bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular mechanism of emodin action: Transition from laxative ingredient to an antitumor agent
Authors: Srinivas Gopal , Babykutty Suboj , Sathiadevan Priya Prasanna , Srinivas Priya
Published: October 2006

Anthraquinones represent a large family of compounds having diverse biological properties. Emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone) is a naturally occurring anthraquinone present in the roots and barks of numerous plants, molds, and lichens, and an active ingredient of various Chinese herbs. Earlier studies have documented mutagenic/genotoxic effects of emodin, mainly in bacterial system. Emodin, first assigned to be a specific inhibitor of the protein tyrosine kinase p65lck, has now a number of cellular targets interacting with it. Its inhibitory effect on mammalian cell cycle modulation in specific oncogene overexpressed cells formed the basis of using this compound as an anticancer agent. Identification of apoptosis as a mechanism of elimination of cells treated with cytotoxic agents initiated new studies deciphering the mechanism of apoptosis induced by emodin. At present, its role in combination chemotherapy with standard drugs to reduce toxicity and to enhance efficacy is pursued vigorously. Its additional inhibitory effects on angiogenic and metastasis regulatory processes make emodin a sensible candidate as a specific blocker of tumor‐associated events. Additionally, because of its quinone structure, emodin may interfere with electron transport process and in altering cellular redox status, which may account for its cytotoxic properties in different systems. However, there is no documentation available which reviews the biological activities of emodin, in particular, its growth inhibitory effects. This review is an attempt to analyze the biological properties of emodin, a molecule offering a broad therapeutic window, which in future may become a member of anticancer armamentarium. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 5, 591–608, 2007
Drained and undrained pullout capacity of a stiff inclusion in a saturated poroelastic matrix
Authors: Bobet Antonio , Lee Hong‐Sung , Santagata Maria C.
Published: October 2006

Shear‐lag analysis is used to obtain closed‐form solutions for the problem of a stiff inclusion embedded in a poroelastic soil matrix. The following assumptions are made: the soil matrix and the inclusion are elastic; plane strain conditions apply; and shear stresses at the soil‐inclusion interface follow Coulomb's friction law. Two solutions are obtained, the first one for drained conditions where no excess pore pressures are generated, and the second one for undrained conditions where excess pore pressures are produced and the soil does not change volume during pullout. The solutions are verified by comparing analytical predictions with numerical results obtained using a finite element method. Predictions from the analytical solutions are also compared with results from experiments conducted in a large‐scale pullout box. Both comparisons show good agreement. The analytical solution shows that the pullout capacity in drained and undrained conditions is overall independent of the relative stiffness of the soil and the inclusion. The most important factor controlling the pullout capacity is the coefficient of friction between the soil and the inclusion. Both drained and undrained pullout capacities increase with the coefficient of friction; although the drained capacity shows a proportional increase, it is not so for the undrained capacity. The ratio of undrained to drained pullout capacity is about 0.9 for friction coefficients smaller than 0.2, but can be as small as 0.6 for a coefficient of friction of 1.0. Copyright © 2006 John Wiley & Sons, Ltd.
Relationship for the different processing properties of polyolefin homopolymers and copolymers
Authors: Halász L. , Vorster O.
Published: October 2006

An important method of the modification of the properties of poly(ethylene) and poly(propylene) is the copolymerization with α‐olefins. The α‐olefin behaves as a short branch in the structure, and the rheological and thermal properties of copolymers change significantly. A new method is suggested to evaluate the rheological and thermal properties of copolymers on the basis of homopolymer properties, by introducing a short branch degree parameter. The zero shear viscosity, characteristic relaxation time plateau modulus, fractional free volume, glass transition temperature and thermodynamical melting point were calculated. Copyright © 2006 John Wiley & Sons, Ltd.
Crystal structures of E. coli CcmG and its mutants reveal key roles of the N‐terminal β‐sheet and the fingerprint region
Authors: Ouyang Nan , Gao Yong‐Guang , Hu Hong‐Yu , Xia Zong‐Xiang
Published: October 2006

