small number of inflammatory cells. Application of the selective ?7nAChR agonist PNU-282987 decreased TNF-? level and enhanced axonal regeneration, but this effect was blocked by concomitant treatment with methyllycaconitine, a ?7nAChR antagonist. The results indicate that the local expression of ?7nAChR is increased during the early stages of sciatic nerve injury, and application of a ?7nAChR agonist promotes axonal regeneration by suppression of TNF-?-mediated inflammation. The ?7nAChR can act as a neuroprotective agent and ?7nAChR activation may be a useful therapeutic strategy to treat peripheral nerve injury. PMID:25370336

Wang, Dewei; Wang, Xuming; Geng, Shuo; Bi, Zhenggang

2015-03-01

155

Design, Synthesis and Structure-Activity Relationship (SAR) Studies of 2,4-Disubstituted Pyrimidine Derivatives: Dual Activity as Cholinesterase and A?-Aggregation Inhibitors  

PubMed Central

A novel class of 2,4-disubstituted pyrimidines (7a–u, 8a–f, 9a–e) that possess substituents with varying steric and electronic properties at the C-2 and C-4 positions, were designed, synthesized and evaluated as dual cholinesterase and amyloid-? (A?)-aggregation inhibitors. In vitro screening identified N-(naphth-1-ylmethyl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (9a) as the most potent AChE inhibitor (IC50 = 5.5 ?M). Among this class of compounds, 2-(4-methylpiperidin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine (9e) was identified as the most potent and selective BuChE inhibitor (IC50 = 2.2 ?M, Selectivity Index = 11.7) and was about 5.7-fold more potent compared to the commercial, approved reference drug galanthamine (BuChE IC50 = 12.6 ?M). In addition, the selective AChE inhibitor N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (7d), exhibited good inhibition of hAChE-induced aggregation of A?1–40 fibrils (59% inhibition). Furthermore, molecular modeling studies indicate that a central pyrimidine ring serves as a suitable template to develop dual inhibitors of cholinesterase and AChE-induced A? aggregation thereby targeting multiple pathological routes in AD. PMID:21429752

Mohamed, Tarek; Zhao, Xiaobei; Habib, Lila K.; Yang, Jerry; Rao, Praveen P. N.

2011-01-01

156

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. PMID:22361591

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

2012-01-01

157

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

158

Lipase-catalysed synthesis of new acetylcholinesterase inhibitors: N-benzylpiperidine aminoacid derivatives.  

PubMed

New acetylcholinesterase inhibitors were synthetized via a lipase-mediated regioselective amidation using Candida antarctica lipase B as a biocatalyst in the key step. The new compounds have two different structural fragments: a N-benzylpiperidine moiety to anchor the enzyme active site and a dicarboxylic aminoacid to act as a biological carrier. Some analogues of N-benzylpiperazine were also synthesised and studied but they did not display AChE inhibitor activity. A preliminary structure activity relationship study was performed employing some computational techniques as similarity indices and electrostatic potential maps. PMID:10819162

Martínez, A; Lanot, C; Perez, C; Castro, A; López-Serrano, P; Conde, S

2000-04-01

159

Memantine and Acetylcholinesterase Inhibitor Treatment in Cases of CDR 0.5 or Questionable Impairment  

PubMed Central

The biological meaning of uncertain dementia ratings (CDR 0.5) and its treatment implications are unclear. Our study examines the frequency of anti-dementia medication use in individuals with CDR 0.5 and the cognitive, behavioral, and demographic factors associated with memantine and acetylcholinesterase inhibitor (AChEI) use. Subjects were drawn from the National Alzheimer Coordinating Center database, which collects data from 30 Alzheimer Disease Centers. There were 2,512 subjects with the following diagnoses: Normal, 11.8%; Mild cognitive impairment, 44.6%; Alzheimer's disease, 34.9%; and other dementias, 8.7%. Overall, 35% used AChEIs and 13% used memantine. AChEI and memantine use was greater in subjects who were referred by clinics and diagnosed with Alzheimer's disease. AChEI use was associated with being married, younger, male, and more educated while memantine use was associated with less severe apathy and other dementia diagnosis. Non-Hispanic whites were more likely to use AChEI and memantine than non-Hispanic blacks (OR=2.2,2.5). Hispanics were more likely to use AChEI than non-Hispanic blacks. It appears anti-dementia medication use in CDR 0.5 is frequent and represents evidence for extensive off label usage. Diagnosis, severity of impairment, and race, among other variables, affect the likelihood of AChEI and memantine use in this population. PMID:19276552

McClendon, McKee J.; Hernandez, Santiago; Smyth, Kathleen A.; Lerner, Alan J.

2010-01-01

160

Erosion of a-C:H films under interaction with nitrous oxide afterglow discharge  

NASA Astrophysics Data System (ADS)

Hydrocarbon film removal using chemically active oxygen formed in a direct current glow discharge with a hollow cathode in nitrous oxide was investigated. In the afterglow region sufficiently fast removal of a-C:H films about 500 nm thick during about 8 h was achieved at N 2O pressure of 12 Pa and 370 K. The erosion rate in the afterglow region was directly proportional to the initial pressure and increased two orders of magnitude at temperature rising from 300 to 500 K. The products of a-C:H film plasmolysis were CO, CO 2, H 2O, and H 2. After removal of a-C:H films previously deposited on stainless steel, molybdenum or tungsten 3-30 nm thick oxide films were formed on the substrates. Reactions of oxygen ion neutralization and atomic oxygen recombination suppressed further oxidation of the materials.

Zalavutdinov, R. Kh.; Gorodetsky, A. E.; Bukhovets, V. L.; Zakharov, A. P.; Mazul, I. V.

2009-06-01

161

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

162

Insect nicotinic acetylcholine receptors (nAChRs): Important amino acid residues contributing to neonicotinoid insecticides selectivity and resistance  

Microsoft Academic Search

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels which mediate fast cholinergic synaptic transmission in insect and vertebrate nervous systems. The great abundance of nAChRs within the insect central nervous system has led to the development of insecticides targeting these receptors, such as neonicotinoid insecticides. Neonicotinoid insecticides act selectively on insect nAChRs, accounting at least in part for the selective

Zewen Liu; Xiangmei Yao; Yixi Zhang

2008-01-01

163

Plasma from patients with seronegative myasthenia gravis inhibit nAChR responses in the TE671\\/RD cell line  

Microsoft Academic Search

Myasthenia gravis (MG) is an autoimmune disorder in which anti-acetylcholine receptor (AChR) antibodies cause muscle weakness. In 10–15% of MG patients anti-AChR antibodies are undetectable (seronegative MG, SMG), though clinical and experimental evidence points to causative circulating factors. Using whole-cell patch-clamp techniques, we investigated the effects of heat-inactivated plasma from SMG patients (n=7) on voltage-gated sodium [INa(V)] and ACh-induced nicotinic

Richard Barrett-Jolley; Nick Byrne; Angela Vincent; John Newsom-Davis

1994-01-01

164

Prefrontal ?2 subunit-containing and ?7 nAChRs differentially control glutamatergic and cholinergic signaling  

PubMed Central

Second-long increases in prefrontal cholinergic activity (“transients”) were previously demonstrated to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at ?4?2* nicotinic acetylcholine receptors (nAChRs), enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of ?2-containing and ?7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the ?4?2* nAChR agonist ABT-089 or the ?7 nAChR agonist A-582941. Transients were recorded in mice lacking ?2 or ?7 nAChRs and in rats following removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of ?4?2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking ?2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by ?2* knockout. Conversely, in mice lacking the ?7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of ?7 nAChR in controlling the duration of release events, stimulation of ?7 nAChR produced cholinergic transients that lasted 10–15 fold longer than those evoked by nicotine. ?7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal ?4?2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance. PMID:20203212

Parikh, Vinay; Ji, Jinzhao; Decker, Michael W.; Sarter, Martin

2010-01-01

165

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

166

Tribendimidine: Mode of Action and nAChR Subtype Selectivity in Ascaris and Oesophagostomum  

PubMed Central

The cholinergic class of anthelmintic drugs is used for the control of parasitic nematodes. One of this class of drugs, tribendimidine (a symmetrical diamidine derivative, of amidantel), was developed in China for use in humans in the mid-1980s. It has a broader-spectrum anthelmintic action against soil-transmitted helminthiasis than other cholinergic anthelmintics, and is effective against hookworm, pinworms, roundworms, and Strongyloides and flatworm of humans. Although molecular studies on C. elegans suggest that tribendimidine is a cholinergic agonist that is selective for the same nematode muscle nAChR as levamisole, no direct electrophysiological observations in nematode parasites have been made to test this hypothesis. Also the hypothesis that levamisole and tribendimine act on the same receptor, does not explain why tribendimidine is effective against some nematode parasites when levamisole is not. Here we examine the effects of tribendimidine on the electrophysiology and contraction of Ascaris suum body muscle and show that tribendimidine produces depolarization antagonized by the nicotinic antagonist mecamylamine, and that tribendimidine is an agonist of muscle nAChRs of parasitic nematodes. Further pharmacological characterization of the nAChRs activated by tribendimidine in our Ascaris muscle contraction assay shows that tribendimidine is not selective for the same receptor subtypes as levamisole, and that tribendimidine is more selective for the B-subtype than the L-subtype of nAChR. In addition, larval migration inhibition assays with levamisole-resistant Oesophagostomum dentatum isolates show that tribendimidine is as active on a levamisole-resistant isolate as on a levamisole-sensitive isolate, suggesting that the selectivity for levamisole and tribendimidine is not the same. It is concluded that tribendimidine can activate a different population of nematode parasite nAChRs than levamisole, and is more like bephenium. The different nAChR subtype selectivity of tribendimidine may explain why the spectrum of action of tribendimidine is different to that of other cholinergic anthelmintics like levamisole. PMID:25679515

Robertson, Alan P.; Puttachary, Sreekanth; Buxton, Samuel K.; Martin, Richard J.

2015-01-01

167

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

168

Angiogenesis Inhibitors  

MedlinePLUS

... natural and synthetic angiogenesis inhibitors, also called antiangiogenic agents, with the idea that these molecules will prevent ... anticancer drugs? Angiogenesis inhibitors are unique cancer-fighting agents because they tend to inhibit the growth of ...

169

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

PubMed Central

The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13–15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD. PMID:25378907

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

2014-01-01

170

Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.  

PubMed

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 ?M) and BuChE (IC50=0.46±0.06 ?M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A? aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. PMID:22023459

Bolea, Irene; Juárez-Jiménez, Jordi; de Los Ríos, Cristóbal; Chioua, Mourad; Pouplana, Ramón; Luque, F Javier; Unzeta, Mercedes; Marco-Contelles, José; Samadi, Abdelouahid

2011-12-22

171

Quantum description of quaternary nuclear fission  

Microsoft Academic Search

The quantum theory of binary and ternary fission is generalized to the case of recently observed quaternary nuclear fission.\\u000a Formulas for the amplitudes of partial fission widths and angular and energy distributions of quaternary fission products\\u000a are derived with allowance for strong channel coupling. The nonevaporation mechanism for formation of light particles is used\\u000a to explain the experimentally observed decrease

S. G. Kadmensky; O. V. Smolyansky

2007-01-01

172

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

173

Optogenetic Release of ACh Induces Rhythmic Bursts of Perisomatic IPSCs in Hippocampus  

Microsoft Academic Search

Acetylcholine (ACh) influences a vast array of phenomena in cortical systems. It alters many ionic conductances and neuronal firing behavior, often by regulating membrane potential oscillations in populations of cells. Synaptic inhibition has crucial roles in many forms of oscillation, and cholinergic mechanisms regulate both oscillations and synaptic inhibition. In vitro investigations using bath-application of cholinergic receptor agonists, or bulk

Daniel A. Nagode; Ai-Hui Tang; Miranda A. Karson; Matthias Klugmann; Bradley E. Alger

2011-01-01

174

Genome Sequence of the Mycorrhiza Helper Bacterium Streptomyces sp. Strain AcH 505  

PubMed Central

A draft genome sequence of Streptomyces sp. strain AcH 505 is presented here. The genome encodes 22 secondary metabolite gene clusters and a large arsenal of secreted proteins, and their comparative and functional analyses will help to advance our knowledge of symbiotic interactions and fungal and plant biomass degradation. PMID:25838498

Feldhahn, L.; Buscot, F.; Wubet, T.

2015-01-01

175

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

176

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

PubMed

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. PMID:9742217

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

1998-10-01

177

Development and testing of a low-toxicity acid corrosion inhibitor for industrial cleaning applications  

SciTech Connect

A low toxicity corrosion inhibitor for use in hydrochloric acid cleaning formulations has been developed. This formulation does not contains formaldehyde. It contains cinnamaldehyde, quaternary nitrogen salts, and a nonionic surfactant, none of which are currently known or suspected to be carcinogens. In laboratory tests, corrosion protection values were equivalent to those provided by current commercial acid inhibitors. Field tests using the low toxicity inhibitor have been conducted.

Frenier, W.W. [HydroChem Industrial Services, Inc., Houston, TX (United States)

1996-12-01

178

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

179

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

Microsoft Academic Search

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

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

2006-01-01

180

Anisotropies in Quaternary Intermetallic Compounds  

NASA Astrophysics Data System (ADS)

From the high-temperature series expansion of magnetic susceptibilities and the anisotropic Weiss temperatures, the first Steven's parameter, B2^0 , and the magnetic exchange interaction constant Jex^ll of each R^=3 ions magnetic sublattice in quaternary intermetallic compounds, RNi2B2C B(R= Tm, Er, Ho, Dy, and Tb) were obtained. The R =Dy system shows the biggest B2^0 value and the R = Tb system does the smallest one. Also we have measured and analyzed the anisotropic M(H) isotherms as a function of applied magnetic fields for H perpendicular and parallel to the c-axis for each compounds to check out our crystalline electric field (CEF) results obtained from the previous mentioned method by using the anisotropic Weiss temperatures. It turned out that most of the temperature dependence of magnetization curve M (T) for H perpendicular the c-axis at low temperature comes from the temperature dependent population of the singlet ground state in group L among groups L(low-lying levels of ground states), H(high levels of ground states), and M(first excited states).

Lee, W. C.

2008-03-01

181

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

182

Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat  

PubMed Central

Purpose Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight ?=?220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. Results The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. Conclusions We demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors. PMID:25225806

Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

2014-01-01

183

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

184

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

185

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

186

Synthesis of Brominated 2-Phenitidine Derivatives as Valuable Inhibitors of Cholinesterases for the Treatment of Alzheimer’s Disease  

PubMed Central

The present study reports the synthesis of a series N-substituted derivatives of brominated 2-phenitidine. First, the reaction of 2-phenitidine (1) with benzenesulfonyl chloride (2) in aqueous media yielded N-(2-ethoxyphenyl) benzenesulfonamide (3), which was then subjected to bromination with bromine in the presence of glacial acetic acid to give N-(4,5-dibromo-2-ethoxyphenyl) benzenesulfonamide (4). Secondly, the product (4) on further treatment with alkyl/aryl halides (5a-l) in the presence of lithium hydride (LiH) produced twelve new derivatives of N-substituted sulfonamides (6a-l). These were characterized by 1H-NMR spectrum and screened against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX) and were found to be valuable inhibitors of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). Few of them were also active against LOX. PMID:24734059

Abbasi, Muhammad Athar; Saeed, Amna; Aziz-ur-Rehman; Mohmmed Khan, Khalid; Ashraf, Muhammad; Ejaz, Syeda Abida

2014-01-01

187

ACE Inhibitors  

MedlinePLUS

... ACEIs can also be used to slow down kidney failure in people who have high blood pressure or diabetes, or both. Why is it important to control high blood pressure? High blood pressure is a ... How do ACE inhibitors help? ACE inhibitors help ...

188

Corrosion inhibitor  

SciTech Connect

A corrosion inhibitor for use in synthetic ester lubricating oils is disclosed. It comprises an effective amount of: at least one aromatic amide; and at least one hydroxy substituted aromatic compound. The corrosion inhibitor thus formed is particularly useful in synthetic ester turbo lubricating oils.

Wisotsky, M.J.; Metro, S.J.

1989-10-31

189

Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective ?4?2-nAChR Ligands.  

PubMed

We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at ?4?2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR ?2 subunit-containing nAChR subtypes (?2*-nAChRs) over ?4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for ?4?2- and ?4?2*-nAChRs with negligible interaction. Functional assays confirm selectivity for ?4?2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15. PMID:25408831

Onajole, Oluseye K; Eaton, J Brek; Lukas, Ronald J; Brunner, Dani; Thiede, Lucinda; Caldarone, Barbara J; Kozikowski, Alan P

2014-11-13

190

Rinodina sophodes (Ach.) Massal.: a bioaccumulator of polycyclic aromatic hydrocarbons (PAHs) in Kanpur City, India  

Microsoft Academic Search

The aim of this study is to determine the possibility of using Rinodina sophodes (Ach.) Massal., a crustose lichen as polycyclic aromatic hydrocarbons (PAHs) bioaccumulator for evaluation of atmospheric\\u000a pollution in tropical areas of India, where few species of lichens are able to grow. PAHs were identified, quantified and\\u000a compared to evaluate the potential utility of R. sophodes. The limit

Satya; Dalip K. Upreti; D. K. Patel

191

DIRECT OBSERVATION OF COMPOSITIONALLY HOMOGENEOUS ACH BAND-GAP-MODULATED SUPERLATTICES  

Microsoft Academic Search

It is shown that amorphous hydrogenated carbon (a-C:H) band-gap-modulated superlattices can be observed by transmission electron microscopy. The layering proves to be well defined and it is demonstrated that changes in the band gap from 1.5 to 2.8 eV cannot be associated with ordered graphitic regions, in that crystalline regions larger than 0.5 nm are not observed. Differences in the

CA DAVIS; SRP SILVA; RE DUNINBORKOWSKI; GAJ AMARATUNGA; KM KNOWLES; WM STOBBS

1995-01-01

192

Deposition of a-C:H films on UHMWPE substrate and its wear-resistance  

NASA Astrophysics Data System (ADS)

In prosthetic hip replacements, ultrahigh molecular weight polyethylene (UHMWPE) wear debris is identified as the main factor limiting the lifetime of the artificial joints. Especially UHMWPE debris from the joint can induce tissue reactions and bone resorption that may lead to the joint loosening. The diamond like carbon (DLC) film has attracted a great deal of interest in recent years mainly because of its excellent tribological property, biocompatibility and chemically inert property. In order to improve the wear-resistance of UHMWPE, a-C:H films were deposited on UHMWPE substrate by electron cyclotron resonance microwave plasma chemical vapor deposition (ECR-PECVD) technology. During deposition, the working gases were argon and acetylene, the microwave power was set to 800 W, the biased pulsed voltage was set to -200 V (frequency 15 kHz, duty ratio 20%), the pressure in vacuum chamber was set to 0.5 Pa, and the process time was 60 min. The films were analysed by X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, nano-indentation, anti-scratch and wear test. The results showed that a typical amorphous hydrogenated carbon (a-C:H) film was successfully deposited on UHMWPE with thickness up to 2 ?m. The nano-hardness of the UHMWPE coated with a-C:H films, measured at an applied load of 200 ?N, was increased from 10 MPa (untreated UHMWPE) to 139 MPa. The wear test was carried out using a ball (Ø 6 mm, SiC) on disk tribometer with an applied load of 1 N for 10000 cycles, and the results showed a reduction of worn cross-sectional area from 193 ?m 2 of untreated UHMWPE to 26 ?m 2 of DLC coated sample. In addition the influence of argon/acetylene gas flow ratio on the growth of a-C:H films was studied.

Xie, Dong; Liu, Hengjun; Deng, Xingrui; Leng, Y. X.; Huang, Nan

2009-10-01

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

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 PMID:23062057

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

2013-01-01

195

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

196

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

197

Electron cyclotron resonance deposition 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 have been deposited by electron cyclotron resonance (ECR) microwave plasma enhanced CVD. A high deposition rate of 25 A/sec and a light-to-dark conductivity ratio of 500,000 for a-Si:H films have been achieved by the ECR process using a pure silane plasma. ECR microwave plasmas have been analyzed by in situ optical emission spectroscopy (OES) and have shown a strong H-asterisk emission at 434 nm indicating higher chemical reactivity than RF plasmas. The linear correlation between the film deposition rate and the SiH-asterisk emission intensity of ECR silane plasma suggests that SiH-asterisk species are related to the neutral radicals which are responsible for the a-Si:H film deposition. Hard and soft a-C:H films have been deposited by ECR with and without RF bias power, respectively. The RF 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. Raman spectra of these films indicate that ECR deposition conditions can be optimized to produce diamond films.

Shing, Y. H.; Yang, C. L.; Allevato, C. E.; Pool, F. S.