CcmG, also designated DsbE, functions as a periplasmic protein thiol:disulfide oxidoreductase and is required for cytochrome c maturation. Here we report the crystal structures of Escherichia coli CcmG and its two mutants, P144A and the N‐terminal fifty seven‐residue deletion mutant, and two additional deletion mutants were studied by circular dichroism. Structural comparison of E. coli CcmG with its deletion mutants reveals that the N‐terminal β‐sheet is essential for maintaining the folding topology and consequently maintaining the active‐site structure of CcmG. Pro144 and Glu145 are key residues of the fingerprint region of CcmG. Pro144 is in cis‐configuration, and it makes van der Waals interactions with the active‐site disulfide Cys80–Cys83 and forms a CH…O hydrogen bond with Thr82, helping stabilize the active‐site structure. Glu145 forms a salt‐bridge and hydrogen‐bond network with other residues of the fingerprint region and with Arg158, further stabilizing the active‐site structure. The cis‐configuration of Pro144 makes the backbone nitrogen and oxygen of Ala143 exposed to solvent, favorable for interacting with binding partners. The key role of cis‐Pro144 is verified by the P144A mutant, which contains trans‐Ala144 and displays redox property changes. Structural comparison of E. coli CcmG with the recently reported structure of CcmG in complex with the N‐terminal domain of DsbD reveals that Tyr141 undergoes conformational changes upon binding DsbD. A cis‐proline located at the N‐terminus of the first β‐strand of the ββα motif of the thioredoxin‐like domain is a conserved structural feature of the thioredoxin superfamily. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Properties of analysis methods that account for clustering in volume–outcome studies when the primary predictor is cluster size
Authors: Panageas Katherine S. , Schrag Deborah , Russell Localio A. , Venkatraman E. S. , Begg Colin B.
Published: October 2006

In recent years health services researchers have conducted ‘volume–outcome’ studies to evaluate whether providers (hospitals or surgeons) who treat many patients for a specialized condition have better outcomes than those that treat few patients. These studies and the inherent clustering of events by provider present an unusual statistical problem. The volume–outcome setting is unique in that ‘volume’ reflects both the primary factor under study and also the cluster size. Consequently, the assumptions inherent in the use of available methods that correct for clustering might be violated in this setting. To address this issue, we investigate via simulation the properties of three estimation procedures for the analysis of cluster correlated data, specifically in the context of volume–outcome studies. We examine and compare the validity and efficiency of widely‐available statistical techniques that have been used in the context of volume–outcome studies: generalized estimating equations (GEE) using both the independence and exchangeable correlation structures; random effects models; and the weighted GEE approach proposed by Williamson et al. (Biometrics 2003; 59:36–42) to account for informative clustering. Using data generated either from an underlying true random effects model or a cluster correlated model we show that both the random effects and the GEE with an exchangeable correlation structure have generally good properties, with relatively low bias for estimating the volume parameter and its variance. By contrast, the cluster weighted GEE method is inefficient. Copyright © 2006 John Wiley & Sons, Ltd.
Estimation of the proportion of overweight individuals in small areas—a robust extension of the Fay–Herriot model
Authors: Xie Dawei , Raghunathan Trivellore E. , Lepkowski James M.
Published: October 2006

Hierarchical model such as Fay–Herriot (FH) model is often used in small area estimation. The method might perform well overall but is vulnerable to outliers. We propose a robust extension of the FH model by assuming the area random effects follow atdistribution with an unknown degrees‐of‐freedom parameter. The inferences are constructed using a Bayesian framework. Monte Carlo Markov Chain (MCMC) such as Gibbs sampling and Metropolis–Hastings acceptance and rejection algorithms are used to obtain the joint posterior distribution of model parameters. The procedure is used to estimate the county‐level proportion of overweight individuals from the 2003 public‐use Behavioral Risk Factor Surveillance System (BRFSS) data. We also discuss two approaches for identifying outliers in the context of this application. Copyright © 2006 John Wiley & Sons, Ltd.
Bayesian analysis of structural equation models with multinomial variables and an application to type 2 diabetic nephropathy
Authors: Song Xin‐Yuan , Lee Sik‐Yum , Ng Maggie C. Y. , So Wing‐Yee , Chan Juliana C. N.
Published: October 2006