1989-01-01

198

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. PMID:8953710

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

1996-01-01

199

Spectral analysis and modelling of ACh and NE effects on shark nervus terminalis activity.  

PubMed

We investigated the effects of acetylcholine (ACh) and norepinephrine (NE) on activity in the nervus terminalis (NT) ganglion of the bonnethead shark (Sphyrna tiburo) using an in vitro preparation and whole nerve recordings. Spectral analysis indicated that ACh (10 and 100 microM) had a variable effect on the total spectral power of whole nerve activity but produced a consistent decrease in half power frequency (HPF; the median frequency of the power spectrum). Norepinephrine (10 microM) reduced baseline activity and total spectral power but produced an increase in HPF in all NT preparations. Computer simulations of extracellular recordings suggested a general explanation for these findings. Acetylcholine may have opposite effects on activity in two NT cell populations with axons in the central nerve trunk, increasing activity in cells whose axons have broad spikes (low spectral frequency) and decreasing activity in cells whose axons have narrow spikes (high spectral frequency). The NE effects are consistent with a decrease in activity of cells whose axons have broad spikes (low spectral frequency) and little or no change in cells whose axons have narrow spikes (high spectral frequency). The physiological data, together with the theoretical analysis, suggest that cholinergic and catecholaminergic neurotransmitter systems are active in the bonnethead NT ganglion, and that ACh and NE have different effects on two populations of ganglion cells. PMID:8490734

White, J; Meredith, M

1993-01-01

200

40 CFR 721.10569 - Tricyclic quaternary amine salt (generic).  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false Tricyclic quaternary amine salt (generic). 721.10569 Section 721...721.10569 Tricyclic quaternary amine salt (generic). (a) Chemical substance...generically as tricyclic quaternary amine salt (PMN P-08-471) is subject to...

2013-07-01

201

Catalytic enantioselective synthesis of quaternary carbon stereocentres  

NASA Astrophysics Data System (ADS)

Quaternary carbon stereocentres--carbon atoms to which four distinct carbon substituents are attached--are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

Quasdorf, Kyle W.; Overman, Larry E.

2014-12-01

202

Catalytic enantioselective synthesis of quaternary carbon stereocentres.  

PubMed

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials. PMID:25503231

Quasdorf, Kyle W; Overman, Larry E

2014-12-11

203

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 PMID:8821535

Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

1996-01-01

204

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

205

Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes.  

PubMed

Effects of glyphosate based herbicide, Excel Mera 71 at a dose of 17.20mg/l on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content were measured in different tissues of two Indian air-breathing teleosts, Anabas testudineus (Bloch) and Heteropneustes fossilis (Bloch) during an exposure period of 30 days under laboratory condition. AChE activity was significantly increased in all the investigated tissues of both fish species and maximum elevation was observed in brain of H. fossilis, while spinal cord of A. testudineus showed minimum increment. Fishes showed significant increase LPO levels in all the tissues; highest was observed in gill of A. testudineus but lowest LPO level was observed in muscle of H. fossilis. CAT was also enhanced in both the fishes, while GST activity in liver diminished substantially and minimum was observed in liver of A. testudineus. Total protein content showed decreased value in all the tissues, maximum reduction was observed in liver and minimum in brain of A. testudineus and H. fossilis respectively. The results indicated that Excel Mera 71 caused serious alterations in the enzyme activities resulting into severe deterioration of fish health; so, AChE, LPO, CAT and GST can be used as suitable indicators of herbicidal toxicity. PMID:24927388

Samanta, Palas; Pal, Sandipan; Mukherjee, Aloke Kumar; Ghosh, Apurba Ratan

2014-09-01

206

The Relationship Between Pain and Mood: Does Mood Predict Reports of Aches and Pains in a Healthy Sample?  

E-print Network

The current study examined the predictive relationship between positive affect (PA), negative affect (NA) and reports of general aches and pains. Because little is known about the relationship between emotion arousal levels ...

Clausius, Rebecca

2010-12-15

207

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. PMID:23331030

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

2014-01-01

208

CM ofe ach pe riod, th e se m ak e up th e CA CM ofth e nanotube  

E-print Network

alize ultra-se nsitive m ass re sonators, and to ach ie ve th e ultim ate single m ole cule de te ction lim it. Th e de te ction sch e m e for m ass se nsing w ith a m e ch anicalre sonator is ach ie ve d ode fre q ue ncy on th e e ffe ctive m ass M allow s for se nsitive de te ction ofadditionalm ass

Adler, Joan

209

Direct Proof of the In Vivo Pathogenic Role of the AChR Autoantibodies from Myasthenia Gravis Patients  

PubMed Central

Several studies have suggested that the autoantibodies (autoAbs) against muscle acetylcholine receptor (AChR) of myasthenia gravis (MG) patients are the main pathogenic factor in MG; however, this belief has not yet been confirmed with direct observations. Although animals immunized with AChR or injected with anti-AChR monoclonal Abs, or with crude human MG Ig fractions exhibit MG symptoms, the pathogenic role of isolated anti-AChR autoAbs, and, more importantly, the absence of pathogenic factor(s) in the autoAb-depleted MG sera has not yet been shown by in vivo studies. Using recombinant extracellular domains of the human AChR ? and ? subunits, we have isolated autoAbs from the sera of four MG patients. The ability of these isolated anti-subunit Abs and of the Ab-depleted sera to passively transfer experimental autoimmune MG in Lewis rats was investigated. We found that the isolated anti-subunit Abs were at least as efficient as the corresponding whole sera or whole Ig in causing experimental MG. Abs to both ?- and ?-subunit were pathogenic although the anti-?-subunit were much more efficient than the anti-?-subunit ones. Interestingly, the autoAb-depleted sera were free of pathogenic activity. The later suggests that the myasthenogenic potency of the studied anti-AChR MG sera is totally due to their anti-AChR autoAbs, and therefore selective elimination of the anti-AChR autoAbs from MG patients may be an efficient therapy for MG. PMID:25259739

Kordas, Gregory; Lagoumintzis, George; Sideris, Sotirios; Poulas, Konstantinos; Tzartos, Socrates J.

2014-01-01

210

Antibacterial and Hemolytic Activities of Quaternary Pyridinium  

E-print Network

bacteria but not mammalian cells.[2­4] Polymers have been used as antimicrobial agents due commonly used as biocidal agents.[6­15] A number of polymeric disinfectants based on quaternary pyridinium bacteria. Recently, Gao and coworkers synthesized random copolymers of acrylamide and vinyl pyridine

211

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

212

Quaternary Geochronology 2 (2007) 290295 Research paper  

E-print Network

at the beginning of the Last Interglacial. These are in good agreement with the 10 Be cosmogenic dates obtained of the strongest ever recorded intracontinental earthquakes (magnitude 8.3 on Richter scale). PreviousQuaternary Geochronology 2 (2007) 290­295 Research paper Luminescence dating of a gigantic

Long, Bernard

213

Quaternary geology of the Amazonian Lowland  

Microsoft Academic Search

The Quaternary history of the Amazon lowlands is characterized by deposition of sediments of Andean provenance and by the influences of changing sea levels. Areas well above the present water tables were not reached by Pleistocene high-water stages. These areas have been intensively weathered since the Tertiary, forming hard lateritic weathering horizons. These weathering horizons are best explained by the

Georg Irion; Jens Müller; Jose Nunes de Mello; Wolfgang J. Junk

1995-01-01

214

Rapid and sensitive detection of the inhibitive activities of acetyl- and butyryl-cholinesterases inhibitors by UPLC-ESI-MS/MS.  

PubMed

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are legitimate therapeutic targets for Alzheimer's disease. The classical approach for screening potential AChE/BChE inhibitors was developed by Ellman. However, the background color of compounds or plant extracts remained uncertain and frequently interfered with the detection of the secondary reaction, thereby easily yielding false positive or false negative results. Rapid, selective, and sensitive ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry method was developed and used for the detection of AChE and BChE inhibition by directly determining the common product, choline (Ch). Proper separation was achieved for choline and chlormequat (internal standard) within 1.2min via isocratic elution (0.1% fromic acid:methanol=98:2) on an HSS T3 column following a simple precipitation of proteins for sample treatment. The relative standard deviations of the intra- and inter-day precisions were below 7.34 and 9.09%, respectively, whereas the mean accuracy for the quality control samples was 100.31±10.93%. The method exhibited the advantages of small total reaction volume (100?L), short analysis time (1.2min), high sensitivity (LOQ of 0.036?M for Ch), and low cost (little consumption enzymes of 0.0035 and 0.008unitmL(-1) for AChE and BChE, and substrates of 5.505 and 7.152?M for ACh and BCh in individual inhibition, respectively), and without matrix effect (90.00-105.03%). The developed method was successfully applied for detecting the AChE and BChE inhibitive activities for model drugs, including galanthamine, tacrine, neostigmine methylsulfate, eserine, as well as ?-carboline and quinazoline alkaloids from Peganum harmala. PMID:24631841

Liu, Wei; Yang, Yadi; Cheng, Xuemei; Gong, Can; Li, Shuping; He, Dandan; Yang, Li; Wang, Zhengtao; Wang, Changhong

2014-06-01

215

Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses  

PubMed Central

To elucidate the nature of signals that control the level and spatial distribution of mRNAs encoding acetylcholine receptor (AChR), alpha-, beta-, gamma-, delta- and epsilon-subunits in muscle fibers chronic paralysis was induced in rat leg muscles either by surgical denervation or by different neurotoxins that cause disuse of the muscle or selectively block neuromuscular transmission pre- or postsynaptically and cause an increase of AChRs in muscle membrane. After paralysis, the levels and the spatial distributions of the different subunit-specific mRNAs change discoordinately and seem to follow one of three different patterns depending on the subunit mRNA examined. The level of epsilon- subunit mRNA and its accumulation at the end-plate are largely independent on the presence of the nerve or electrical muscle activity. In contrast, the gamma-subunit mRNA level is tightly coupled to innervation. It is undetectable or low in innervated normally active muscle and in innervated but disused muscle, whereas it is abundant along the whole fiber length in denervated muscle or in muscle in which the neuromuscular contact is intact but the release of transmitter is blocked. The alpha-, beta-, and delta-subunit mRNA levels show a different pattern. Highest amounts are always found at end-plate nuclei irrespective of whether the muscle is innervated, denervated, active, or inactive, whereas in extrasynaptic regions they are tightly controlled by innervation partially through electrical muscle activity. The changes in the levels and distribution of gamma- and epsilon- subunit-specific mRNAs in toxin-paralyzed muscle correlate well with the spatial appearance of functional fetal and adult AChR channel subtypes along the muscle fiber. The results suggest that the focal accumulation at the synaptic region of mRNAs encoding the alpha-, beta- , delta-, and epsilon-subunits, which constitute the adult type end- plate channel, is largely determined by at least two different neural factors that act on AChR subunit gene expression of subsynaptic nuclei. PMID:1646821

1991-01-01

216

Tribological Properties of Ultrathin a-C:H Overcoat on a Magnetic Hard Disk  

NASA Astrophysics Data System (ADS)

The durability of the carbon thin film on magnetic hard disk has become increasingly important due to the reduced head to disk spacing. Amorphous hydrogenated carbon (a-C: H) films formed by plasma chemical vapor deposition (p-CVD) show superior tribological properties on magnetic hard disk. We need p-CVD deposition system with hot filament plasma source and toluence as a precursor material. In this paper, the material characterization and the tribological properties of a few nonometers thick a-C:H films by p-CVD are discussed by using XPS and Raman scattering spectroscopy, and pin-on-disk sliding test.

Yamamoto, Takayuki; Toyoguchi, Takashi; Honda, fumihiro

217

A comparative molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors.  

PubMed

A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives and of N-benzylpiperidine benzisoxazoles has been investigated using the comparative molecular field analysis (CoMFA) approach. These compounds have been found to inhibit the metabolic breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in patients with Alzheimer's Disease by potentiating cholinergic transmission. Development of the CoMFA model considered two separate alignments: (i) alignment I which emphasized the electrostatic fitting of the subject compounds and (ii) alignment II which emphasized their steric fitting. In addition, the inhibitor compounds were considered both as neutral species and as N-piperidine-protonated species. The resulting 3D-QSAR indicates a strong correlation between the inhibitory activity of these N-benzylpiperidines and the steric and electronic factors which modulate their biochemical activity. A CoMFA model with considerable predictive ability was obtained. PMID:8558505

Tong, W; Collantes, E R; Chen, Y; Welsh, W J

1996-01-19

218

The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers  

Microsoft Academic Search

A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. We conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1–10 of this protocol are described in a separate publication.

R. De La Garza; J MAHONEYIII; C. Culbertson; S. Shoptaw; T. F. Newton

2008-01-01

219

Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.  

PubMed

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities. PMID:24905476

Martis, Elvis A F; Chandarana, Rakesh C; Shaikh, Mushtaque S; Ambre, Premlata K; D'Souza, Jacinta S; Iyer, Krishna R; Coutinho, Evans C; Nandan, Santosh R; Pissurlenkar, Raghuvir R S

2015-05-01

220

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

221

New generic approach to the treatment of organophosphate poisoning: adenosine receptor mediated inhibition of ACh-release.  

PubMed

Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is stated that other therapeutic approaches may improve protection. Former studies on the "direct effects" of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) after the acute OP-intoxication, could prevent and counteract convulsions and improve survival. In general, the accumulation of ACh in the synaptic cleft is considered to be responsible for the symptoms that ultimately lead to death. Therefore, prevention or suppression of this excessive accumulation of ACh could be a generic approach to antagonize OP-poisoning. Preliminary evidence for this concept has been put forward. Evaluation of drugs that would be able to prevent and counteract ACh accumulation, led to the conclusion that adenosine receptor agonists could be promising candidates. Pilot experiments demonstrated that intramuscular administration of the adenosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N6-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5-2LD50) in rats, resulted in (1) prevention or postponement of chewing, salivation, convulsive activity, and respiratory distress (cholinergic symptoms), (2) improvement of survival rate (24 h), (3) a low level of extracellular brain ACh, as opposed to high levels of extracellular brain ACh in untreated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diazepam, (2) prevention of ACh accumulation in this way may be a new generic approach in the treatment of OP-poisoning. PMID:10028409

van Helden, H P; Groen, B; Moor, E; Westerink, B H; Bruijnzeel, P L

1998-01-01

222

Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption.  

PubMed

Recently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA). To gain insight into which nAChR subtypes may be involved in the response to alcohol, we analyzed nAChR subunit gene expression in posterior VTA DAergic neurons. Ethanol-activated DAergic neurons expressed higher levels of alpha4, alpha6, and beta3 subunit genes compared with nonactivated neurons. To examine the role of nicotinic receptors containing the alpha4 subunit (alpha4* nAChRs) in varenicline-induced reduction of alcohol consumption, we examined the effect of the drug in two complementary mouse models, a knock-out line that does not express the alpha4 subunit (alpha4 KO) and another line that expresses alpha4* nAChRs hypersensitive to agonist (Leu9'Ala). While varenicline (0.1-0.3 mg/kg, i.p.) reduced 2% and 20% alcohol consumption in wild-type (WT) mice, the drug did not significantly reduce consumption in alpha4 KO animals. Conversely, low doses of varenicline (0.0125-0.05 mg/kg, i.p.) that had little effect in WT mice dramatically reduced ethanol intake in Leu9'Ala mice. Infusion of varenicline into the posterior, but not the anterior VTA was sufficient to reduce alcohol consumption. Together, our data indicate that activation of alpha4* nAChRs is necessary and sufficient for varenicline reduction of alcohol consumption. PMID:20668200

Hendrickson, Linzy M; Zhao-Shea, Rubing; Pang, Xueyan; Gardner, Paul D; Tapper, Andrew R

2010-07-28

223

PARP Inhibitors  

Microsoft Academic Search

Poly (ADP-ribose) polymerase (PARP) is a novel therapeutic target in cancer. Preclinical studies demonstrate that PARP inhibitors\\u000a selectively kill BRCA-deficient cells and potentiate the effects of DNA-damaging agents. There are several PARP inhibitors in clinical development,\\u000a including olaparib, iniparib, veliparib, PF-01367338, and MK-4827. Phase II studies of single-agent olaparib demonstrate activity\\u000a in BRCA-associated cancers. A randomized phase II trial showed

Hongyan Liang; Antoinette R. Tan

2011-01-01

224

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) PMID:8019748

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

1994-01-01

225

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

226

Synthesis of novel N-alkyl carbamates of a-substituted amides of g-hydroxybutyric acid as potential acetylcholinesterase inhibitors.  

PubMed

In a search for new acetylcholinesterase (AChE) inhibitors, derivatives of N-alkyl carbamates of a-substituted N-benzylamides of g-hydroxybutyric acid (GHB) 2(a-d); 3(a-d); 4(a-d) were obtained. Starting from 3-bromo-tetrahydrofuran-2-one, and N-phenylpiperazine 3-(4-phenylpiperazin-1-yl) tetrahydrofuran-2-one (1) was obtained. The aminolysis of lactone 1 with 4-substituted derivatives of benzylamine yielded N-substituted benzylamides of a-(4-phenylpiperazin-1-yl)-g-hydroxy-butyric acid (2-4). The target compounds were prepared by refluxing N-substituted benzyl-amides of a-(4-phenylpiperazinyl-1-)-GHB with ethyl-, i-propyl-, n-propyl- or n-butyl-isocyanate in dry acetonitrile. The inhibitory potency of AChE was evaluated by means of Ellman's in vitro test. PMID:15909954

Musia?, Anna; Malawska, Barbara

2004-12-01

227

Immobilized cholinesterases capillary reactors on-flow screening of selective inhibitors.  

PubMed

The discovery of selective inhibitors for acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) is extremely important for the development of drugs that can be used in the treatment of patients diagnosed with the Alzheimer's disease (AD). For this reason, there is a growing interest in developing rapid and effective assays techniques for cholinesterases (ChE) enzymes ligand screening. Herein is presented the results of selective screening assays of a coumarin derivatives library using BChE and AChE covalently immobilized onto silica fused capillaries (ICERs, 15 cm × 0.1 mm ID). The statistical comparison of the ICERs screening assay with that of the free enzymes is reported and highlights the advantages of the on-flow ICERs assay. Two out of 20 coumarin derivatives could be highlighted: compound 17 is more active toward BChE (IC??=109 ± 21 ?M) and 19 showed activity against both enzymes (BChE IC??=128 ± 28 ?M and hu-AChE IC??=144 ± 40 ?M). The statistical evaluation of the results of the ICERs and free enzyme assays showed no difference between them, further validating the ICERs assay model. The ICERs ability to recognize selective ligands and its use for characterization of the inhibition mechanisms of the hits consolidates the approach here reported. PMID:24321276

Vilela, Adriana Ferreira Lopes; da Silva, Joyce Izidoro; Vieira, Lucas Campos Curcino; Bernasconi, Gilberto C R; Corrêa, Arlene Gonçalves; Cass, Quezia Bezerra; Cardoso, Carmen Lúcia

2014-10-01

228

Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors.  

PubMed

Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation. PMID:25445524

Qian, Shuai; He, Lisi; Mak, Marvin; Han, Yifan; Ho, Chun-Yu; Zuo, Zhong

2014-12-30

229

Carboxylesterase inhibitors  

PubMed Central

Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

Hatfield, M. Jason; Potter, Philip M.

2011-01-01

230

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

231

Late Quaternary Environments in the Nile Basin  

Microsoft Academic Search

The Late Quaternary history of the Nile has been reconstructed using well-dated sedimentary, stable isotope and fossil records\\u000a and associated archaeological remains. The White Nile flows over the bed of an ancient lake dating to ~ 400 ka (Marine Isotope\\u000a Stage 11). High flood levels in the White Nile since that time appear to coincide with times of sapropel accumulation

Martin A. J. Williams; Michael R. Talbot

232

Palladium-catalyzed asymmetric quaternary stereocenter formation.  

PubMed

An efficient palladium catalyst is presented for the formation of benzylic quaternary stereocenters by conjugate addition of arylboronic acids to a variety of ?,?-disubstituted carbocyclic, heterocyclic, and acyclic enones. The catalyst is readily prepared from PdCl(2), PhBOX, and AgSbF(6), and provides products in up to 99% enantiomeric excess, with good yields. Based on this strategy, (-)-?-cuparenone has been prepared in only two steps. PMID:22532469

Gottumukkala, Aditya L; Matcha, Kiran; Lutz, Martin; de Vries, Johannes G; Minnaard, Adriaan J

2012-05-29

233

Control of ACh sensitivity in temporarily unconnected ("decentralized") segments of diaphragm-muscle fibres of the rat.  

PubMed

1. After a local lesion of the diaphragm muscle, which produced a segment of innervated muscle fibres connected with an intact nerve-free segment by a region of crushed muscle fibres, the sensitivity to ACh, the presence of tetrodotoxin resistant action potentials (AP) and the transmission of AP along the muscle fibres were studied. 2. Three days after local injury of the diaphragm muscle ACh sensitivity and TTX resistance appeared in the crushed and nerve-free segments between the place of injury and the tendineous attachment. 5-7 days after injury transmission of action potentials through the damaged to the undamaged ("decentralized"), nerve-free part of the fibres is restored. High ACh sensitivity and TTX resistance of the latter segment, however, are completely lost only 20 days after the local injury. During this period contractility of the muscle remains practically unchanged. Enzymatic activities (SDH, ATPase and phosphorylase) of the damaged part were lost 3 days after crushing and recovered slowly between 7-10 days of regeneration of the diaphragm muscle fibres. 3. The experiments suggest that during regeneration of damaged muscle fibres supersensitivity to ACh remains high inspite of normal AP activity and that intracellular mechanisms may be involved in the induction and disappearance of ACh hypersensitivity. PMID:188011

Vyskocil, F; Gutmann, E

1976-11-30

234

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. PMID:22792283

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

2012-01-01

235

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. PMID:24274400

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

236

Aleksis Dreimanis: a legacy in Quaternary science  

NASA Astrophysics Data System (ADS)

Aleksis Dreimanis was born and raised in Latvia. His interest in Quaternary and glacial geology began early and developed into a career that has spanned 7 decades. At age 20 he published his first paper in glacial geology and soon after began teaching at the University of Latvia. Teaching and research were interrupted by World War II but resumed at the Baltic University (Pinneberg, Germany), then at the University of Western Ontario where he has been ever since. Throughout his career, Dreimanis has successfully balanced the twin disciplines of Quaternary history and glacial geology. He was among the first to study quantitatively the relationship between till lithology and till formation and to study how glacial transport and dynamics affect till texture and deformation. With co-workers he developed the well-known stratigraphic scheme of the last glaciation in the Great Lakes region of North America. Aleksis became world-renowned through his committee work, especially as President of the INQUA Commission on Genesis and Lithology of Glacial Quaternary Deposits. His diplomacy, enthusiasm, and passion for his subject have inspired students and colleagues around the globe and resulted in remarkable international dialogue, cooperation, and consensus. Professor Aleksis Dreimanis is an honest scientist, a gentleman, and a true scholar who has left a rich legacy for future Quaternarists.

Hicock, Stephen R.; Menzies, John

2000-12-01

237

Late quaternary sequence stratigraphy, South Florida margin  

SciTech Connect

Late Quaternary sea-level change and the Florida Current have combined to produce a progradational shelf-slope margin along the western portion of the south Florida Platform facing the Straits of Florida. Analysis of high resolution seismic reflection profiles suggest at least eight 5th order late Quaternary sequences downlap onto the Pourtales Terrace at 250 m water depth. Along most of the south Florida margin, this Late Quaternary section is very thin, and only where significant accumulations occur can the stratigraphic patterns produced by sea-level change be clearly observed. Recognition of systems tracts and their boundaries from high-resolution seismic data is important for prediction of sedimentary facies and stratigraphic development of margins. Many south Florida seismic boundaries can be fit to the Exxon sequence stratigraphy model. Others appear to reflect the added effect of bottom-current erosion that complicates the signal produced by sea-level change. Overall, the sea-level signal appears to dominate the stratigraphic record, especially from the 2-dimensional perspective of dip-oriented seismic profiles. However, the 3-dimensional geometry of deposits are strongly influenced by along slope accumulation patterns controlled by the Florida Current. This study provides new insight on the importance of both geostrophic boundary currents and sea-level change in controlling stratigraphic development of a carbonate platform margin. Similar anomalously thick slope deposits in ancient sequences may indicate similar controls on accumulation and could lend to predictions of related paleo-platform configurations.

Locker, S.D.; Hine, A.C. [Univ. of South Florida, St. Petersburg, FL (United States). Dept. of Marine Science

1995-12-01

238

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

239

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

240

Gravity anomalies, Quaternary vents, and Quaternary faults in the southern Cascade Range, Oregon and California: Implications for arc and backarc evolution  

Microsoft Academic Search

Isostatic residual gravity anomalies in the southern Cascade Range of northern California and southern Oregon are spatially correlated with broad zones of Quaternary magmatism as reflected by the total volume of Quaternary volcanic products, the distribution of Quaternary vents, and the anomalously low teleseismic P wave velocities in the upper 30 km of crust. The orientation of Quaternary faults also

Richard J. Blakely; Robert L. Christiansen; Marianne Guffanti; Ray E. Wells; Julie M. Donnelly-Nolan; L. J. Patrick Muffler; Michael A. Clynne; James G. Smith

1997-01-01

241

Conformational analyses and molecular-shape comparisons of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.  

PubMed

Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring. PMID:1738152

Cardozo, M G; Kawai, T; Iimura, Y; Sugimoto, H; Yamanishi, Y; Hopfinger, A J

1992-02-01

242

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

243

Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses.  

PubMed

Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. PMID:25114227

Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo; Sumikawa, Katumi

2014-08-26

244

Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses  

PubMed Central

Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. PMID:25114227

Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo; Sumikawa, Katumi

2014-01-01

245

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

246

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

247

NMR structures of the human ?7 nAChR transmembrane domain and associated anesthetic binding sites.  

PubMed

The ?7 nicotinic acetylcholine receptor (nAChR), assembled as homomeric pentameric ligand-gated ion channels, is one of the most abundant nAChR subtypes in the brain. Despite its importance in memory, learning and cognition, no structure has been determined for the ?7 nAChR TM domain, a target for allosteric modulators. Using solution state NMR, we determined the structure of the human ?7 nAChR TM domain (PDB ID: 2MAW) and demonstrated that the ?7 TM domain formed functional channels in Xenopus oocytes. We identified the associated binding sites for the anesthetics halothane and ketamine; the former cannot sensitively inhibit ?7 function, but the latter can. The ?7 TM domain folds into the expected four-helical bundle motif, but the intra-subunit cavity at the extracellular end of the ?7 TM domain is smaller than the equivalent cavity in the ?4?2 nAChRs (PDB IDs: 2LLY; 2LM2). Neither drug binds to the extracellular end of the ?7 TM domain, but two halothane molecules or one ketamine molecule binds to the intracellular end of the ?7 TM domain. Halothane and ketamine binding sites are partially overlapped. Ketamine, but not halothane, perturbed the ?7 channel-gate residue L9'. Furthermore, halothane did not induce profound dynamics changes in the ?7 channel as observed in ?4?2. The study offers a novel high-resolution structure for the human ?7 nAChR TM domain that is invaluable for developing ?7-specific therapeutics. It also provides evidence to support the hypothesis: only when anesthetic binding perturbs the channel pore or alters the channel motion, can binding generate functional consequences. PMID:24384062

Bondarenko, Vasyl; Mowrey, David D; Tillman, Tommy S; Seyoum, Edom; Xu, Yan; Tang, Pei

2014-05-01

248

In search of allosteric modulators of a7-nAChR by solvent density guided virtual screening.  

PubMed

Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of ?7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of ?7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of ?1 nAChR, suggesting that the surface cavities in the ?7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of ?7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of ?7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators. PMID:21294583

Dey, Raja; Chen, Lin

2011-04-01

249

MusÃ?©e AchÃ?©mÃ?©nide  

NSDL National Science Digital Library

Drawing on the expertise of a number of well-regarded institutions, the online Mus�©e Ach�©m�©nide will bring users into the world of the ancient worlds of Persia, Babylonia, and the Egyptian empire. While the graphic interfaces used throughout the site take some getting used to, there are a number of lovely features here. In the "Consultation" section, visitors can browse around through various collections, such as archival drawings and renderings from the various geographic areas covered here. They can also view objects from the ancient world and learn about their historical and cultural importance. Visitors can also move through the sections to create their own archive, which they can share with friends or colleagues. Finally, there is a "Help" section that explains how to effectively navigate the site's different areas.

250

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

251

Efficient Expression of Functional (?6?2)2?3 AChRs in Xenopus Oocytes from Free Subunits Using Slightly Modified ?6 Subunits  

PubMed Central

Human (?6?2)(?4?2)?3 nicotinic acetylcholine receptors (AChRs) are essential for addiction to nicotine and a target for drug development for smoking cessation. Expressing this complex AChR is difficult, but has been achieved using subunit concatamers. In order to determine what limits expression of ?6* AChRs and to efficiently express ?6* AChRs using free subunits, we investigated expression of the simpler (?6?2)2?3 AChR. The concatameric form of this AChR assembles well, but is transported to the cell surface inefficiently. Various chimeras of ?6 with the closely related ?3 subunit increased expression efficiency with free subunits and produced pharmacologically equivalent functional AChRs. A chimera in which the large cytoplasmic domain of ?6 was replaced with that of ?3 increased assembly with ?2 subunits and transport of AChRs to the oocyte surface. Another chimera replacing the unique methionine 211 of ?6 with leucine found at this position in transmembrane domain 1 of ?3 and other ? subunits increased assembly of mature subunits containing ?3 subunits within oocytes. Combining both ?3 sequences in an ?6 chimera increased expression of functional (?6?2)2?3 AChRs to 12-fold more than with concatamers. This is pragmatically useful, and provides insights on features of ?6 subunit structure that limit its expression in transfected cells. PMID:25068303

Ley, Carson Kai-Kwong; Kuryatov, Alexander; Wang, Jingyi; Lindstrom, Jon Martin

2014-01-01

252

A positive allosteric modulator of ?7 nAChRs augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia  

PubMed Central

Background and Purpose Activation of ?7 nicotinic acetylcholine receptors (nAChRs) can be neuroprotective. However, endogenous choline and ACh have not been regarded as potent neuroprotective agents because physiological levels of choline/ACh do not produce neuroprotective levels of ?7 activation. This limitation may be overcome by the use of type-II positive allosteric modulators (PAMs-II) of ?7 nAChRs, such as 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea (PNU-120596). This proof-of-concept study presents a novel neuroprotective paradigm that converts endogenous choline/ACh into potent neuroprotective agents in cerebral ischaemia by inhibiting ?7 nAChR desensitization using PNU-120596. Experimental Approach An electrophysiological ex vivo cell injury assay (to quantify the susceptibility of hippocampal neurons to acute injury by complete oxygen and glucose deprivation; COGD) and an in vivo middle cerebral artery occlusion model of ischaemia were used in rats. Key Results Choline (20–200 ?M) in the presence, but not absence of 1 ?M PNU-120596 significantly delayed anoxic depolarization/injury of hippocampal CA1 pyramidal neurons, but not CA1 stratum radiatum interneurons, subjected to COGD in acute hippocampal slices and these effects were blocked by 20 nM methyllycaconitine, a selective ?7 antagonist, thus, activation of ?7 nAChRs was required. PNU-120596 alone was ineffective ex vivo. In in vivo experiments, both pre- and post-ischaemia treatments with PNU-120596 (30 mg·kg?1, s.c. and 1 mg·kg?1, i.v., respectively) significantly reduced the cortical/subcortical infarct volume caused by transient focal cerebral ischaemia. PNU-120596 (1 mg·kg?1, i.v., 30 min post-ischaemia) remained neuroprotective in rats subjected to a choline-deficient diet for 14 days prior to experiments. Conclusions and Implications PNU-120596 and possibly other PAMs-II significantly improved neuronal survival in cerebral ischaemia by augmenting neuroprotective effects of endogenous choline/ACh. PMID:23713819

Kalappa, Bopanna I; Sun, Fen; Johnson, Stephen R; Jin, Kunlin; Uteshev, Victor V

2013-01-01

253

Fusion-independent expression of functional ACh receptors in mouse mesoangioblast stem cells contacting muscle cells  

PubMed Central

Mesoangioblasts are vessel-associated fetal stem cells that can be induced to differentiate into skeletal muscle, both in vitro and in vivo. Whether this is due to fusion or to transdifferentiation into bona fide satellite cells is still an open question, for mesoangioblasts as well as for other types of stem cells. The early steps of satellite cell myogenic differentiation involve MyoD activation, membrane hyperpolarization and the appearance of ACh sensitivity and gap junctional communication. If mesoangioblasts differentiate into satellite cells, these characteristics should be observed in stem cells prior to fusion into multinucleated myotubes. We have investigated the functional properties acquired by mononucleated green fluorescent protein (GFP)-positive mesoangioblasts co-cultured with differentiating C2C12 myogenic cells, using the patch-clamp technique. Mesoangioblasts whose membrane contacted myogenic cells developed a hyperpolarized membrane resting potential and ACh-evoked current responses. Dye and electrical coupling was observed among mesoangioblasts but not between mesoangioblasts and myotubes. Mouse MyoD was detected by RT-PCR both in single, mononucleated mesoangioblasts co-cultured with C2C12 myotubes and in the total mRNA from mouse mesoangioblasts co-cultured with human myotubes, but not in human myotubes or stem cells cultured in isolation. In conclusion, when co-cultured with muscle cells, mesoangioblasts acquire many of the functional characteristics of differentiating satellite cells in the absence of cell fusion, strongly indicating that these stem cells undergo transdifferentiation into satellite cells, when exposed to a myogenic environment. PMID:15319417

Grassi, Francesca; Pagani, Francesca; Spinelli, Gabriele; Angelis, Luciana De; Cossu, Giulio; Eusebi, Fabrizio

2004-01-01

254

Fusion-independent expression of functional ACh receptors in mouse mesoangioblast stem cells contacting muscle cells.  

PubMed

Mesoangioblasts are vessel-associated fetal stem cells that can be induced to differentiate into skeletal muscle, both in vitro and in vivo. Whether this is due to fusion or to transdifferentiation into bona fide satellite cells is still an open question, for mesoangioblasts as well as for other types of stem cells. The early steps of satellite cell myogenic differentiation involve MyoD activation, membrane hyperpolarization and the appearance of ACh sensitivity and gap junctional communication. If mesoangioblasts differentiate into satellite cells, these characteristics should be observed in stem cells prior to fusion into multinucleated myotubes. We have investigated the functional properties acquired by mononucleated green fluorescent protein (GFP)-positive mesoangioblasts co-cultured with differentiating C2C12 myogenic cells, using the patch-clamp technique. Mesoangioblasts whose membrane contacted myogenic cells developed a hyperpolarized membrane resting potential and ACh-evoked current responses. Dye and electrical coupling was observed among mesoangioblasts but not between mesoangioblasts and myotubes. Mouse MyoD was detected by RT-PCR both in single, mononucleated mesoangioblasts co-cultured with C2C12 myotubes and in the total mRNA from mouse mesoangioblasts co-cultured with human myotubes, but not in human myotubes or stem cells cultured in isolation. In conclusion, when co-cultured with muscle cells, mesoangioblasts acquire many of the functional characteristics of differentiating satellite cells in the absence of cell fusion, strongly indicating that these stem cells undergo transdifferentiation into satellite cells, when exposed to a myogenic environment. PMID:15319417

Grassi, Francesca; Pagani, Francesca; Spinelli, Gabriele; De Angelis, Luciana; Cossu, Giulio; Eusebi, Fabrizio

2004-10-15

255

Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala  

E-print Network

Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala Christine Authemayou,1 transform boundary between the North American and Caribbean plates in Guatemala and the associated seismic), Quaternary seismo-tectonic activity of the Polochic Fault, Guatemala, J. Geophys. Res., 117, B07403, doi:10

Paris-Sud XI, Université de

256

Applications 1/2 1. Dating Quaternary basalt volcanism  

E-print Network

Radiocarbon dating (if charcoal in between) K-Ar or Ar-Ar dating or: Cosmogenic 3He 1. Dating QuaternaryApplications 1/2 1. Dating Quaternary basalt volcanism 2. Timing of landslides 3. Tectonic displacement 4. Glaciers and ice-sheets 5. Meteorite impacts 6. Sedimentation rates 7. (Ground) water dating 8

Siebel, Wolfgang

257

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

258

Germination inhibitors  

Microsoft Academic Search

Summary  The presence of germination-inhibiting substances in plants seems to be a wide-spread phenomenon. They occur in all parts\\u000a of plants —in fruit pulp, fruit coats, endosperm, seed coat, embryo, leaves, bulbs and roots. They are non-specific in their\\u000a effects.\\u000a \\u000a Besides inhibitors, high osmotic pressure and acid pH are often partly responsible for the germination inhibition caused by\\u000a sap, juices and

Michael Evenari

1949-01-01

259

Angiotensin-Converting Enzyme Inhibitor Prevents Age-Related Endothelial Dysfunction  

Microsoft Academic Search

Abstract—Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme,inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg z kg,5 mol\\/L ACh in the

Kenichi Goto; Koji Fujii; Uran Onaka; Isao Abe; Masatoshi Fujishima

260

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

261

R86Q, a mutation in BmAChE3 yielding a Rhipicephalus microplus organophosphate-insensitive acetylcholinesterase  

Technology Transfer Automated Retrieval System (TEKTRAN)

Mutations were identified in the sequence encoding the acetylcholinesterase, BmAChE3, in strains of Rhipicephalus (Boophilus) microplus (Canestrini) resistant or susceptible to orgaonphosphorus acaricide. The mutation which appeared most frequently in the organophosphorus-resistant San Román strain...

262

PARP inhibitors.  

PubMed

Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs. PMID:25606064

Anwar, Maheen; Aslam, Hafiz Muhammad; Anwar, Shahzad

2015-01-01

263

Involvement of ?7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation.  

PubMed

Oxaliplatin, unlike other platinum anticancer agents, has only mild toxic effects on the hematopoietic, urinary and gastrointestinal systems. Its dose-limiting side effect is neurotoxicity that may evolve to a neuropathic syndrome which is difficult to treat. In this study we treated rats with oxaliplatin (2.4 mg/kg/day intraperitoneally, for 3 weeks), and observed that expression levels of the ?7 nicotinic acetylcholine receptor (nAChR) subunit were dramatically decreased both in the peripheral and central nervous system. The repeated administration (30 mg/kg/day per os, for 3 weeks) of (R)-ICH3, the most active enantiomer of a novel ?7 nAChR agonist, and of PNU-282987 prevented the receptor down-regulation. On the other hand, both agonists per se up-regulated the ?7 nAChR subunit compared to control. (R)-ICH3 and PNU-282987 significantly reduced oxaliplatin-dependent alterations of the pain threshold when noxious or non-noxious stimuli were used. Further ex vivo analysis highlighted their neuroprotective effects in dorsal root ganglia and peripheral nerves. The two agonists did not prevent the increase in microglia cell number induced by oxaliplatin in the central nervous system. Astrocyte density was enhanced by the agonist treatment in the spinal cord, thalamus and somatosensory area 1 as opposed to the effects of oxaliplatin treatment. (R)-ICH3 and PNU-282987 per se increased glial cell number in a region-specific manner. In summary, ?7 nAChR is involved in oxaliplatin-dependent neuropathology and the agonists (R)-ICH3 and PNU-282987 reduce pain and protect nervous tissue with concomitant glial activation. Since glial cells play a role both in pain and in neuroprotection, an ?7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway. PMID:24225197

Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Matera, Carlo; Zanardelli, Matteo; Mello, Tommaso; De Amici, Marco; Dallanoce, Clelia; Ghelardini, Carla

2014-04-01

264

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

265

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

266

Genotyping mutation in BmAChE3: A survey of laboratory and Mexican strains of Rhipicephalus (Boophilus) microplus that are resistant or susceptible to coumaphos  

Technology Transfer Automated Retrieval System (TEKTRAN)

BmAChE3 mutations I48L, I54V, R86Q, V137I, I492M, and T548A were previously identified in the organophosphate (OP) acaricide-resistant San Román strain of Rhipicephalus (Boophilus) microplus. Recombinant BmAChE3 acetylcholinesterase containing the R86Q mutation was shown to exhibit nearly 20-fold r...

267

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

268

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

269

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 Central

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 (Rinput) in high membrane potential (Vm) (~?40 mV) cells but with no change or an increase in Rinput in low Vm (~?75 mV) cells. ACh-depolarization was attenuated by background membrane depolarization from ~?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 20 mM 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

2008-01-01

270

Benzodiazepines inhibit the acetylcholine receptor-operated potassium current (IK.ACh) by different mechanisms in guinea-pig atrial myocytes.  