There is now increasing evidence proving that many complex diseases can be significantly influenced by correlated phenotype and genotype variables, as well as their interactions. Effective and rigorous assessment of such influence is difficult, because the number of phenotype and genotype variables of interest may not be small, and a genotype variable is an unordered categorical variable that follows a multinomial distribution. To address the problem, we establish a novel nonlinear structural equation model for analysing mixed continuous and multinomial data that can be missing at random. A confirmatory factor analysis model with Kronecker product is proposed for grouping the manifest continuous and multinomial variables into latent variables according to their functions; and a nonlinear structural equation is formulated to assess the linear and interaction effects of the independent latent variables to the dependent latent variables. Bayesian methods for estimation and model comparison are developed through Markov chain Monte Carlo techniques and path sampling. The newly developed methodologies are applied to a case–control cohort of type 2 diabetic patients with nephropathy. Copyright © 2006 John Wiley & Sons, Ltd.
Pain and falls in older people
Authors: Blyth Fiona M. , Cumming Robert , Mitchell Paul , Wang Jie Jin
Published: October 2006

Pain and falling both affect substantial segments of the older population. Despite the presence of several plausible mechanisms for pain to contribute to falling, very few studies have investigated this relationship in older people. If pain is a falls risk factor, this represents a potentially important point of intervention for falls prevention. Falls are a major cause of disability and loss of independent living status in older people. We examined the relationship between pain, pain‐related interference with activities and falls in a cross‐sectional analysis of 3509 people aged 49 years or more in two postal code areas in New South Wales, Australia (the Blue Mountains Eye Study). We found that subjects reporting pain with moderate to severe level of pain‐related interference with activities were more likely to report any falls or multiple falls in the past 12 months than subjects not reporting pain (adjusted prevalence ratios 1.42, p=0.0001 and 1.62, p=0.0156, respectively). We also found a significant trend in the association indicating an increasing likelihood of self‐reported falls associated with increasing level of pain‐related interference with activities. The association was stronger for multiple falls than for any falls. Excluding subjects with recent fractures did not alter the findings. Given the high prevalence and public health importance of both conditions, further investigation of this association in prospective studies is recommended.
CHD6 is a DNA‐dependent ATPase and localizes at nuclear sites of mRNA synthesis
Authors: Lutz Thomas , Stöger Reinhard , Nieto Amelia
Published: October 2006

The CHD family of proteins comprises ATP‐dependent chromatin remodeling enzymes, which combine chromodomains, with SWI2/SNF2 ATPase/helicase motifs and DNA‐binding capability. In the last few years, CHD proteins have drawn increased attention, because some of them were found to form large multi‐subunit complexes, involved in transcription‐related events like gene activation, suppression, or histone modification. We previously described the identification of CHD6, a protein of the CHD subfamily III. In the present study, we report that CHD6 is expressed in cells of human origin and in various mouse tissues. Subcellular distribution of CHD6 is restricted to the nucleoplasm. We further show that CHD6 colocalizes with both hypo‐ and hyperphosphorlylated forms of RNA polymerase II. CHD6 was found to be present at sites of mRNA synthesis and to be part of a high molecular weight complex. Moreover, we demonstrate DNA‐dependent ATPase activity of CHD6.
Mapping contacts of the S12–S7 intercistronic region of str operon mRNA with ribosomal protein S7 of E. coli
Authors: Golovin Andrey , Spiridonova Vera , Kopylov Alexei
Published: October 2006