PubMed

The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (I(K).(ACh)) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3-300 µM) inhibited carbachol (1 µM)-induced I(K).(ACh) in a concentration-dependent manner. The ascending order of IC(50) values for carbachol-induced I(K).(ACh) was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 µM). The compounds, except for bromazepam, also inhibited I(K).(ACh) activated by an intracellular loading of 100 µM guanosine 5'-[?-thio]triphosphate (GTP?S) in a concentration-dependent manner. The ascending order of IC(50) values for GTP?S-activated I(K).(ACh) was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 µM) and bromazepam (>300 µM). To clarify the molecular mechanism of the inhibition, IC(50) ratio, the ratio of IC(50) for GTP?S-activated I(K).(ACh) to carbachol-induced I(K).(ACh), was calculated. The IC(50) ratio for camazepam, diazepam, lorazepam, medazepam and triazolam was close to unity, while it for chlordiazepoxide could not be calculated. These compounds would act on the GTP binding protein and/or potassium channel to achieve the anticholinergic effects in atrial myocytes. In contrast, since the IC(50) ratio for bromazepam is presumably much higher than unity judging from the IC(50) values (104.0 ± 30.0 µM for carbachol-induced I(K).(ACh) and >300 µM for GTP?S-activated I(K).(ACh), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting I(K).(ACh) by different molecular mechanisms. PMID:22333515

Okada, Muneyoshi; Mizuno, Wataru; Nakarai, Ryu; Matada, Takashi; Yamawaki, Hideyuki; Hara, Yukio

2012-07-01

271

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

272

Rinodina sophodes (Ach.) Massal.: a bioaccumulator of polycyclic aromatic hydrocarbons (PAHs) in Kanpur City, India.  

PubMed

The aim of this study is to determine the possibility of using Rinodina sophodes (Ach.) Massal., a crustose lichen as polycyclic aromatic hydrocarbons (PAHs) bioaccumulator for evaluation of atmospheric pollution in tropical areas of India, where few species of lichens are able to grow. PAHs were identified, quantified and compared to evaluate the potential utility of R. sophodes. The limit of detection for different PAHs was found to be 0.008-0.050 ?g g(?-?1). The total PAHs in different sites were ranged between 0.189 ± 0.029 and 0.494 ± 0.105 ?g g(?-?1). The major sources of PAHs were combustion of organic materials, traffic and vehicular exhaust (diesel and gasoline engine). Significantly higher concentration of acenaphthylene and phenanthrene indicates road traffic as major source of PAH pollution in the city. Two-way ANOVA also confirms that all PAHs content showed significant differences between all sampling sites (P 1%). This study establishes the utility of R. sophodes in monitoring the PAHs accumulation potentiality for development of effective tool and explores the most potential traits resistant to the hazardous environmental conditions in the tropical regions of north India, where no such other effective way of biomonitoring is known so far. PMID:21465135

Satya; Upreti, Dalip K; Patel, D K

2012-01-01

273

New method for the determination of the half inhibition concentration (IC50) of cholinesterase inhibitors.  

PubMed

A new and simple analytical method is described for the determination of the IC50 values of the inhibitors of the hydrolysis of acetylcholine (ACh) or acetylthiocholine (ATCh) by cholinesterases. The method is based on monitoring the time course of the pH value during the uninhibited and inhibited reaction. It requires only a pH meter with a suitable pH measuring cell and a small thermostated stirred batch reactor. The method has been validated for twelve different types of cholinesterase inhibitors. The determined IC50 values are comparable to those obtained by independent, more complicated, and expensive methods (Ellman's and pH-stat). PMID:23819309

Kovárová, Markéta; Komers, Karel; Stepánková, Sárka; Parík, Patrik; Cegan, Alexander

2013-01-01

274

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. PMID:21506274

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

2011-01-01

275

Hepatitis C virus NS5A inhibitors and drug resistance mutations  

PubMed Central

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

2014-01-01

276

Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts  

PubMed Central

Polymeric materials containing quaternary ammonium and/or phosphonium salts have been extensively studied and applied to a variety of antimicrobial-relevant areas. With various architectures, polymeric quaternary ammonium/phosphonium salts were prepared using different approaches, exhibiting different antimicrobial activities and potential applications. This review focuses on the state of the art of antimicrobial polymers with quaternary ammonium/phosphonium salts. In particular, it discusses the structure and synthesis method, mechanisms of antimicrobial action, and the comparison of antimicrobial performance between these two kinds of polymers. PMID:25667977

Xue, Yan; Xiao, Huining; Zhang, Yi

2015-01-01

277

Biocide comparison: Aldehyde versus mixture of aldehyde and quaternary amine  

SciTech Connect

Glutaraldehyde and quaternary ammonium chloride salts are widely used biocides in oil field systems to control microbiologically influenced corrosion (MIC). These biocides and others were evaluated for their efficacy to control sessile and planktonic sulfate reducing bacteria (SRB) and aerobic bacteria. The efficacy of these biocides was then compared. In addition to laboratory evaluation, all the biocides were evaluated against SRB and acid producing bacteria in two different field waters. It was found that the blend containing aldehyde and quaternary amino was, in general, a more effective biocide than either glutaraldehyde or quaternary amine alone.

Prasad, R. [Champion Technologies, Inc., Houston, TX (United States)

1994-12-31

278

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

279

Dimeric quaternary structure of human laforin.  

PubMed

The phosphatase laforin removes phosphate groups from glycogen during biosynthetic activity. Loss-of-function mutations in the gene encoding laforin is the predominant cause of Lafora disease, a fatal form of progressive myoclonic epilepsy. Here, we used hybrid structural methods to determine the molecular architecture of human laforin. We found that laforin adopts a dimeric quaternary structure, topologically similar to the prototypical dual specificity phosphatase VH1. The interface between the laforin carbohydrate-binding module and the dual specificity phosphatase domain generates an intimate substrate-binding crevice that allows for recognition and dephosphorylation of phosphomonoesters of glucose. We identify novel molecular determinants in the laforin active site that help decipher the mechanism of glucan phosphatase activity. PMID:25538239

Sankhala, Rajeshwer S; Koksal, Adem C; Ho, Lan; Nitschke, Felix; Minassian, Berge A; Cingolani, Gino

2015-02-20

280

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer’s disease  

PubMed Central

Objective Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer’s disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. Methods In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. Results A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510–70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. Conclusion FOXO1 may influence the clinical response to AChEIs in AD patients. PMID:25364236

Paroni, Giulia; Seripa, Davide; Fontana, Andrea; D’Onofrio, Grazia; Gravina, Carolina; Urbano, Maria; Cascavilla, Leandro; Pellegrini, Fabio; Greco, Antonio; Pilotto, Alberto

2014-01-01

281

Left frontal lobe hypoperfusion and depressive symptoms in Alzheimer's disease patients taking cholinesterase inhibitors.  

PubMed

Depressive symptoms are common in patients with Alzheimer's disease (AD) and increase the caregiver burden. Many studies have reported dorsolateral prefrontal hypometabolism or hypoperfusion in AD patients with depressive symptoms, most of whom did not take acetylcholinesterase inhibitors (AChEI). It is not clear, however, whether a similar condition is present in patients taking AChEI medication. Fifty-seven consecutive AD patients taking AChEI were recruited at a memory clinic. Objective depressive symptoms were evaluated using the depression domain of the Neuropsychiatric Inventory (NPI-dep). All patients underwent brain single photon emission computed tomography (SPECT) with (99m)Tc-ethylcysteinate dimer, and the SPECT images were analyzed using the Statistical Parametric Mapping 8 program. No significant differences between groups with positive and negative NPI-dep scores were found with respect to age, sex, years of education, and cognitive function. Compared with patients with negative NPI-dep scores, patients with NPI-dep scores ?1 showed significant hypoperfusion in the left middle frontal region. Our results indicate that the dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD patients being treated with AChEI. The area on the left side especially may be closely related to the depressive symptoms evaluated using the NPI. PMID:25453992

Oshima, Etsuko; Terada, Seishi; Sato, Shuhei; Ikeda, Chikako; Oda, Koji; Inoue, Shinichiro; Kawada, Kiyohiro; Yokota, Osamu; Uchitomi, Yosuke

2014-12-30

282

Recombinant expression of the AChR-alpha1 subunit for the detection of conformation-dependent epitopes in Myasthenia Gravis.  

PubMed

Detection of autoantibodies associated with neurological disease typically involves immunoprecipitation of radioactively labeled native proteins. We explored whether single receptor subunits, fused to Renilla luciferase (Ruc), could detect patient autoantibodies in Luciferase Immunoprecipitation Systems. Myasthenia Gravis patient sera were tested for conformational autoantibodies to only the ?1-subunit of the nicotinic acetylcholine receptor (AChR). Using a panel of 10 AChR-?1 fragments, AChR-?1-?5-Ruc demonstrated the highest immunoreactivity with a conformational-specific antibody and the highest sensitivity in a pilot cohort. Testing a larger cohort with AChR-?1-?5-Ruc demonstrated 21% sensitivity and 97% specificity. A point mutation within Ruc increased the diagnostic performance of AChR-?1-?5 (32% sensitivity, 97% specificity). The (125)I-?-bungarotoxin multi-subunit AChR assay demonstrated 63% sensitivity and 97% specificity. These findings highlight the difficulty in detecting Myasthenia Gravis conformational epitopes across assay formats and lay the foundation for detecting autoantibodies to defined recombinant chains of the AChR and potentially other neurotransmitter receptors. PMID:21195619

Ching, Kathryn H; Burbelo, Peter D; Kimball, Richard M; Clawson, Lora L; Corse, Andrea M; Iadarola, Michael J

2011-03-01

283

Recombinant expression of the AChR-alpha1 subunit for the detection of conformation-dependent epitopes in Myasthenia Gravis  

PubMed Central

Detection of autoantibodies associated with neurological disease typically involves immunoprecipitation of radioactively labeled native proteins. We explored whether single receptor subunits, fused to Renilla luciferase (Ruc), could detect patient autoantibodies in Luciferase Immunoprecipitation Systems. Myasthenia Gravis patient sera were tested for conformational autoantibodies to only the ?1-subunit of the nicotinic acetylcholine receptor (AChR). Using a panel of 10 AChR-?1 fragments, AChR-?1-?5-Ruc demonstrated the highest immunoreactivity with a conformational-specific antibody and the highest sensitivity in a pilot cohort. Testing a larger cohort with AChR-?1-?5-Ruc demonstrated 21% sensitivity and 97% specificity. A point mutation within Ruc increased the diagnostic performance of AChR-?1-?5 (32% sensitivity, 97% specificity). The 125I-?-bungarotoxin multi-subunit AChR assay demonstrated 63% sensitivity and 97% specificity. These findings highlight the difficulty in detecting Myasthenia Gravis conformational epitopes across assay formats and lay the foundation for detecting autoantibodies to defined recombinant chains of the AChR and potentially other neurotransmitter receptors. PMID:21195619

Ching, Kathryn H.; Burbelo, Peter D.; Kimball, Richard M.; Clawson, Lora L.; Corse, Andrea M.; Iadarola, Michael J.

2011-01-01

284

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. PMID:24758923

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

2014-01-01

285

The newsletter of the CAMBRIDGE QUATERNARY ISSUE 32 MICHAELMAS 2005  

E-print Network

sheets during the 20th century" November Tues 15th ESC Don Canfield (Odense, Denmark) "Neoproterozoic://www.quaternary.group.cam.ac.uk/ #12;Dates for your Diary Michaelmas 2005 October Tue 25th ESC Jake Lowenstern (Yellowstone Volcano

de Gispert, Adrià

286

Catalytic asymmetric synthesis of all-carbon quaternary stereocenters  

PubMed Central

Only a few catalytic asymmetric C—C bond-forming reactions have been shown to be useful for constructing all-carbon quaternary stereocenters. This Perspective examines the current state of such methods. PMID:14724294

Douglas, Christopher J.; Overman, Larry E.

2004-01-01

287

Heritability and fitness correlates of personality in the Ache, a natural-fertility population in Paraguay.  

PubMed

The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n?=?110) and other-reports (n?=?66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n?=?2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality. PMID:23527163

Bailey, Drew H; Walker, Robert S; Blomquist, Gregory E; Hill, Kim R; Hurtado, A Magdalena; Geary, David C

2013-01-01

288

Heritability and Fitness Correlates of Personality in the Ache, a Natural-Fertility Population in Paraguay  

PubMed Central

The current study assessed the heritability of personality in a traditional natural-fertility population, the Ache of eastern Paraguay. Self-reports (n?=?110) and other-reports (n?=?66) on the commonly used Big Five Personality Inventory (i.e., extraversion, agreeableness, conscientiousness, neuroticism, openness) were collected. Self-reports did not support the Five Factor Model developed with Western samples, and did not correlate with other-reports for three of the five measured personality factors. Heritability was assessed using factors that were consistent across self- and other-reports and factors assessed using other-reports that showed reliabilities similar to those found in Western samples. Analyses of these items in combination with a multi-generation pedigree (n?=?2,132) revealed heritability estimates similar to those found in most Western samples, although we were not able to separately estimate the influence of the common environment on these traits. We also assessed relations between personality and reproductive success (RS), allowing for a test of several mechanisms that might be maintaining heritable variation in personality. Phenotypic analyses, based largely on other-reports, revealed that extraverted men had higher RS than other men, but no other dimensions of personality predicted RS in either sex. Mothers with more agreeable children had more children, and parents mated assortatively on personality. Of the evolutionary processes proposed to maintain variation in personality, assortative mating, selective neutrality, and temporal variation in selection pressures received the most support. However, the current study does not rule out other processes affecting the evolution and maintenance of individual differences in human personality. PMID:23527163

Bailey, Drew H.; Walker, Robert S.; Blomquist, Gregory E.; Hill, Kim R.; Hurtado, A. Magdalena; Geary, David C.

2013-01-01

289

Liquid crystal alignment on aC:H films by an argon plasma jet at atmospheric pressure  

Microsoft Academic Search

A novel liquid crystal alignment method has been successfully developed. The alignment layer was made of a hydrogenated amorphous carbon film (a-C:H). At atmospheric pressure, the surface of the film was treated by a low temperature argon plasma jet. Experimental results showed that uniform alignment of the liquid crystal (ZLI-2293) has been achieved with a pretilt angle of 2.32° in

H. K. Wei; C. S. Kou; K. Y. Wu; J. Hwang

2008-01-01

290

aC(:H) and aCN x (:H) films deposited by magnetron sputtering and PACVD  

Microsoft Academic Search

Hydrogenated amorphous carbon films (a-C:H) and hydrogenated carbon films containing as much as 15 at.% nitrogen (a-CNx:H) were synthesised by a plasma-assisted chemical vapour deposition (PACVD) apparatus. By changing the gaseous precursor (CH4, C6H12, C6H6, C2H2) the hydrogen content of the films can be varied between 26 and 58 at.%; serious adhesion problems were found when the hydrogen percentage attains

L Nobili; P. L Cavallotti; G Coccia Lecis; G De Ponti; C Lenardi

1998-01-01

291

Developmental Regulation of Nicotinic ACh Receptor Subunit mRNAs in the Rat Central and Peripheral Nervous Systems  

Microsoft Academic Search

In the present study we have investigated the anatomical distribution pattern of nAChR (~3, 0~4, p2, and f34 subunit mRNAs during prenatal and perinatal development of the rat CNS and PNS. Three main developmental patterns have been recognized. (1) In the majority of cases studied (cau- dal brain, spinal cord, dorsal root ganglia, trigeminal and geniculate ganglia) all four subunit

Michele Zoli; Joseph A. Hill; Jean-Pierre Changeux

1995-01-01

292

The effects of climatic pattern on lichen productivity: Cetraria cucullata (Bell.) Ach. in the arctic tundra of northern Alaska  

Microsoft Academic Search

The climatic control of productivity for two populations of the lichen Cetraria cucullata (Bell.) Ach. growing in the arctic tundra of northern Alaska (70°28'N, 157°23'W) was examined. Respiratory losses of carbon vary with tissue temperature, tissue water content, and time since wetting. Potential net photosynthetic gains of carbon are affected by photon flux density, tissue temperature, and water content. The

Martin J. Lechowicz

1981-01-01

293

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits  

PubMed Central

Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. PMID:23659787

2013-01-01

294

Density of ?4?2* nAChR on the surface of neurons is modulated by chronic antagonist exposure  

PubMed Central

The expression of high-affinity ?4?2* nicotinic acetylcholine receptors (nAChR) increases following chronic exposure to nicotinic agonists. While, nAChR antagonists can also produce upregulation, these changes are often less pronounced than achieved with agonists. It is unknown if nAChR agonists and antagonists induce receptor upregulation by the same mechanisms. In this study, primary neuronal cultures prepared from cerebral cortex, hippocampus, diencephalon, and midbrain/hindbrain of C57BL/6J mouse embryos were treated chronically with nicotine (agonist), mecamylamine (noncompetitive antagonist) or dihydro-?-erythroidine (competitive antagonist) or the combination of nicotine with each antagonist. The distribution of intracellular and surface [125I]epibatidine-binding sites were subsequently measured. Treatment with 1 ?mol/L nicotine upregulated intracellular and cell surface [125I]epibatidine binding after 96 h. Chronic dihydro-?-erythroidine (10 ?mol/L) treatment also increased [125I]epibatidine binding on the cell surface; however, mecamylamine was ineffective in upregulating receptors by itself. The combination of 1 ?mol/L nicotine plus 10 ?mol/L mecamylamine elicited a significantly higher upregulation than that achieved by treatment with nicotine alone due to an increase of [125I]epibatidine binding on the cell surface. This synergistic effect of mecamylamine and nicotine was found in neuronal cultures from all four brain regions. Chronic treatment with nicotine concentrations as low as 10 nmol/L produced upregulation of [125I]epibatidine binding. However, the effect of mecamylamine was observed only after coincubation with nicotine concentrations equal to or greater than 100 nmol/L. Vesicular trafficking was required for both nicotine and nicotine plus mecamylamine-induced upregulation. Results presented here support the idea of multiple mechanisms for nAChR upregulation. PMID:25729578

Zambrano, Cristian A; Short, Caitlin A; Salamander, Rakel M; Grady, Sharon R; Marks, Michael J

2015-01-01

295

A novel Voltage-mode CMOS quaternary logic design  

Microsoft Academic Search

This brief presents a novel kind of voltage-mode CMOS design that uses multiple threshold voltage transistors and three power supply lines to implement quaternary logic gates, showing lower power dissipation and using less area than the present voltage-mode quaternary circuits. Inverter, NMIN, and NMAX gates are simulated with the Spice tool using TSMC 0.18-?m technology. The proposed logic circuits overcome

R. C. G. da Silva; H. Boudinov; L. Carro

2006-01-01

296

The tempo of avian diversification during the Quaternary  

Microsoft Academic Search

It is generally assumed that the Quaternary was a period of heightened diversification in temperate ver- tebrate organisms. Previous molecular systematics studies have challenged this assertion. We re-examined this issue in north temperate birds using log-lineage plots and distributions of sister-taxon distances. Log- lineage plots support earlier conclusions that avian diversification slowed during the Quaternary. To test plots of empirical

Robert M. Zink; John Klicka; Brian R. Barber

2004-01-01

297

Aromatase and its inhibitors  

Microsoft Academic Search

Inhibitors of aromatase (estrogen synthetase) have been developed as treatment for postmenopausal breast cancer. Both steroidal substrate analogs, type I inhibitors, which inactivate the enzyme and non-steroidal competitive reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione (4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum estrogen concentrations and cause complete and partial responses in approximately 25% of

Angela Brodie; Qing Lu; Brian Long

1999-01-01

298

Synthesis and anticoagulant activity of the quaternary ammonium chitosan sulfates.  

PubMed

Quaternary ammonium chitosan sulfates with diverse degrees of substitution (DS) ascribed to sulfate groups between 0.52 and 1.55 were synthesized by reacting quaternary ammonium chitosan with an uncommon sulfating agent (N(SO(3)Na)(3)) that was prepared from sodium bisulfite (NaHSO(3)) through reaction with sodium nitrite (NaNO(2)) in the aqueous system homogeneous. The structures of the derivatives were characterized by FTIR, (1)H NMR and (13)C NMR. The factors affecting DS of quaternary ammonium chitosan sulfates which included the molar ratio of NaNO(2) to quaternary ammonium chitosan, sulfated temperature, sulfated time and pH of sulfated reaction solution were investigated in detail. Its anticoagulation activity in vitro was determined by an activated partial thromboplastin time (APTT) assay, a thrombin time (TT) assay and a prothrombin time (PT) assay. Results of anticoagulation assays showed quaternary ammonium chitosan sulfates significantly prolonged APTT and TT, but not PT, and demonstrated that the introduction of sulfate groups into the quaternary ammonium chitosan structure improved its anticoagulant activity obviously. The study showed its anticoagulant properties strongly depended on its DS, concentration and molecular weight. PMID:21996571

Fan, Lihong; Wu, Penghui; Zhang, Jinrong; Gao, Song; Wang, Libo; Li, Mingjia; Sha, Mingming; Xie, Weiguo; Nie, Min

2012-01-01

299

Redefining the role of the quaternary shift in Bacillus stearothermophilus phosphofructokinase.  

PubMed

Bacillus stearothermophilus phosphofructokinase (BsPFK) is a homotetramer that is allosterically inhibited by phosphoenolpyruvate (PEP), which binds along one dimer-dimer interface. The substrate, fructose 6-phosphate (Fru-6-P), binds along the other dimer-dimer interface. Evans et al. observed that the structure with inhibitor (phosphoglycolate) bound, compared to the structure of wild-type BsPFK with substrate and activator bound, exhibits a 7° rotation about the substrate-binding interface, termed the quaternary shift [Schirmer, T., and Evans, P. R. (1990) Nature 343, 140-145]. We report that the variant D12A BsPFK exhibits a 100-fold increase in its binding affinity for PEP, a 50-fold decrease in its binding affinity for Fru-6-P, but an inhibitory coupling comparable to that of the wild type. Crystal structures of the apo and PEP-bound forms of D12A BsPFK have been determined (Protein Data Bank entries 4I36 and 4I7E , respectively), and both indicate a shifted structure similar to the inhibitor-bound structure of the wild type. D12 does not directly bind to either substrate or inhibitor and is located along the substrate-binding interface. A conserved hydrogen bond between D12 and T156 forms across the substrate-binding subunit-subunit interface in the substrate-bound form of BsPFK. The variant T156A BsPFK, when compared to the wild type, shows a 30-fold increase in PEP binding affinity, a 17-fold decrease in Fru-6-P binding affinity, and an estimated coupling that is also approximately equal to that of the wild type. In addition, the T156A BsPFK crystal structure bound to PEP is reported (Protein Data Bank entry 4I4I ), and it exhibits a shifted structure similar to that of D12A BsPFK and the inhibitor-bound structure of the wild type. The results suggest that the main role of the quaternary shift may be to influence ligand binding and not to cause the heterotropic allosteric inhibition per se. PMID:23859543

Mosser, Rockann; Reddy, Manchi C M; Bruning, John B; Sacchettini, James C; Reinhart, Gregory D

2013-08-13

300

Redefining the Role of the Quaternary Shift in Bacillus stearothermophilus Phosphofructokinase  

PubMed Central

Bacillus stearothermophilus PFK (BsPFK) is a homotetramer that is allosterically inhibited by phosphoenolpyruvate (PEP), which binds along one dimer-dimer interface. The substrate, fructose 6-phosphate (Fru-6-P), binds along the other dimer-dimer interface. Evans et al., observed that the inhibitor, phosphoglycolate, bound structure, when compared to the substrate and activator bound structure of wild-type BsPFK, exhibits a 7° rotation about the substrate-binding interface, termed the quaternary shift [Schirmer, T., and Evans, P. R. (1990) Nature 343, 140-145]. We report that the variant D12A BsPFK exhibits a 100-fold increase in the binding affinity for PEP, a 50-fold decrease in the binding affinity for Fru-6-P, but an inhibitory coupling comparable to wild type. Crystal structures of the apo and PEP bound forms of D12A BsPFK have been determined (Protein Data Bank ID codes 4I36 and 4I7E, respectively), and both indicate a shifted structure similar to the inhibitor-bound structure of wild type. D12 does not directly bind to either substrate or inhibitor and is located along the substrate-binding interface. A conserved hydrogen bond between D12 and T156 forms across the substrate-binding subunit-subunit interface in the substrate-bound form of BsPFK. The variant T156A BsPFK, when compared to wild-type, shows a 30-fold increase in PEP binding affinity, a 17-fold decrease in Fru-6-P binding affinity, and an estimated coupling that is also approximately equal to wild-type. In addition, the T156A BsPFK crystal structure bound to PEP is reported (Protein Data Bank ID code 4I4I), and it exhibits a shifted structure similar to D12A BsPFK and the inhibitor-bound structure of wild type. The results suggest that main role of the quaternary shift may be to influence ligand binding and not to cause the heterotropic allosteric inhibition per se. PMID:23859543

Mosser, Rockann; Reddy, Manchi C. M.; Bruning, John B.; Sacchettini, James C.; Reinhart, Gregory D.

2013-01-01

301

Bis-quaternary oximes amplify the effectiveness of acetylcholinesterase to detoxify organophosphorus compounds  

SciTech Connect

Pretreatment of rhesus monkeys with fetal bovine serum acetylcholinesterase (FBS AChE) provides complete protection against 5 LD(50), of organophosphate (OP) without any signs of toxicity or performance decrements as measured by serial probe recognition tests or primate equilibrium platform performance (7,8). Although such use of enzyme as a single pretreatment drug for OP toxicity is sufficient to provide complete protection, a relatively large (stoichiometric) amount of enzyme was required in vivo to neutralize OP. To improve the efficacy of ChEs as pretreatment drugs, we have developed an approach in which the catalytic activity of OP-inhibited FBS AChE was rapidly and continuously restored, thus detoxifying the OP and minimizing enzyme aging by having sufficient amounts of appropriate oxime present. The efficacy of FBS AChE to detoxify several OPs was amplified by addition of bisquaternary oximes, particularly HI-6. When mice were pretreated with sufficient amounts of FBS AChE and HI-6 and challenged with repeated doses of sarin, the OP was continuously detoxified so long as the molar concentration of the sarin dose was less than the molar concentration of AChE in circulation. The in vitro experiments showed that the stoichiometry of sarin:FBS AChE was higher than 3200:1 and in vivo stoichiometry with mice was as high as 57:1. Addition of HI-6 to FBS AChE as a pretreatment drug amplified the efficacy of enzyme as a scavenger of nerve agents.

Caranto, G.R.; Waibel, K.H.; Asher, J.M.; Larrison, R.W.; Brecht, K.M.

1993-05-13

302

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

303

Identification and Characterization of ML352: A Novel, Noncompetitive Inhibitor of the Presynaptic Choline Transporter.  

PubMed

The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents. PMID:25560927

Ennis, Elizabeth A; Wright, Jane; Retzlaff, Cassandra L; McManus, Owen B; Lin, Zhinong; Huang, Xiaofang; Wu, Meng; Li, Min; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Blakely, Randy D

2015-03-18

304

Identification and Characterization of ML352: A Novel, Noncompetitive Inhibitor of the Presynaptic Choline Transporter  

PubMed Central

The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents. PMID:25560927

2015-01-01

305

Experimental investigation into Quaternary badland geomorphic development  

NASA Astrophysics Data System (ADS)

Badland morphology is commonly linked to lithological properties of the bedrock. However, recent investigations indicate that the geomorphic development is sensitive to climate and in particular to precipitation characteristics. In this study, the precipitation characteristics that are critical for the Quaternary landscape development in the Dinosaur Badlands in Alberta, Canada, and Zin Valley Badlands, Negev Desert, Israel are investigated. Runoff, erosion and weathering were simulated in the field and the laboratory to determine rates for modeling different precipitation regimes. Currently, the geomorphic development in the Dinosaur badlands is characterized by weathering/supply limited conditions, leading to slope retreat independent of lithology. In the Negev, transport limited conditions cause frequent runoff discontinuity, creating a pattern of areas dominated by erosion or deposition. The results of the weathering and erosion experiments show that the balance between snowmelt induced weathering in the spring and summer rainfall and erosion determine the rate of slope retreat in the Dinosaur Badlands. In the Zin Valley, on the other hand, the magnitude of the individual rainstorms determines whether a slope section is eroded or acts as a sediment sink. The experiments illustrate that the badland slopes experienced an auto-stabilization during the Quaternary in the Zin Valley. In the Dinosaur Badlands Holocene climatic variations have not caused a permanent differentiation of patterns of erosion and deposition. Based on these results the reaction of badland slopes to changing precipitation characteristics was modeled. In their current state, both badland slope systems appear to be fairly stable against climate change in the range of those occurring during the Holocene. However, the stability is achieved in different ways. In the Dinosaur Badlands, weathering rates are low compared to erosion capacity, maintaining continuous evacuation of sediment from slopes to the flood planes of the Red Deer River system. Only a very pronounced contrast between winter weathering and drier summers would generate a colluvium and thus change slope hydrology. In the Zin Valley the development of a thick colluvium at the foot of the slopes has increased infiltration capacity, reducing runoff and sediment yield into the floodplain. Here, only an increase in rainfall magnitude would improve runoff continuity and induce the erosion of the colluvium. This would in turn reduce infiltration capacity and thus initiate a positive feedback on runoff and sediment yield into the Zin River. Overall, Holocene climate change appears to be insufficient to change the geomorphic development in both badlands. However, this stability is achieved not despite of climate, but because of the specific history of geomorphic development. In addition, the combination of erosion and weathering experiments with numerical modeling demonstrates the versatility of Experimental Geomorphology in landscape evolution studies.

Kasanin-Grubin, Milica; Kuhn, Nikolaus; Yair, Aaron; Bryan, Rorke; Schwanghart, Wolfgang

2010-05-01

306

ARIA\\/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras\\/MAPK pathway  

Microsoft Academic Search

AChR-inducing activity (ARIA)\\/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces ex- pression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction

Maid G. Tansey; Gerald C. Chu; John P. Meflie

1996-01-01

307

A combined molecular docking and charge density analysis is a new approach for medicinal research to understand drug-receptor interaction: curcumin-AChE model.  

PubMed

In the present study, a molecular docking analysis has been performed on diketone form of curcumin molecule with acetylcholinesterase (AChE). The calculated lowest docked energy of curcumin molecule in the active site of AChE is -11.21 kcal/mol; this high negative value indicates that the molecule exhibits large binding affinity towards AChE. When the curcumin molecule present in the active site of AChE, subsequently, its conformation has altered significantly and the molecule adopts a U-shape geometry as it is linear in gas phase (before entering into the active site). This conformational transition facilitates curcumin to form strong interaction with Phe330 of acyl-binding pocket and the choline binding site with indole ring of Trp84 and Asp72. The gas phase and the active site analysis of curcumin allows to understand the conformational geometry, nature of molecular flexibility, charge density redistribution and the variation of electrostatic properties of curcumin in the active site. To obtain the gas phase structure, the curcumin molecule was optimized using Hartree-Fock and density functional methods (B3LYP) with the basis set 6-311G(??). A charge density analysis on both gas phase as well as the molecule lifted from the active site was carried out using Bader's theory of atoms in molecules (AIM). The difference in molecular electrostatic potential between the two forms of curcumin displays the difference in charge distribution. The large dipole moment of curcumin (7.54 D) in the active site reflects the charge redistribution as it is much less in the gas phase (4.34 D). PMID:25446495

Renuga Parameswari, A; Rajalakshmi, G; Kumaradhas, P

2015-01-01

308

Evidence that CGRP and cAMP increase transcription of AChR ?-subunit gene, but not of other subunit genes  

Microsoft Academic Search

Calcitonin gene-related peptide (CGRP) is present in embryonic chick motoneurons and their terminals during myogenesis. We\\u000a have studied the effect of CGRP on the expression of mRNA encoding the four subunits (?, ?, ?, ?) of ACh receptors in cultured\\u000a myotubes derived from embryonic chicks. Northern blot analysis showed that treatment with 10?7 M CGRP caused an increase in ACh

S. J. Moss; P. C. Harkness; I. J. Mason; E. A. Barnard; A. W. Mudge

1991-01-01

309

High therapeutic potential of positive allosteric modulation of ?7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept.  

PubMed

There are currently no clinically efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously reported highly selective Type-II positive allosteric modulator (?7-PAM) of ?7 nicotinic acetylcholine receptors (nAChRs). ?7-PAMs enhance and prolong ?7 nAChR activation, but do not activate ?7 nAChRs when administered without an agonist. The rational basis for the use of an ?7-PAM as a post-TBI treatment is tripartite and arises from: (1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of ?7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; (2) the ubiquitous expression of functional ?7 nAChRs in neuronal and glial/immune brain cells; and (3) the potent neuroprotective and anti-inflammatory effects of ?7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the ?7 nAChR) using ?7-PAMs to enhance the activation of ?7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of ?7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients. PMID:25647232

Gatson, Joshua W; Simpkins, James W; Uteshev, Victor V

2015-03-01

310

Quaternary ammonium biocides: efficacy in application.  

PubMed

Quaternary ammonium compounds (QACs) are among the most commonly used disinfectants. There has been concern that their widespread use will lead to the development of resistant organisms, and it has been suggested that limits should be place on their use. While increases in tolerance to QACs have been observed, there is no clear evidence to support the development of resistance to QACs. Since efflux pumps are believe to account for at least some of the increased tolerance found in bacteria, there has been concern that this will enhance the resistance of bacteria to certain antibiotics. QACs are membrane-active agents interacting with the cytoplasmic membrane of bacteria and lipids of viruses. The wide variety of chemical structures possible has seen an evolution in their effectiveness and expansion of applications over the last century, including non-lipid-containing viruses (i.e., noroviruses). Selection of formulations and methods of application have been shown to affect the efficacy of QACs. While numerous laboratory studies on the efficacy of QACs are available, relatively few studies have been conducted to assess their efficacy in practice. Better standardized tests for assessing and defining the differences between increases in tolerance versus resistance are needed. The ecological dynamics of microbial communities where QACs are a main line of defense against exposure to pathogens need to be better understood in terms of sublethal doses and antibiotic resistance. PMID:25362069

Gerba, Charles P

2015-01-01

311

Quaternary structure of hemoglobin in solution  

NASA Astrophysics Data System (ADS)

Many important proteins perform their physiological functions under allosteric control, whereby the binding of a ligand at a specific site influences the binding affinity at a different site. Allosteric regulation usually involves a switch in protein conformation upon ligand binding. The energies of the corresponding structures are comparable, and, therefore, the possibility that a structure determined by x-ray diffraction in the crystalline state is influenced by its intermolecular contacts, and thus differs from the solution structure, cannot be excluded. Here, we demonstrate that the quaternary structure of tetrameric human normal adult carbonmonoxy-hemoglobin can readily be determined in solution at near-physiological conditions of pH, ionic strength, and temperature by NMR measurement of 15N-1H residual dipolar couplings in weakly oriented samples. The structure is found to be a dynamic intermediate between two previously solved crystal structures, known as the R and R2 states. Exchange broadening at the subunit interface points to a rapid equilibrium between different structures that presumably include the crystallographically observed states.

Lukin, Jonathan A.; Kontaxis, Georg; Simplaceanu, Virgil; Yuan, Yue; Bax, Ad; Ho, Chien

2003-01-01

312

Late Quaternary mammalian zoogeography of eastern Washington  

NASA Astrophysics Data System (ADS)

The late Quaternary mammalian zoogeographic history of eastern Washington as revealed by archaeological and paleontological research conforms to a set of past environmental conditions inferred from botanical data. During the relatively cool and moist late Pleistocene and early Holocene, Cervus cf. elaphus, Ovis canadensis, Vulpes vulpes, Martes americana, Alopex lagopus, and perhaps Rangifer sp., taxa with ecological preferences for mesic steppe habitats, were present in the now xeric Columbia Basin. As the climate became progressively warmer and drier during the late Pleistocene and early Holocene, Antilocapra americana, Onychomys leucogaster, Spermophilus townsendii, and Neotoma cinerea, taxa with ecological preferences for xeric steppe habitats, appear in the Columbia Basin. Bison sp. and Taxidea taxus may have been present in eastern Washington for the last 20,000 yr. Middle and late Holocene records for Oreamnos americanus, Spermophilus columbianus, S. townsendii, Lagurus curtatus, and Urocyon cinereoargenteus in central eastern Washington suggest fluctuations in the ranges of these taxa that conform to a middle Holocene period of less effective precipitation and a ca. 3500-yr-old period of more effective precipitation before essentially modern environmental conditions prevailed.

Lyman, R. Lee; Livingston, Stephanie D.

1983-11-01

313

Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.  

PubMed

A large series of pharmacological agents, distinct from the typical competitive antagonists, block in a noncompetitive manner the permeability response of the nicotinic acetylcholine receptor (nAChR) to the neurotransmitter acetylcholine. Taking the neuroleptic chlorpromazine (CPZ) as an example of such agents, the blocking mechanism of noncompetitive inhibitors to the ion channel pore of the nAChR has been explored at the atomic level using both conventional and steered molecular dynamics (MD) simulations. Repeated steered MD simulations have permitted calculation of the free energy (approximately 36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at approximately 4 A from the pore entrance. Coulomb and the Lennard-Jones interactions between CPZ and the ion channel as well as the conformational fluctuations of CPZ were examined to assess the contribution of each to the binding of CPZ to the nAChR. The MD simulations disclose a dynamic interaction of CPZ binding to the nAChR ionic channel. The cationic ammonium head of CPZ forms strong hydrogen bonds with Glu262 (alpha), Asp268 (beta), Glu272 (beta), Ser276 (beta), Glu280 (delta), Gln271 (gamma), Glu275 (gamma), and Asn279 (gamma) nAChR residues. Finally, the conventional MD simulation of CPZ at its identified binding site demonstrates that the binding of CPZ not only blocks ion transport through the channel but also markedly inhibits the conformational transitions of the channel, necessary for nAChR to carry out its biological function. PMID:17034254

Xu, Yechun; Barrantes, Francisco J; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Chen, Kaixian; Jiang, Hualiang

2006-10-19

314

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

315

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

316

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. PMID:10631970

Arnon, R.; Silman, I.; Tarrab-Hazdai, R.

1999-01-01

317

On the origin and fate of external acetylcholinesterase in peripheral nerve.  

PubMed Central

1. Rabbit peroneal nerves were exposed to echothiophate, a quaternary ammonium inhibitor of acetylcholinesterase (AChE), and 217-AO, its tertiary analogue, in an attempt to characterize the localization of the enzyme. Although 217-AO readily inhibited AChE throughout the nerves, echothiophate spared significant amounts unless the tissues had first been homogenized. Notably, doses of echothiophate inhibiting 84% of the total AChE inhibited only 30% of the rapidly transported enzyme, suggesting that AChE was distributed between compartments differing greatly in their accessibility to this drug. 2. Since charged molecules penetrate cells poorly, it seemed likely that the more accessible compartment of AChE was external, perhaps consisting mainly of enzyme incorporated into the outer surface of the axolemma. If one assumes that the inhibition of the transported enzyme accurately reflected the inhibition throughout the inaccessible compartment, it can be calculated that external AChE comprised about 80% of the total. 3. The quasi-irreversible inhibition of AChE by echothiophate was used to probe the dynamics of the external enzyme. Locally exposing nerves to this drug in vivo markedly inhibited the AChE in a short region, which subsequently recovered with a half-time of about 5 days. Recovery appeared to reflect delivery of new enzyme into the inhibited region rather than spontaneous reactivation or local synthesis of AChE. Surprisingly, the zone of inhibition neither broadened nor moved noticeably for at least 8 days. This implies that external AChE is largely fixed in place and must be renewed locally, presumably by incorporation of rapidly transported enzyme from the internal compartment. PMID:84869

Brimijoin, S; Skau, K; Wiermaa, M J

1978-01-01

318

Proton pump inhibitors  

MedlinePLUS

Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

319

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

320

Chemical sputtering of a-C:H films by simultaneous exposure to energetic Ar+ ions and water vapor  

NASA Astrophysics Data System (ADS)

Amorphous hydrocarbon films (a-C:H) were exposed to a beam of 800eV Ar+ ions. The temperature of the films was varied between 110 an 800K. When backfilling the chamber with water vapor during ion bombardment there is a marked increase of the erosion rate at and below 200 K, while there is no influence on the erosion rate at room temperature and above. We explain the observed synergism by an ion-induced reaction between adsorbed water molecules and the film surface in which volatile erosion products are formed.

Hopf, C.; Schlüter, M.; Jacob, W.

2008-03-01

321

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

322

[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. PMID:24556591

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

323

The isotope hydrology of Quaternary climate change.  

PubMed

Understanding the links between climate change and human migration and culture is an important theme in Quaternary archaeology. While oxygen and hydrogen stable isotopes in high-latitude ice cores provide the ultimate detailed record of palaeoclimate extending back to the Middle Pleistocene, groundwater can act as a climate archive for areas at lower latitudes, permitting a degree of calibration for proxy records such as lake sediments, bones, and organic matter. Not only can oxygen and hydrogen stable isotopes be measured on waters, but the temperature of recharge can be calculated from the amount of the atmospheric noble gases neon, argon, krypton, and xenon in solution, while residence time can be estimated from the decay of the radioisotopes carbon-14, chlorine-36, and krypton-81 over timescales comparable to the ice core record. The Pleistocene-Holocene transition is well characterised in aquifers worldwide, and it is apparent that isotope-temperature relationships of the present day are not necessarily transferable to past climatic regimes, with important implications for the interpretation of proxy isotope data. Groundwaters dating back to one million years, i.e., to beyond the Middle Pleistocene, are only found in major aquifer basins and information is relatively sparse and of low resolution. Speleothem fluid inclusions offer a way of considerably increasing this resolution, but both speleothem formation and large-scale groundwater recharge requires humid conditions, which may be relatively infrequent for areas currently experiencing arid climates. Both types of record therefore require caution in their interpretation when considering a particular archaeological context. PMID:21051074

Darling, W G

2011-04-01

324

Acute toxicity of a commercial glyphosate formulation on European sea bass juveniles (Dicentrarchus labrax L.): gene expressions of heme oxygenase-1 (ho-1), acetylcholinesterase (AChE) and aromatases (cyp19a and cyp19b).  