In E. coli, S7 initiates 30S ribosome assembly by binding to 16S rRNA. It also regulates translation of the S12 and S7 cistrons of the ‘streptomycin’ operon transcript by binding to the S12–S7 intercistronic region. Here, we describe the contacts of N‐terminally His6‐tagged S7 with this region as mapped by UV‐induced cross‐linking. The cross‐links are located at U(−34), U(−35), quite distant from the start codons of the two cistrons. In order to explain the mechanism of translational repression of S12–S7, we consider a possible conformational rearrangement of the intercistronic RNA structure induced by S7 binding.
Interannual variation in the moult cycle and size at double breeding of mature female western rock lobster (Panulirus cygnus)
Authors: de Lestang Simon , Melville-Smith Roy
Published: October 2006

The moult cycle of mature female Panulirus cygnus was examined from data recorded over 32 years at four sites along the coast of Western Australia. A repeating trend for mature females was inferred from samples taken between 15 November and 15 August. Setae were present on the endopodites of all large females from June until February–March; between March and June the proportions of females with setae declined sharply as about 80% moulted into a non-setose phase. Females that did not undergo this moult in February remained setose throughout the “normal” non-setose period before moulting and producing a new set of setae by midwinter. New or eroded spermatophores were present on most large females between November and January, but their presence declined sharply during the February–March moult, to be absent by May. The percentage of mature females that bypassed the non-setose moult varied markedly from 1% to 40%, and was well correlated with mean water temperatures in January and February. The proportion that did not undergo a moult increased when these months were cool but decreased when they were warm. The size (carapace width) at which females carry two batches of eggs in one breeding season (double breeder) declined progressively from 96.6 mm to 84.1 mm with decreasing latitude (32°S to 28°S), and further declined at the offshore Abrolhos Islands (29°S) to 78.7 mm. The implications of these findings are discussed in relation to management measures designed to protect females in a setose condition.
PAGING THE ORACLE: INTERPRETATION, IDENTITY AND PERFORMANCE IN HERODOTUS' HISTORY
Authors: BARKER ELTON
Published: October 2006

In his early Byzantine Chronicle, Johannes Malalas fills out the figure of Cyrus, Croesus' silent antagonist in Herodotus. While Croesus is consulting the Delphic oracle, Cyrus enjoys a quite different divine audience:

And the prophet Daniel came to the King of the Persians, Cyrus. And Cyrus says to him: ‘Tell me, am I going to conquer Croesus King of the Lydians?’

When the Christian prophet hesitates, Cyrus throws him to the lions – only swiftly to repent. Daniel returns the favour by confirming that Cyrus will defeat Croesus because God breaks the ‘might of kings’. Malalas' version of divine counselling clearly draws on Christian moralizing traditions; but it also flags up the confrontation between the powerful king and the word of god in Herodotus' narrativisation of Croesus' downfall. At the same time, however, it offers a radically different interpretative model. Here we don't just have a Croesus consulting the oracle and failing to comprehend it; Cyrus is told what will happen – and why – by the prophet Daniel! From Croesus (mis)reading the oracle to Cyrus receiving instruction from God, narrative dynamics have undergone a fundamental shift. It's now the gospel…

Scholarship on Croesus testing Delphi, and on oracles more generally, has tended to focus on reconstructing the ‘original’ oracular texts and assessing Herodotus' role as a historian (in the modern sense of the word) in the light of how accurate his record is deemed to be. Notwithstanding the fact that such positivist approaches to historical writing have been challenged and that recent studies have been far more nuanced, the oracles themselves remain the focus of investigation. In tracing their ‘changing representations’ I want to look exclusively at how they function within Herodotus' narrative.
INTERTEXTUALITY AS IRONY: HERACLES IN EPIC AND IN SOPHOCLES
Authors: LIAPIS VAYOS
Published: October 2006