PubMed

Acute toxicity of Roundup, a commercial glyphosate--based herbicide, was evaluated in a teleost marine fish, the European sea bass, after 96 h of exposure. The LC50 96-h value of Roundup was 529 mg/L. Juveniles (Dicentrarchus labrax L.) were exposed to a sublethal concentration (35% of the LC50, i.e. 193 mg/L) of Roundup for 96-h. The study of heme oxygenase-1 (ho-1) gene expression was performed in four tissues (liver, gills, brain and gonads) and highlighted the disruption of antioxidant defence system. Results showed that ho-1 mRNA levels in liver and gills significantly decreased (p<0.001 and p<0.01 respectively) in fish exposed to 193 mg/L of Roundup, whereas in brain and gonads, ho-1 mRNA level was not altered. The analysis of acetylcholinesterase expression was used to evaluate the overall neurotoxicity of the herbicide and aromatase genes to assess the alteration of the endocrine system. Results showed that AChE and cyp19b gene transcriptions significantly increased (p<0.01) in brain of sea bass, whereas aromatase gene expression (cyp19a) in gonads was not significantly altered. Our results showed complex tissue-specific transcriptional responses after 96 h of exposure to a sublethal concentration. All these disruptions confirmed the deleterious effects of this glyphosate-based herbicide in a marine species. PMID:24461331

Prevot-D'Alvise, N; Richard, S; Coupé, S; Bunet, R; Grillasca, J P

2013-01-01

325

Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity  

SciTech Connect

The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

1984-04-01

326

Tertiary and Quaternary Research with Remote Sensing Methods  

NASA Technical Reports Server (NTRS)

Problems encountered in mapping the Quaternary section of the Wind River Region using remote sensing methods are discussed. Analysis of the stratigraphic section is a fundamental aspect of the geologic study of sedimentary basins. Stratigraphic analysis of post-Cretaceous rocks in the Wind River Basin encounters problems of a distinctly different character from those involved in studying the pre-Cretaceous section. The interior of the basin is predominantly covered by Tertiary and Quaternary sediments. These rocks, except on the basin margin to the north, are mostly flat lying or gently dipping. The Tertiary section consists of sandstones, siltstones, and tuffaceous sediments, some variegated, but in general poorly bedded and of great lithologic similarity. The Quaternary sediments consist of terrace, fan, and debris tongue deposits, unconsolidated alluvium occupying the bottoms of modern watercourses, deposits of eolian origin and tufa. Terrace and fan deposits are compositionally diverse and reflect the lithologic diversity of the source terranes.

Conel, J. E.

1985-01-01

327

Tertiary and quaternary research with remote sensing methods  

NASA Astrophysics Data System (ADS)

Problems encountered in mapping the Quaternary section of the Wind River Region using remote sensing methods are discussed. Analysis of the stratigraphic section is a fundamental aspect of the geologic study of sedimentary basins. Stratigraphic analysis of post-Cretaceous rocks in the Wind River Basin encounters problems of a distinctly different character from those involved in studying the pre-Cretaceous section. The interior of the basin is predominantly covered by Tertiary and Quaternary sediments. These rocks, except on the basin margin to the north, are mostly flat lying or gently dipping. The Tertiary section consists of sandstones, siltstones, and tuffaceous sediments, some variegated, but in general poorly bedded and of great lithologic similarity. The Quaternary sediments consist of terrace, fan, and debris tongue deposits, unconsolidated alluvium occupying the bottoms of modern watercourses, deposits of eolian origin and tufa. Terrace and fan deposits are compositionally diverse and reflect the lithologic diversity of the source terranes.

Conel, J. E.

1985-08-01

328

The tempo of avian diversification during the Quaternary.  

PubMed Central

It is generally assumed that the Quaternary was a period of heightened diversification in temperate vertebrate organisms. Previous molecular systematics studies have challenged this assertion. We re-examined this issue in north temperate birds using log-lineage plots and distributions of sister-taxon distances. Log-lineage plots support earlier conclusions that avian diversification slowed during the Quaternary. To test plots of empirical sister-taxon distances we simulated three sets of phylogenies: constant speciation and extinction, a pulse of recent speciation, and a pulse of recent extinction. Previous opinions favour the model of recent speciation although our empirical dataset on 74 avian comparisons failed to reject a distribution derived from the constant and extinction models. Hence, it does not appear that the Quaternary was a period of exceptional rates of diversification, relative to the background rate. PMID:15101578

Zink, Robert M; Klicka, John; Barber, Brian R

2004-01-01

329

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

Code of Federal Regulations, 2013 CFR

...2013-07-01 2013-07-01 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...

2013-07-01

330

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

331

Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes.  

PubMed

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTP?S). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTP?S-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 ?M, clozapine 0.06 ?M, fluphenazine 2.69 ?M, haloperidol 2.66 ?M, sulpiride 42.3 ?M, thioridazine 0.07 ?M, amitriptyline 0.03 ?M, imipramine 0.22 ?M and maprotiline 1.81 ?M. The drugs, except for sulpiride, inhibited GTP?S-activated IK.ACh with following IC50 values; chlorpromazine 1.71 ?M, clozapine 14.9 ?M, fluphenazine 3.55 ?M, haloperidol 2.73 ?M, thioridazine 1.90 ?M, amitriptyline 7.55 ?M, imipramine 7.09 ?M and maprotiline 5.93 ?M. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel. PMID:23343658

Okada, Muneyoshi; Watanabe, Shinya; Matada, Takashi; Asao, Yoko; Hamatani, Ramu; Yamawaki, Hideyuki; Hara, Yukio

2013-01-01

332

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. PMID:22957729

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

333

Structure of ?-conglutin: insight into the quaternary structure of 7S basic globulins from legumes.  

PubMed

?-Conglutin from lupin seeds is an unusual 7S basic globulin protein. It is capable of reducing glycaemia in mammals, but the structural basis of this activity is not known. ?-Conglutin shares a high level of structural homology with glycoside hydrolase inhibitor proteins, although it lacks any kind of inhibitory activity against plant cell-wall degradation enzymes. In addition, ?-conglutin displays a less pronounced structural similarity to pepsin-like aspartic proteases, but it is proteolytically dysfunctional. Only one structural study of a legume 7S basic globulin, that isolated from soybean, has been reported to date. The quaternary assembly of soybean 7S basic globulin (Bg7S) is arranged as a cruciform-shaped tetramer comprised of two superposed dimers. Here, the crystal structure of ?-conglutin isolated from Lupinus angustifolius seeds (LangC) is presented. The polypeptide chain of LangC is post-translationally cleaved into ? and ? subunits but retains its covalent integrity owing to a disulfide bridge. The protomers of LangC undergo an intricate quaternary assembly, resulting in a ring-like hexamer with noncrystallographic D3 symmetry. The twofold-related dimers are similar to those in Bg7S but their assembly is different as a consequence of mutations in a ?-strand that is involved in intermolecular ?-sheet formation in ?-conglutin. Structural elucidation of ?-conglutin will help to explain its physiological role, especially in the evolutionary context, and will guide further research into the hypoglycaemic activity of this protein in humans, with potential consequences for novel antidiabetic therapies. PMID:25664733

Czubinski, Jaroslaw; Barciszewski, Jakub; Gilski, Miroslaw; Szpotkowski, Kamil; Debski, Janusz; Lampart-Szczapa, Eleonora; Jaskolski, Mariusz

2015-02-01

334

Quaternary tectonics of the southeastern coastal area, Korea: subsidence of marine terrace and late Quaternary faults  

NASA Astrophysics Data System (ADS)

Strong earthquake has rarely occurred in Korean peninsula and a few events were recorded since 27 A.D. Historical and recent earthquakes are concentrated in the southeastern area of Korean peninsula, where more than 30 Quaternary fault exposures have recently been founded. The southern tip of the southeastern coastal area has been known as a stable block: quaternary fault and micro-earthquakes haven’t occurred. To clarify whether the active tectonic movement is or not, digital marine terrace mapping and fracture mapping have been done for the southeastern coastal area. The area is composed of the Late Cretaceous volcanic rocks, sedimentary rocks and the Early Tertiary granite. Wave-cut platform in the area is comparatively smaller and narrower than that of other southeastern parts. Most of platforms have no Quaternary sediments and or very thin sediments. Platforms except the Holocene are generally divided into three steps. The lowest platform has a height of 8-11m. The middle one is broad with a height of 17 to 22m. The highest is narrowly scattered with a height of 33-41m. The lowest platform is correlated to the 2nd terrace of the northern area, which has been attributed to the isotopic substage, 5a. The uplift rate based on the altimetrical and indirect chronological data ranges from 0.072-0.108 m/ky. Such a low uplift rate indicates that the area is very stable because of belonging to intra-plate or continental block. The elevation of platform is getting lower from the north to the south. Reducing altitude of platform towards the south might be interpreted to a local block tilting within Yangsan Fault Belt during the Latest Pleistocene or an active tectonic subsidence to the south throughout the whole Korean peninsula. Several Quaternary faults supporting the active tectonic movement have been found from marine terrace feature mapping. Two sites have been proved the presence of fault by geophysical survey and cut-slope. Flight of marine terrace at two fault sites inclines slowly to the inland side and shows topographically vertical offset with small amount. Local block tilting and subsiding platforms from the north to the south are both due to the active tectonic fault movement of the Latest Pleistocene. Accompanied reverse Pleistocene faults dip to the east and show the top-up-to-the-west reverse movement sense. GPS measurement revealed the west of northwestern vector. Differential tectonic stress regime to the west has occurred to Korean peninsula during the Latest Pleistocene. Stronger tectonic force from the Pacific Ocean Plate gave an effect of high platform to the northern area. Weaker dynamic force due to the Philippine Plate caused low elevation to the southern area.

Choi, S.-J.; Ota, Y.; Chwae, U.

2003-04-01

335

Cancer ‘survivor-care’: I. the ?7 nAChR as potential target for chemotherapy-related cognitive impairment  

PubMed Central

SUMMARY What is known and Objective Far more patients are now surviving cancer than ever before because of major advances in the diagnosis and treatment of primary and metastatic malignancy. Adjuvant chemotherapeutic drug and combination regimens have contributed to the success. However, persistent residual adverse effects involving mild impairment of cognitive impairment have been reported. Our objective is to review and to comment on the basic science and clinical evidence of potential pharmacologic targets for managing this emerging concern. Comment A search was conducted of basic science and clinical literature related to the objective and the information obtained was organized and evaluated from the perspective of its insight into potential pharmacotherapeutic targets. A large body of evidence suggests that the nicotinic acetylcholine receptor (nAChR), and in particular the ?7 subtype, is involved in memory and that agonists and positive allosteric modulators of this receptor have potential in schizophrenia and Alzheimer animal models and patients. What is new and Conclusion We identify significant indirect evidence that the selective ?7 nAChR drugs that are currently being investigated for cognitive improvement in schizophrenia and Alzheimer disease patients may be useful in cancer chemotherapy-related cognitive impairment. The clinical use of those drugs should be explored. PMID:21729110

Raffa, R. B.

2011-01-01

336

Design of efficient DNAzymes against muscle AChR ?-subunit cRNA in vitro and in HEK 293 cells  

PubMed Central

DNAzymes are catalytic DNA which bind to target RNA by complementary sequence arms on a Watson-Crick basis and cleave RNA at specific sites. Potential therapeutic applications require DNAzymes that can efficiently cleave their target. Here we investigate factors affecting DNAzyme cleavage efficacy against the muscle acetylcholine receptor (AChR) ?-subunit. The 10-23 DNAzymes cleave at Y-R nucleotide motifs, where R is A or G, and Y is U or C. Targeting a series of sites within different regions of the full-coding length cRNA under simulated physiological conditions found that the most efficient motifs for cleavage were in the hierarchy: GU ? AU > GC ? AC. This order is consistent with the kinetic analysis of short synthetic RNA substrates that have the same binding arms but different cleavage sites. DNAzymes with longer symmetric binding arms were more efficient than those with shorter arms, while asymmetric DNAzymes with a longer arm I were also more efficient, suggesting a dominant role for arm I in determining cleavage activity. Modification of one DNAzyme by inverted thymidine (iT) or locked nucleic acids (LNA) showed the LNA-modified DNAzyme gave efficient silencing of AChR expression in HEK 293 cells. Our data demonstrate the usefulness of screening in vitro for an efficient DNAzyme prior to cellular applications. PMID:19771209

Abdelgany, Amr; Uddin, M Khabir; Wood, Matthew; Taira, Kazunari; Beeson, David

2005-01-01

337

LATE QUATERNARY EVOLUTION OF THE NORTHEAST FAN, OFFSHORE NOVA SCOTIA  

E-print Network

LATE QUATERNARY EVOLUTION OF THE NORTHEAST FAN, OFFSHORE NOVA SCOTIA Matthew Robichaud Submitted of Earth Sciences Dalhousie University, Halifax, Nova Scotia March 2006 #12;jt Dalhousie University Department of Earth Sciences Halifax, Nova Scotia Canada B3H 3|5 (902) 494-2358 FAX 1902) 494-f>8«9 DATE

Beaumont, Christopher

338

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

339

Future climate change and the British Quaternary research community  

Microsoft Academic Search

The uncertainty surrounding estimates of future global warming, even given a single scenario for increasing greenhouse gas emissions, is unacceptably large and has not declined substantially over the last three decades. The Quaternary science community is uniquely placed to constrain the array of possible futures by providing reconstructions of past climate that can be used, together with instrumental data, to

Danny McCarroll

2010-01-01

340

Quaternary research in Poland: selected achievements and prospects  

Microsoft Academic Search

A b s t r a c t . During the last thirty years there were several turnouts in Quaternary studies that increasingly accelerated our under- standing of natural processes and opened new research fields. Among others, they included complex reconstruction of palaeoclimatic phenomena, studies of deep-sea and long-term continental record, and extensive application of reliable dating methods. In Poland

Leszek Marks

341

Application of Analytic Geometry to Ternary and Quaternary Diagrams.  

ERIC Educational Resources Information Center

Advantages of representing ternary and quaternary composition diagrams by means of rectangular coordinates were pointed out in a previous paper (EJ 288 693). A further advantage of that approach is that analytic geometry, based on rectangular coordinates, is directly applicable as demonstrated by the examples presented. (JN)

MacCarthy, Patrick

1986-01-01

342

8 | Quaternary AUSTRALASIA 26 (2) The PAGES 3rd  

E-print Network

8 | Quaternary AUSTRALASIA 26 (2) The PAGES 3rd Open Science Meeting (OSM) and 1st Young Scientists key topics such as public awareness of palaeoclimate research, the involvement of young scientists in the palaeoclimate community, and access to published data. Each group reported back the following day, giving

Phipps, Steven J.

343

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.

Martin Farley

344

The Croonian Lecture: Radiocarbon Dating and Quaternary History in Britain  

Microsoft Academic Search

The lecture is an attempt to show the way in which research upon the Quaternary Period in Britain is being affected by the application to it of radiocarbon dating. Mild interstadial periods during the last glaciation can be distinguished, set in sequence and related to similar European interstadials. It is shown that a brief climatic oscillation occurs widely in the

H. Godwin

1961-01-01

345

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

346

Range Shifts and Adaptive Responses to Quaternary Climate Change  

Microsoft Academic Search

Tree taxa shifted latitude or elevation range in response to changes in Quaternary climate. Because many modern trees display adaptive differentiation in relation to latitude or elevation, it is likely that ancient trees were also so differentiated, with environmental sensitivities of populations throughout the range evolving in conjunction with migrations. Rapid climate changes challenge this process by imposing stronger selection

Margaret B. Davis; Ruth G. Shaw

2001-01-01

347

Late Quaternary vegetational and climatic changes in Brazil  

Microsoft Academic Search

Brazil comprises about 50% of the South American continent including prominent ecosystems like the Amazon and the Atlantic rain forests, semideciduous forests, cerrado, Araucaria forests and campos (grasslands). Detailed palynological studies on new sediment cores located on a transect from southern to northern Brazil allow a regional reconstruction of late Quaternary vegetation and climate history. This paper presents an overview

Hermann Behling

1998-01-01

348

Quaternary Glacial Mapping in Western Wisconsin Using Soil Survey Information  

ERIC Educational Resources Information Center

The majority of soils in the western Wisconsin have developed from glacial sediments deposited during the Quaternary Period (2.6 million years before present). In many regions, multiple advances and retreats have left a complex landscape of diverse glacial sediments and landforms. The soils that have developed on these deposits reflect the nature…

Oehlke, Betsy M.; Dolliver, Holly A. S.

2011-01-01

349

Molecular Basis of Downregulation of G-Protein-Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation: Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor-Mediated Shortening of Action Potentials  

Microsoft Academic Search

Background—Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K current (IK,ACh) contribute to chronic AF. Methods and Results—In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in IK,ACh and the level

D. Dobrev; E. Graf; E. Wettwer; H. M. Himmel; O. Hala; C. Doerfel; T. Christ; S. Schuler; U. Ravens

2001-01-01

350

Calculating Quaternary glacial erosion rates in northeast Scotland  

NASA Astrophysics Data System (ADS)

Northeast Scotland is an area exhibiting selective erosion by Quaternary ice sheets. In this area both glacial and preglacial landforms exist in close proximity. The depths of erosion which this modification represents are calculated on the assumption of various depths of preglacial weathering. A depth of erosion of between 34 and 62 m per unit area is indicated. Calculated rates of erosion are 0.021 mm a -1 for the entire 2.3 m.y. of the Quaternary, and between 0.1 and 0.5 mm a -1 on the assumption that glacial conditions existed in this area for 500,000 years and 100,000 years, respectively. These figures are compared to the offshore sedimentary record in the adjacent west-central North Sea. The volume of sediment deposited offshore is equivalent to a depth of erosion of 195 m per unit area, yielding an average erosion rate of 0.085 mm a -1 over the entire Quaternary. Rates of erosion were low in the preglacial Pliocene (0.049 mm a -1) and early Quaternary (0.063 mm a -1). The expansion of ice sheets across the area in the middle Quaternary was associated with a sharp increase in the rates of erosion (> 0.13 mm a -1) but the last (late Devensian) ice sheet in the area was less erosive (< 0.095 mm a -1). The estimated rates of erosion represented by the offshore sedimentary record therefore exceed the estimated rates of glacial erosion from the onshore geomorphological reconstruction.

Glasser, Neil F.; Hall, Adrian M.

1997-09-01

351

Different pharmacology of N-desmethylclozapine at human and rat M2 and M 4 mAChRs in neocortex.  

PubMed

Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue. PMID:25592256

Gigout, S; Wierschke, S; Dehnicke, C; Deisz, R A

2015-05-01

352

Potentiation by tonic A2a-adenosine receptor activation of CGRP-facilitated [3H]-ACh release from rat motor nerve endings.  

PubMed Central

1. The effect of calcitonin gene-related peptide (CGRP) on [3H]-acetylcholine ([3H]-ACh) release from motor nerve endings and its interaction with presynaptic facilitatory A2a-adenosine and nicotinic acetylcholine receptors was studied on rat phrenic nerve-hemidiaphragm preparations loaded with [3H]-choline. 2. CGRP (100-400 nM) increased electrically evoked [3H]-ACh release from phrenic nerve endings in a concentration-dependent manner. 3. The magnitude of CGRP excitation increased with the increase of the stimulation pulse duration from 40 microseconds to 1 ms, keeping the frequency, the amplitude and the train length constants. With 1 ms pulses, the evoked [3H]-ACh release was more intense than with 40 microseconds pulse duration. 4. Both the nicotinic acetylcholine receptor agonist, 1,1-dimethyl-4-phenylpiperazinium, and the A2a adenosine receptor agonist, CGS 21680C, increased evoked [3H]-ACh release, but only CGS 21680C potentiated the facilitatory effect of CGRP. This potentiation was prevented by the A2a adenosine receptor antagonist, PD 115,199. 5. Adenosine deaminase prevented the excitatory effect of CGRP (400 nM) on [3H]-ACh release. This effect was reversed by the non-hydrolysable A2a-adenosine receptor agonist, CGS 21680C. 6. The nicotinic antagonist, tubocurarine, did not significantly change, whereas the A2-adenosine receptor antagonist, PD 115,199, blocked the CGRP facilitation. The A1-adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine, potentiated the CGRP excitatory effect. 7. The results suggest that the facilitatory effect of CGRP on evoked [3H]-ACh release from rat phrenic motor nerve endings depends on the presence of endogenous adenosine which tonically activates A2a-adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8004402

Correia-de-Sá, P.; Ribeiro, J. A.

1994-01-01

353

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. PMID:23004024

Freitas, K; Negus, SS; Carroll, FI; Damaj, MI

2013-01-01

354

Development of stomach-ache and headache during middle childhood: co-occurrence and psychosocial risk factors.  

PubMed

Development of somatic symptoms and associations with psychosocial risk factors were investigated in a longitudinal study of Norwegian children aged 4-10 years. Complaints of stomach-ache only were associated with emotionally well-adapted children, and mothers with low education and high emotional support. Children complaining of headache only behaved well as preschoolers, showed a tendency towards high achievement motivation at school and their mothers were employed outside the home. Children with the co-occurrence syndrome seemed to constitute a separate entity. They differed from the others as the syndrome was associated with previous behavioural and emotional problems, current emotional disturbances and mothers with less support. Family demographic stability, further child health problems and school factors were not associated with the co-occurrence syndrome. PMID:7549300

Borge, A I; Nordhagen, R

1995-07-01

355

Inhibitors of Pyruvate Carboxylase  

PubMed Central

This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. PMID:22180764

Zeczycki, Tonya N.; Maurice, Martin St.; Attwood, Paul V.

2010-01-01

356

Use of proteasome inhibitors.  

PubMed

Proteasome inhibitors are indispensable research tools in immunology and cell biology. With numerous proteasome inhibitors available commercially, choosing the appropriate compound for a biological experiment may be challenging, especially for a novice. This unit provides an overview of the proteasome inhibitors commonly used in research. It discusses how to select an appropriate highly specific inhibitor, its concentration, and length of exposure for mammalian cell culture experiments. In addition, assays that can be used to confirm proteasome inhibition are discussed. © 2015 by John Wiley & Sons, Inc. PMID:25845565

Downey, Sondra L; Florea, Bogdan I; Overkleeft, Herman S; Kisselev, Alexei F

2015-01-01

357

Clinical measurement of antibodies against acetylcholine receptor (AchR), SOD and LPO in patients with myasthenia gravis (MG) before and after thymectomy.  

PubMed

The antibodies against acetylcholine receptor AchR and levels of SOD and LPO were measured in 11 patients with myasthenia gravis (MG), and the results were compared with normal controls and patients with diseases other than MG. The results showed that the antibodies against AchR were higher as compared with other groups before and after operation. The post-operative level of antibodies was obviously lower than the pre-operative value. An slight increase in SOD and significant decrease in mean value of LPO after surgery were noted. The possible mechanism was discussed. PMID:7760440

Pan, T C; Yang, M S; Cao, X B; Ge, Y X; Zhang, B G; Zhao, J P; Cheng, X F

1994-01-01

358

Patterned high-frequency stimulation induces a form of long-term depression dependent on GABAA and mACh receptors in the hippocampus.  

PubMed

Certain patterns of neural activity can induce N-methyl-D-aspartic acid receptor (NMDAR)-dependent synaptic plasticity, one of the important foundations of memory. Here, we report that a patterned high-frequency stimulation (PHS) induces rat hippocampal long-term depression (LTD) in an NMDAR-independent manner that requires coactivation of GABA(A)Rs and muscarinic acetylcholine receptors (mAChRs), and endocytosis of AMPARs. Thus, we disclose that a patterned high-frequency stimulation triggers GABAAR and mAChR-dependent LTD in the hippocampus. PMID:23911810

Zhu, Y-Y; Jing, L; Duan, T-T; Yuan, Q; Cao, J; Zhou, Q-X; Xu, L

2013-10-10

359

Identification of key amino acid differences contributing to neonicotinoid sensitivity between two nAChR ? subunits from Pardosa pseudoannulata.  

PubMed

Chemical insecticides are still primary methods to control rice planthoppers in China, which not only cause environmental pollution, insecticide residue and insecticide resistance, but also have negative effects on natural enemies, such as Pardosa pseudoannulata (the pond wolf spider), an important predatory enemy of rice planthoppers. Neonicotinoids insecticides, such as imidacloprid and thiacloprid, are insect-selective nAChRs agonists that are used extensively in the areas of crop protection and animal health, but have hypotoxicity to P. pseudoannulata. In the present study, two nAChR ? subunits, Pp?1 or Pp?8, were found to be successfully expressed with r?2 in Xenopus oocytes, but with much different sensitivity to imidacloprid and thiacloprid on two recombinant receptors Pp?1/r?2 and Pp?8/r?2. Key amino acid differences were found in and between the important loops for ligand binding. In order to well understand the relationship between the amino acid differences and neonicotinoid sensitivities, different segments in Pp?8 or Pp?1 with key amino acid differences were introduced into the corresponding regions of Pp?1 or Pp?8 to construct chimeras and then co-expressed with r?2 subunit in Xenopus oocytes. The results from chimeras of both Pp?8 and Pp?1 showed that segments ?5, ?6, and ?7 contributed to neonicotinoid sensitivities directly between two receptors. Although the segment ?4 including all loop B region had no direct influences on neonicotinoid sensitivities, it could more remarkably influence neonicotinoid sensitivities when co-introductions with ?5, ?6 or ?7. So, key amino acid differences in these four segments were important to neonicotinoid sensitivities, but the difference in ?4 was likely ignored because of its indirect effects. PMID:25459289

Meng, Xiangkun; Zhang, Yixi; Guo, Beina; Sun, Huahua; Liu, Chuanjun; Liu, Zewen

2015-01-01

360

Up-scaling the production of modified a-C:H coatings in the framework of plasma polymerization processes  

NASA Astrophysics Data System (ADS)

Hydrogenated amorphous carbon (a-C:H) films with silicon and oxygen additions, which exhibit mechanical, tribological and wetting properties adequate for protective coating performance, have been synthesized at room temperature in a small- (0.1 m 3) and a large-scale (1 m 3) coaters by low-pressure Plasma-Activated Chemical Vapour Deposition (PACVD). Hence, a-C:H:Si and a-C:H:Si:O coatings were produced in atmospheres of tetramethylsilane (TMS) and hexamethyldisiloxane (HMDSO), respectively, excited either by radiofrequency (RF - small scale) or by pulsed-DC power (large scale). Argon was employed as a carrier gas to stabilize the glow discharge. Several series of 2-5 ?m thick coatings have been prepared at different mass deposition rates, Rm, by varying total gas flow, F, and input power, W. Arrhenius-type plots of Rm/ F vs. ( W/ F) -1 show linear behaviours for both plasma reactors, as expected for plasma polymerization processes at moderated energies. The calculation of apparent activation energy, Ea, in each series permitted us to define the regimes of energy-deficient and monomer-deficient PACVD processes as a function of the key parameter W/ F. Moreover, surface properties of the modified a-C:H coatings, such as contact angle, abrasive wear rate and hardness, appear also correlated to this parameter. This work shows an efficient methodology to scale up PACVD processes from small, lab-scale plasma machines to industrial plants by the unique evaluation of macroscopic parameters of deposition.

Corbella, C.; Bialuch, I.; Kleinschmidt, M.; Bewilogua, K.

2009-10-01

361

The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors  

SciTech Connect

APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 ?M), without affecting directly-elicited twitch tension up to 2.72 ?M. The compound (0.007–3.40 ?M) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 ?M, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 ?M) without significant change in the resting membrane potential of the muscle fibers up to 3.40 ?M. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (?1{sub 2}?1??) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 ?M), indicating a higher affinity of the compound for Torpedo (?1{sub 2}?1??) than for the mouse (?1{sub 2}?1??) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ? APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ? APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

Grandi?, Marjana [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia); Aráoz, Romulo; Molgó, Jordi [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Turk, Tom; Sep?i?, Kristina [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia)] [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia); Benoit, Evelyne [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Frangež, Robert, E-mail: robert.frangez@vf.uni-lj.si [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)

2012-12-01

362

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment  

PubMed Central

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-? peptide leads to the secretion of the neurotrophic protein sAPP?. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPP? release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment. PMID:25157130

Lecoutey, Cédric; Hedou, Damien; Freret, Thomas; Giannoni, Patrizia; Gaven, Florence; Since, Marc; Bouet, Valentine; Ballandonne, Céline; Corvaisier, Sophie; Malzert Fréon, Aurélie; Mignani, Serge; Cresteil, Thierry; Boulouard, Michel; Claeysen, Sylvie; Rochais, Christophe; Dallemagne, Patrick

2014-01-01

363

Characterization of Quaternary and suspected Quaternary faults, regional studies, 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 that resulted in the identification of 51 relevant and potentially relevant individual and compound faults and fault zones in the 100-km-radius region around the Yucca Mountain site. Geologic data used to characterize the regional faults and fault zones as relevant or potentially relevant seismic sources includes age and displacement information, maximum fault lengths, and minimum distances between the fault and the Yucca Mountain site. For many of the regional faults, no paleoseismic field studies have previously been conducted, and age and displacement data are sparse to nonexistent. In November 1994, the Branch of Earthquake and Landslide Hazards entered into two Memoranda of Agreement with the Yucca Mountain Project Branch to conduct field reconnaissance, analysis, and interpretation of six relevant and six potentially relevant regional faults. This report describes the results of study of those faults exclusive of those in the Pahrump-Stewart Valley-Ash Meadows-Amargosa Valley areas. We also include results of a cursory study of faults on the west flank of the Specter Range and in the northern part of the Last Chance Range. A four-phase strategy was implemented for the field study.

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

1995-12-31

364

Experimental and computational studies on the inhibition of acetylcholinesterase by curcumin and some of its derivatives.  

PubMed

Recent studies have demonstrated several biological activities of curcumin with therapeutic potential against Alzheimer's disease, among them the inhibition of the enzyme acetylcholinesterase (AChE). Aiming at identifying the chemical features relevant for this activity, the inhibition of curcumin and a set of 7 derivatives against AChE of E. electricus was measured. These derivatives presented lower activity than curcumin, allowing for the identification of possible unfavorable enzyme-inhibitor interactions. Our computational approach was to dock the molecules to the active site of AChE, followed by an analysis of hydrogen bonds and close contacts to relevant aromatic amino acid residues. To account for inhibitory activity, we sought to define the common structural features between known acetylcholinesterase inhibitors and the tested derivatives. A pharmacophore model was generated, which consisted of two hydrophobic, one aromatic and one hydrogen bond acceptor features. We conclude that the presence of two aromatic rings and the distance between them, allows curcumin and its derivatives to favorably interact with both the quaternary and peripheral sites of AChE. Hydrogen bonds can be formed with the quaternary and acyl sites, which should further stabilize the complex. The acylation of the hydroxyl groups and the reduction of the conjugated double bonds lowered the inhibitory activity, pointing to the modification of the keto-enol moiety as the best alternative for the design of more potent curcumin derivatives as acetylcholinesterase inhibitors. PMID:23106780

Tello-Franco, Veronica; Lozada-García, Maria Concepcion; Soriano-García, Manuel

2013-06-01

365

Topoisomerase I Inhibitors  

Microsoft Academic Search

Topoisomerase I inhibitors are a new class of anti- cancer agents with a mechanism of action aimed at inter- rupting DNA replication in cancer cells, the result of which is cell death. Most if not all Topoisomerase I inhibitors are derivatives of the plant extract camp- tothecin. Irinotecan (CPT-11), a semi-synthetic deriva- tive of camptothecin, is approved in the United

REGINALD B. EWESUEDO; MARK J. RATAIN; Pediatric Hematology-Oncology

1997-01-01

366

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors  

SciTech Connect

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in As induced VaD.

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

367

QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.  

PubMed

QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position. PMID:1738151

Cardozo, M G; Iimura, Y; Sugimoto, H; Yamanishi, Y; Hopfinger, A J

1992-02-01

368

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

369

Effects of acetylcholine (ACh) and norepinephrine (NE) on phosphatidylinositol 4,5-bisphosphate (PIP/sub 2/) turnover in rabbit cornea  

SciTech Connect

Muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic agonists provoke hydrolysis of PIP/sub 2/ into diacylglycerol (DG) and inositol trisphosphate (IP/sub 3/) in a wide variety of tissue. Recently, IP/sub 3/ has been shown to mobilize Ca/sup 2 +/ from ER in several permeabilized tissue preparations. Although rabbit cornea is enriched in ACh and NE, the physiological function of these neurotransmitters is unclear. The present studies were initiated to determine the effects of cholinergic and adrenergic agonists on PIP/sub 2/ turnover in the cornea. Addition of ACh or NE (50 ..mu..M each) to the /sup 32/P-labeled corneas for 10 min decreased the radioactivity in PIP/sub 2/ by 33 and 36%, and increased the radioactivity in phosphatidic acid by 72 and 52%, respectively. When the corneas were labeled with myo-(/sup 3/H)inositol, ACh and NE increased the accumulation of IP/sub 3/ by 92 and 48%, respectively. The effects of ACh and NE on phospholipid labeling and IP/sub 3/ accumulation were specifically inhibited by atropine (10 ..mu..M) and prazosin (10 ..mu..M), respectively. The data suggest the presence of muscarinic cholinergic and ..cap alpha../sub 1/-adrenergic receptors in the rabbit cornea. Furthermore, activation of these receptors leads to cleavage of PIP/sub 2/ into DG and IP/sub 3/ which may function as second messengers in this tissue.

Akhtar, R.A.; Abdel-Latif, A.A.

1986-05-01

370

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.

371

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

372

Late-quaternary vegetational dynamics and community stability reconsidered  

NASA Astrophysics Data System (ADS)

Defining the spatial and temporal limits of vegetational processes such as migration and invasion of established communities is a prerequisite to evaluating the degree of stability in plant communities through the late Quaternary. The interpretation of changes in boundaries of major vegetation types over the past 20,000 yr offers a complementary view to that provided by migration maps for particular plant taxa. North of approximately 43°N in eastern North America, continual vegetational disequilibrium has resulted from climatic change, soil development, and species migrations during postglacial times. Between 33° and 39°N, stable full-glacial vegetation was replaced by a relatively unstable vegetation during late-glacial climatic amelioration; stable interglacial vegetation developed there after about 9000 yr B.P. Late-Quaternary vegetation has been in dynamic equilibrium, with a relatively constant flora, south of 33°N on upland interfluves along the northern Gulf Coastal Plain, peninsular Florida, and west-central Mexico.

Delcourt, Paul A.; Delcourt, Hazel R.

1983-03-01

373

Quaternary ammonium polyethylenimine nanoparticles for treating bacterial contaminated water.  

PubMed

This study highlights the potential application of antimicrobial quaternary ammonium nanomaterials for water disinfection. Quaternary ammonium polyethylenimine (QA-PEI) nanoparticles (NPs) were synthesized by polyethylenimine crosslinking and alkylation with octyl iodide followed by methyl iodide quaternization. Particles modified with octyldodecyl alkyl chains were also prepared and evaluated. The antimicrobial activity of QA-PEI NPs was studied after anchoring in non-leaching polymeric coatings and also in aqueous suspension. Particles at different loadings (w/w) were embedded in polyethylene vinyl acetate and polyethylene methacrylic acid coatings and tested for antimicrobial activity against four representative strains of bacteria in static and dynamic modes. Coatings embedded with fluorescent labelled particles tracked by Axioscope fluorescence microscope during the antimicrobial test indicates no particles leaching out. Coatings loaded with 5% w/w QA-PEI exhibited strong antibacterial activity. Aqueous suspension was tested and found effective for bacterial decontamination at 0.1ppm and maintains its activity for several weeks. PMID:25800358

Farah, Shady; Aviv, Oren; Laout, Natalia; Ratner, Stanislav; Beyth, Nurit; Domb, Abraham J

2015-04-01

374

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

375

Synthesis and performance of ester quaternary biodegradable softeners  

Microsoft Academic Search

Reaction of hydroxyethylpiperazine with two moles of fatty acid, followed by quaternization with methyl chloride, methyl bromide\\u000a or dimethyl sulfate, resulted in new quaternaries useful as biodegradable fabric softeners. Additional softeners were synthesized\\u000a from hard tallow propane diamine by reaction with butyrolactone, followed by ethoxylation, esterification with one mole of\\u000a fatty acid and quaternization.

R. Lagerman; S. Clancy; D. Tanner; N. Johnston; B. Callian; F. Friedli

1994-01-01

376

Vegetation ecotone dynamics in Southwest Alaska during the Late Quaternary  

Microsoft Academic Search

To examine Late Quaternary vegetation change across the modern vegetation gradient from continuous boreal forest (central Alaska) to Betula shrub tundra (Bristol Bay region), pollen records from Idavain and Snipe Lakes are described and compared to those of four other sites in southwest Alaska. Major features of the vegetation history at Idavain Lake include herb-dominated tundra (ca 14–12kaBP), mixed herb\\/Betula

Linda B. Brubaker; Patricia M. Anderson; Feng Sheng Hu

2001-01-01

377

Quaternary TL Surveys: A Guide to Thermoluminescence (TL) Date Measurement  

NSDL National Science Digital Library

Quaternary TL Surveys, a company that provides date measurement services to archaeologists and geologists, offers this comprehensive tutorial on archaeometric dating techniques. The tutorial contains a general overview as well as specific information on dating flint and stone, stalagmitic calcite, sediments, and methods of interpreting and using TL dates. For ease of use, portions of the guide are marked to alert users to their relative importance.

378

Preparation of bis -quaternary ammonium salts from epichlorohydrin  

Microsoft Academic Search

A novelbis-quaternary ammonium salt was prepared conveniently and almost quantitatively fromN,N-dimethyldodecylamine, its hydrochloride, and epichlorohydrin. Reaction ofN,N-dimethyldodecylamine with epichlorohydrin (in the presence of the amine hydrochloride) or various dichloro compounds was\\u000a investigated by using1H nuclear magnetic resonance. The reaction route was studied by examining the reactivity of reagents with the amine and the\\u000a effect of reaction temperature. The ease of

Tae-Seong Kim; Toshikazu Hirao; Isao Ikeda

1996-01-01

379

Petrogenesis of Plio-Quaternary basalts in Mahabad, NW Iran  

NASA Astrophysics Data System (ADS)

The Mahabad1:100000 sheet is located mostly in the Kurdestan district on southern part of west Azerbijan province between east Longitude 45? 30'- 46 ?, and northern Latitude 36? 30'- 37?. Geographic position, geological and structural setting as well as general geological characters of this zone is very similar to Sanandaj-Sirjan zone. Topography is dominated by mountainous terrain with an average elevation around 1800 meters. The oldest rocks belong to intrusive rocks, Mahabad Rhyolite. The younger ones include Plio-Quaternary basalt to alkali basalt, andesite, trachyte and alluvium terraces and salt marsh. The young quaternary volcanoes occur in the southern range east and east of mahabad map sheet. The Plio-Quaternary volcanic lava are seen in the Borhan village? It is built almost entirely of fluid lava flows?. The volcanic rocks are basic in composition (basalt, tephrit basanite). The petrographic and geochemical evidences, related diagrams show fractionation. By studying the major and trace elements variation diagrams, a trend of normal crystallization can be seen crustal contamination in extensional environments. It seems that the original magma has an ultrabasic composition. Some of the phenocrysts of olivine, pyroxene & plagioclase are seen in thin sections. These rocks have microlitic porphyritic? hyallo microlithic porphyritic textures in thin sections. On the basis of chemical analysis? magma that has formed the rocks had alkaline nature. The ratio of nephelin norm is around 5.3 in this rocks. A primitive mantle- normalized incompatible trace element diagram shows close similarity to typical OIB pattern. All of documents denote that magma originated from an enriched asthenospheric mantle and low degree of partial melting in source. Key words: alkali basalt, Quaternary, Volcanic, Compression. asthenospher

Shojaei, Masoomeh; Kheirkhah, Monireh; Hashem Emami, Mohamad; Maleki, Glavig

2010-05-01

380

Quaternary fluvial archives: achievements of the Fluvial Archives Group  

NASA Astrophysics Data System (ADS)

In their geomorphological and sedimentary records, rivers provide valuable archives of environments and environmental change, at local to global scales. In particular, fluvial sediments represent databanks of palaeoenvironment and palaeoclimatic (for example) of fossils (micro- and macro-), sedimentary and post-depositional features and buried soils. Well-dated sequences are of the most value, with dating provided by a wide range of methods, from radiometric (numerical) techniques to included fossils (biostratigraphy) and/or archaeological material. Thus Quaternary fluvial archives can also provide important data for studies of Quaternary biotic evolution and early human occupation. In addition, the physical disposition of fluvial sequences, be it as fragmented terrace remnants or as stacked basin-fills, provides valuable information about geomorphological and crustal evolution. Since rivers are long-term persistent features in the landscape, their sedimentary archives can represent important frameworks for regional Quaternary stratigraphy. Fluvial archives are distributed globally, being represented on all continents and across all climatic zones, with the exception of the frozen polar regions and the driest deserts. In 1999 the Fluvial Archives Group (FLAG) was established, as a working group of the Quaternary Research Association (UK), aimed at bringing together those interested in such archives. This has evolved into an informal organization that has held regular biennial combined conference and field-trip meetings, has co-sponsored other meetings and conference sessions, and has presided over two International Geoscience Programme (IGCP) projects: IGCP 449 (2000-2004) 'Global Correlation of Late Cenozoic Fluvial Deposits' and IGCP 518 (2005-2007) 'Fluvial sequences as evidence for landscape and climatic evolution in the Late Cenozoic'. Through these various activities a sequence of FLAG publications has appeared, including special issues in a variety of journals, amassing a substantial volume of information on fluvial archives worldwide. This presentation will highlight some of these data and will describe important patterns observed and interpretations arising therefrom.

Bridgland, David; Cordier, Stephane; Herget, Juergen; Mather, Ann; Vandenberghe, Jef; Maddy, Darrel

2013-04-01

381

The impact of Quaternary Ice Ages on mammalian evolution.  

PubMed Central

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

2004-01-01

382

Efficient formation of benzylic quaternary centers via palladium catalysis.  

PubMed

Four's a crowd: An efficient protocol for the formation of benzylic quaternary centers via arylation of enones using a catalyst made from Pd(O2 CCF3 )2 and 2,2'-bipyridine is developed. For cyclic substrates, catalyst loadings as low as 1 mol % Pd are enough to afford excellent yields (>90%) using a variety of arylboronic acids. In case of acyclic substrates, the addition of KSbF6 was found to improve conversions and yields. PMID:23821532

Gottumukkala, Aditya L; Suljagic, Jasmin; Matcha, Kiran; de Vries, Johannes G; Minnaard, Adriaan J

2013-09-01

383

Quaternary freshwater Ostracoda from the Great Salt Lake Basin  

E-print Network

THE UNIVERSITY OF KANSAS PALEONTOLOGICAL CONTRIBUTIONS October 23, 1975 Paper 78 QUATERNARY FRESHWATER OSTRACODA FROM THE GREAT SALT LAKE BASIN, UTAH' KENNETH H. LISTER Department of Geology, The University of Kansas, Lawrence; present address: 317... Via Anita, Redondo Beach, California ABSTRACT Ostracodes are described from two cores, each more than 200 m long taken in Quater- nary sediments of the Great Salt Lake Basin, Utah. Thirty-one species of Ostracoda in thirteen genera have been identified...

Lister, K. H.

1975-10-23

384

Multiple sources of alkanes in Quaternary oceanic sediment of Antarctica  

USGS Publications Warehouse

Normal alkanes (n-C13n-C36), isoprenoid hydrocarbons (i-C15, i-C16, i-C18, i-C19, and i-C20) triterpanes (C27C32), and (C27C29) are present in low concentrations offshore Antarctica in near-surface, Quaternary sediment of the Wilkes Land continental margin and of the western Ross Sea. The distributions of these hydrocarbons are interpreted relative to possible sources and processes. The hydrocarbons appear to be mixtures of primary and recycled material from marine and terrigenous sources. The n-alkanes are most abundant and are characterized by two distinct populations, one of probable marine origin and the other likely from terrigenous, vascular plant sources. Because the continent of Antarctica today is devoid of higher plants, the plant-derived hydrocarbons in these offshore sediments probably came from wind-blown material and recycled Antarctic sediment that contains land-plant remains from an earlier period of time. Isoprenoid hydrocarbons are partially recycled and mainly of marine origin; the dominance of pristane over phytane suggests oxic paleoenvironmental conditions. Both modern and ancient triterpanes and steranes are present, and the distribution of these indicates a mixture of primary and recycled bacterial, algal, and possible higher-plant materials. Although the sampled sediments were deposited during the Quaternary, they apparently contain a significant component of hydrocarbons of pre-Quaternary age. ?? 1987.

Kvenvolden, K.A.; Rapp, J.B.; Golan-Bac, M.; Hostettler, F.D.

1987-01-01

385

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

386

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

387

Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups.  

PubMed

Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P(1) had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P(1) group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir. PMID:20226659

Venkatraman, Srikanth; Velazquez, Francisco; Wu, Wanli; Blackman, Melissa; Madison, Vincent; Njoroge, F George

2010-04-01

388

Investigation of Acetylcholine Receptor Diversity in a Nematode Parasite Leads to Characterization of Tribendimidine- and Derquantel-Sensitive nAChRs  

PubMed Central

Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important “classical” anthelmintics like levamisole and pyrantel, as well as “novel” anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. PMID:24497826

Neveu, Cedric; Cabaret, Jacques; Cortet, Jacques; Peineau, Nicolas; Abongwa, Melanie; Courtot, Elise; Robertson, Alan P.; Martin, Richard J.

2014-01-01

389

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. PMID:24454942

Yamamoto, Takeshi; Kodama, Toshihisa; Lee, Jaemin; Utsunomiya, Naho; Hayashi, Shusaku; Sakamoto, Hiroshi; Kuramoto, Hirofumi; Kadowaki, Makoto

2014-01-01

390

LC3 overexpression reduces A? neurotoxicity through increasing ?7nAchR expression and autophagic activity in neurons and mice.  

PubMed

Autophagy is an intracellular degradation pathway with dynamic interactions for eliminating damaged organelles and protein aggregates by lysosomal digestion. The EGFP-conjugated microtubule-associated protein 1 light chain 3 (EGFP-LC3) serves to monitor autophagic process. Extracellular ?-amyloid peptide accumulation is reported as a major cause in Alzheimer's disease (AD) pathogenesis; large numbers of autophagic vacuoles accumulate in patients' brains. We previously demonstrated that extracellular A? (eA?) induces strong autophagic response and ?7nAChR acts as a carrier to bind with eA?; which further inhibits A?-induced neurotoxicity via autophagic degradation. In the present study, we overexpressed LC3 in both neuroblastoma cells (SH-SY5Y/pEGFP-LC3) and mice (TgEGFP-LC3) to assess the effect of LC3 overexpression on A? neurotoxicity. SH-SY5Y/pEGFP-LC3 cells and primary cortical neuron cultures derived from E17 (embryonic day 17) TgEGFP-LC3 mice showed not only better resistance against A? neurotoxicity but also higher ?7nAChR expression and autophagic activity than control. Administration of ?-bungarotoxin (?-BTX) to block ?7nAChR antagonized the neuroprotective action of SH-SY5Y/pECGF-LC3 cells, suggesting that eA? binding with ?7nAChR is an important step in A? detoxification. LC3 overexpression thus exerts neuroprotection through increasing ?7nAChR expression for eA? binding and further enhancing autophagic activity for A? clearance in vitro and in vivo. PMID:25686800

Hung, Shih-Ya; Huang, Wei-Pang; Liou, Houng-Chi; Fu, Wen-Mei

2015-06-01

391

Pharmacological stress is required for the anti-alcohol effect of the ?3?4* nAChR partial agonist AT-1001.  

PubMed

Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the ?3 and ?4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity ?3?4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of ?3?4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague-Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self-administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol-associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the ?3?4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the ?3?4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response. PMID:25689019

Cippitelli, Andrea; Brunori, Gloria; Gaiolini, Kelly A; Zaveri, Nurulain T; Toll, Lawrence

2015-06-01

392

Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy.  

PubMed

Tubal ectopic pregnancy (EP) is the most common cause of maternal mortality in the first trimester of pregnancy; however, its etiology is uncertain. In EP, embryo retention within the Fallopian tube (FT) is thought to be due to impaired smooth muscle contractility (SMC) and alterations in the tubal microenvironment. Smoking is a major risk factor for EP. FTs from women with EP exhibit altered prokineticin receptor-1 (PROKR1) expression, the receptor for prokineticins (PROK). PROK1 is angiogenic, regulates SMC, and is involved in intrauterine implantation. We hypothesized that smoking predisposes women to EP by altering tubal PROKR1 expression. Sera/FT were collected at hysterectomy (n=21). Serum levels of the smoking metabolite, cotinine, were measured by enzyme-linked immunosorbent assay. FTs were analyzed by q-RT-PCR, immunohistochemistry, and Western blotting for expression of PROKR1 and the predicted cotinine receptor, nicotinic acetylcholine receptor ?-7 (AChR?-7). FT explants (n=4) and oviductal epithelial cells (cell line OE-E6/E7) were treated with cotinine and an nAChR?-7 antagonist. PROKR1 transcription was higher in FTs from smokers (P<0.01). nAChR?-7 expression was demonstrated in FT epithelium. Cotinine treatment of FT explants and OE-E6/E7 cells increased PROKR1 expression (P<0.05), which was negated by cotreatment with nAChR?-7 antagonist. Smoking targets human FTs via nAChR?-7 to increase tubal PROKR1, leading to alterations in the tubal microenvironment that could predispose to EP. PMID:20864676

Shaw, Julie L V; Oliver, Elizabeth; Lee, Kai-Fai; Entrican, Gary; Jabbour, Henry N; Critchley, Hilary O D; Horne, Andrew W

2010-11-01

393

Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of A?PP via M1 mAChRs  

PubMed Central

Alzheimer’s disease (AD) is characterized by amyloid-beta (A?) plaques, hyperphosphorylated tau neurofibrillary tangles (NFTs) and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers, and the maintenance of a M1 mAChR dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Interestingly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in AD postmortem human brain. Furthermore, M1 mAChRs have been a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid beta-protein precursor (A?PP). Here we tested the hypothesis that noradrenergic sympathetic sprouting and the associated increase in cholinergic innervation maintains non-amyloidogenic A?PP processing that is dependent upon M1 mAChRs. Also, we investigated the effect of intrahippocampal A?42 infusion on noradrenergic sympathetic and cholinergic sprouting. We found that A?42 is not only toxic to central cholinergic fibers innervating hippocampus but prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target. PMID:24081376

Nelson, Amy R.; Kolasa, Krystyna; McMahon, Lori L.

2014-01-01

394

An explanation for laser-induced spallation effect in a-C:H films: Altered phase evolution route caused by hydrogen doping  

SciTech Connect

The laser-induced spalling effect has been recognized as a unique phenomenon for amorphous carbon (a-C) films during laser processing. In this work, the origin of spalling effect was investigated by ablating two different types of a-C film: hydrogenated a-C (a-C:H) and nonhydrogenated a-C with an Nd-yttrium aluminum garnet laser system. Comparisons of ablating results demonstrated that the spalling effect only occurred in a-C:H rather than nonhydrogenated a-C. Laser heating simulation indicated that the temperature distributions in both films after laser pulse are similar with a high temperature gradient in depth direction. Annealing test results, Raman spectra and nanoindentation show that with the increase in annealing temperature, a-C film transforms into grassy carbon directly, while a-C:H experiences two subprocess under heating: the hydrogen mobilization and rearrangement of C-C network at a relatively low temperature range resulting in a denser C-C network and raised film density; the graphitization at high temperature which would lower the film density. We propose that the reason of laser-induced spalling effect in a-C:H might depend on two aspects: (1) the heat source like laser pulse which could produce a high temperature gradient in depth direction within ultrashort time and (2) the unique evolution process of film microstructure under heating. Based on above model, the spalling effect is ascribed to the concentrated stress caused by different structure evolution subprocess at different depth in a-C:H during the laser irradiation. It is remarkable that the conclusions deduced from our model are proven to be in good agreement with our experimental results and the previous articles reported by others.

Ding Qi; Hu Tianchang [Lanzhou Institute of Chemical Physics, State Key Laboratory of Solid Lubrication, Chinese Academy of Sciences, Lanzhou 730000 (China); Graduate School, Chinese Academy of Sciences, Beijing 100039 (China); Wang Liping; Hu Litian; Wang Yunfeng [Lanzhou Institute of Chemical Physics, State Key Laboratory of Solid Lubrication, Chinese Academy of Sciences, Lanzhou 730000 (China); Zhang Yaonan [Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou 730000 (China)

2011-01-01

395

Database and Map of Quaternary Faults and Folds in Peru and its Offshore Region  

USGS Publications Warehouse

This publication consists of a main map of Quaternary faults and fiolds of Peru, a table of Quaternary fault data, a region inset map showing relative plate motion, and a second inset map of an enlarged area of interest in southern Peru. These maps and data compilation show evidence for activity of Quaternary faults and folds in Peru and its offshore regions of the Pacific Ocean. The maps show the locations, ages, and activity rates of major earthquake-related features such as faults and fault-related folds. These data are accompanied by text databases that describe these features and document current information on their activity in the Quaternary.

Machare, Jose; Fenton, Clark H.; Machette, Michael N.; Lavenu, Alain; Costa, Carlos; Dart, Richard L.

2003-01-01

396

SEDIMENTOLOGY AND GEOMORPHOLOGY OF QUATERNARY ALLUVIAL FANS WITH IMPLICATIONS TO GROWTH STRATA, LOST RIVER RANGE,  

E-print Network

SEDIMENTOLOGY AND GEOMORPHOLOGY OF QUATERNARY ALLUVIAL FANS WITH IMPLICATIONS TO GROWTH STRATA......................................................................................14 5. UPPER CEDAR CREEK ALLUVIAL FAN.............................................. 19 Surface 6. JONES CREEK ALLUVIAL FAN......................................................... 67 Surface

Lawrence, Rick L.

397

Quaternary coastal evolution of Oman (Arabian Peninsula) - a quantitative approach  

NASA Astrophysics Data System (ADS)

The paper reviews the Quaternary coastal evolution of Oman. Emphasise is put on quantifying the different forcing factors. The plate tectonic setting, the Quaternary climate evolution, the sea-level history and the impact of natural hazards are identified as key factors of coastal evolution. The Arabian Plate is characterized by a northward movement forming a continent-continent collision zone in the west and the Makran Subduction Zone in the east. As a result differential land movement is observable in Oman. The Quaternary climate evolution is well understood. Besides other proxies notably spelothems and aeolian deposits allow to draw a consistent picture. It is understood that changes in the position of the intertropical convergence zone result in intensity-changes of the summer monsoon. These changes are related to global atmospheric circulation patterns. Data on the sea-level history are sparse; despite general assumptions of a sea-level lowstand, correlating with the last glacial maximum, resulting in terrestrial conditions within the Arabian Gulf. Furthermore, a mid-Holocene sea level highstand in the range of +2m is documented in several locations. The coastlines of Oman are affected by tsunami and hurricanes. However, almost no instrumental or historical data on the impact of such natural hazards are available due to the isolation of the country in the past. Several Quaternary deposits have been investigated in a reconnaissance survey. There is sound geological evidence for a tsunami to have affected the coastline in 1945, with the possibility of older tsunami events being also recorded in the geological record. There is strong evidence of differential land movement along the coastline; locally indicated by marine terraces in elevations of up to 400m (Rupprechter at al. 2012). By quantifying the differential land movement for numerous sites, the sea-level history will be revealed. Ultimately the data will be utilized to form the base of a modeling approach. Furthermore, a sedimentary archive of past precipitation events is documented which will allow reconstructing frequency and intensity of precipitation events and may indicate the impact of past hurricanes. It is concluded that the geological archives are suitable to quantify the forcing factors of Quaternary coastal evolution on different time scales and that the recurrence intervals of natural hazards will be revealed. Proxy data will be gained in subsequent investigations. This allows a scientific based holistic approach for an integrated coastal zone management that helps to formulate adaptation strategies with regard to global warming and expected environmental changes.

Hoffmann, G.; Rupprechter, M.; Roepert, A.; Quraishi, K. Al; Balushi, N. Al; Grützner, C.; Reicherter, K.

2012-04-01

398

The effect of seasonal changes on the selection of biocide inhibitors for Arabian Gulf seawater for water injection purposes  

SciTech Connect

This investigation was carried out to determine the most effective biocide inhibitor for Northern Arabian Gulf Seawater. This seawater will be used for water injection purposes for some oil fields in Kuwait. Arabian Gulf Seawater is known to be very saline during the summer months and less saline during the rainy season of spring. The biocide inhibitors were tested in a rig with six side streams biofouling monitoring tubes (SBMT). Bacterial nutrients were added to the system and carbon steel studs were placed along the tubes of the biocide evaluation test rig (BETR). After a month, a thin, slimy, and black deposit was formed on the carbon steel studs. The deposit contained 107 general aerobic bacteria (GAB), 107 general anaerobic bacteria (GAnB) and 105 sulfate reducing bacteria (SRB). The most effective biocide inhibitor was found to be a fatty amine aryl quaternary inhibitor at 50% dosage.

Al-Hashem, A.; Salman, M.; Al-Muhanna, K.; Al-Bazzaz, W. [Kuwait Inst. for Scientific Research, Safat (Kuwait)

1997-08-01

399

Drug-like leads for steric discrimination between substrate and inhibitors of human acetylcholinesterase.  

PubMed

Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P-site) near the mouth of the active-site gorge. Compounds that bind to this site may selectively block access to the acylation site (A-site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using AutoDock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A-site or P-site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A-site only and in both and A- and P-sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P-site in an inhibitor competition assay. PMID:21668653

Wildman, Scott A; Zheng, Xiange; Sept, David; Auletta, Jeffrey T; Rosenberry, Terrone L; Marshall, Garland R

2011-10-01

400

[Alpha-glucosidase inhibitor].  

PubMed

Alpha-glucosidase inhibitors (?-GI) have abdominal signs which are generally regarded as side-reaction. The abdominal signs are caused by generation of intestinal gas which contains hydrogen gas. The hydrogen gas absorbed in the body eliminates oxidant stress and consequently the abdominal signs may have beneficial effects preventing onset and progression of arteriosclerosis. Recently, it has been reported that the combination therapy of dipeptidyl peptidase-4 inhibitors with a-GI enhances glucagon like peptide-1 (GLP- 1) secretion and increases active GLP-1 concentration. Therefore, ?-GI is not only a matured and reliable oral anti-diabtic agent (OAD) but also a promising OAD which collaborates effectively with DPP-4 inhibitors or sodium-glucose cotransporter-2 inhibitors. PMID:25812363

Osonoi, Takeshi

2015-03-01

401

Role of aqueous Bryoria capillaris (Ach.) extract as a genoprotective agent on imazalil-induced genotoxicity in vitro.  

PubMed

In recent years, a number of studies have suggested that lichens might be the easily accessible sources of natural drugs that could be used as a possible food supplement. Extensive research is being carried out to explore the importance of lichen species, which are known to contain a variety of pharmacological active compounds. On the other hand, imazalil (IMA), a commonly used fungicide in both agricultural and clinical domains, is suspected to produce very serious toxic effects in vertebrates. In this context, the antigenotoxic effect of aqueous Bryoria capillaris (Ach.) extract (BCE) was studied against the genotoxic damage induced by IMA on cultured human lymphocytes using chromosomal aberrations (CA) and micronucleus (MN) as cytogenetic parameters. Human peripheral lymphocytes were treated in vitro with varying concentrations of BCE (5, 10, 25, 50 and 100 µg/mL), tested in combination with IMA (336 µg/mL). BCE alone was not genotoxic, and when combined with IMA treatment, it reduced the frequency of CAs and the rates of MN. A clear dose-dependent decrease in the genotoxic damage of IMA was observed, suggesting a genoprotective role of BCE. The results of the present study suggest that this plant extract per se do not have genotoxic potential, but can modulate the genotoxicity of IMA on peripheral human lymphocytes in vitro. In conclusion, our findings may have an important application in the protection of cultured human lymphocyte from the genetic damage and side effects induced by agricultural and medical chemicals that are hazardous to people. PMID:22661402

Turkez, Hasan; Aydin, Elanur; Aslan, Ali

2014-02-01

402

Discovery of pyrazole as C-terminus of selective BACE1 inhibitors.  

PubMed

We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous A?1-40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure-activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50=0.025 ?M) and compound 33 showed moderate inhibition effects on A? production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. PMID:23988410

Zou, Yiquan; Xu, Lei; Chen, Wuyan; Zhu, Yiping; Chen, Tiantian; Fu, Yan; Li, Li; Ma, Lanping; Xiong, Bing; Wang, Xin; Li, Jian; He, Jianhua; Zhang, Haiyan; Xu, Yechun; Li, Jia; Shen, Jingkang

2013-10-01

403

A Novel Route to Recognizing Quaternary Ammonium Cations Using Electrospray Mass Spectrometry  

NASA Astrophysics Data System (ADS)

Characterizing and elucidating structures is a commonplace and necessary activity in the pharmaceutical industry with mass spectrometry and NMR being the primary tools for analysis. Although many functional groups are readily identifiable, quaternary ammonium cations have proven to be difficult to unequivocally identify using these techniques. Due to the lack of an N-H bond, quaternary ammonium groups can only be detected in the 1H NMR spectra by weak signals generated from long-range 14N-H coupling, which by themselves are inconclusive evidence of a quaternary ammonium funct