Heracles' image in antiquity is notoriously kaleidoscopic. Comedy represented him as a gluttonous buffoon, and myth made no secret of the brutal violence of many of his exploits. On the other hand, Pindar exalts him as a superlative figure who enforced the nomos of the gods, while Prodicus in a famous myth makes Heracles a supreme example of commendable conduct, a youth who chooses the path of Virtue over the path of Vice out of his own free will. This image of a moralized Heracles soon took root in the Greek imagination, and a whole host of Greek thinkers (Isocrates, Antisthenes, Diogenes the Cynic, and Plutarch, to name but a few) found in him a perfectly malleable exemplum for their various courses in moral edification. After undergoing a large number of transformations in Roman literature and the Church Fathers, Heracles resurfaces unscathed in the early Renaissance, when we find him again as an already established exemplum virtutis, now a man of letters, now a Christian. It would appear that, despite his multifarious metamorphoses, Heracles remained throughout the centuries essentially what he had been since Prodicus' day: an exemplary figure who undertook extreme toils and gained supreme recompense.
OVID, TRISTIA 1.2: HIGH DRAMA ON THE HIGH SEAS
Authors: INGLEHEART JENNIFER
Published: October 2006

In the first poem of Tristia 1, Ovid claims me mare, me uenti, me fera iactat hiems (‘the sea, the winds, the savage winter storm harass me repeatedly’, 1.1.42). This is no mere rhetorical flourish: the immediacy of the present tense becomes apparent in the second poem in the collection, which purports to be the poet's words as he faces a storm at sea. Critics tend to treat this poem as a literary exercise, focusing upon Ovid's exploitation of epic descriptions of the sea as a vast elemental force, subject to the machinations of the gods. In particular, interest has centred upon Ovid's debt to the storms which face Aeneas and Odysseus in Aeneid 1, 3, and 5 and Odyssey 5, as well as the relationship between this poem and Ovid's own version of an ‘epic’ storm in the story of Ceyx and Alcyone at Metamorphoses 11.410–748.

However, this poem contains much more than the sum of its various epic models: 1.2 is programmatic for the rest of Tristia 1, not least because it can be seen as the first ‘proper’ poem of the collection, given that 1.1 is addressed to Ovid's new book of poetry as he sends it to Rome, and as such, self-consciously stands apart from the rest of the book.
Introduction
Authors: Steel Catherine
Published: October 2006

The focus of this survey is on oratory as a spoken phenomenon, intimately related to politics and government at Rome. Its chronological scope is roughly from the beginning of the second century B.C. until the end of the first century A.D.; it has no pretensions to offer a guide to oratory in the later Empire. Its geographical focus is firmly on Rome, reflecting the overwhelming bias in our source material. I start with the occasions for oratory in Rome and turn then to the issues which arise from the process of turning a speech, delivered in front of an audience on a particular occasion, into a written text which can be accessed and enjoyed in private and at any time. I then consider some of the means by which orators of the imperial period explored different means of preserving their oratorical activities for posterity. In the final two chapters I concentrate on orators themselves: how they carried out their task, and reflected upon it, as adult practitioners, and then how boys became the next generation of orators.
The archaeology of apoptosis
Authors: KNIGHT R. A.
Published: October 2006

Human death has been recognised as a significant personal and social event for many thousands of years, and classical archaeologists have revealed the changing complexity of rituals associated with it. The study of cell death, however, is a much more recent event, although many of the molecular pathways involved have now been identified, at least in mammalian systems. In studying the loss of cells, the use of the term ‘death’ is, perhaps, not altogether appropriate both since it carries the cultural resonance associated with bodily death, and because we do not study cell death itself, but rather the processes that lead up to it. Mammalian cell death processes are complex and involve a dynamic equilibrium between death promoting and death inhibiting factors, suggesting that some components of death pathways may have a paradoxical survival function. Since parasites must survive an often hostile environment, they may be a useful model to study whether component molecules of mammalian death pathways originally formed modules of parasite survival strategies, and whether survival and death pathways coevolved.
Phenotypical characteristics, biochemical pathways, molecular targets and putative role of nitric oxide-mediated programmed cell death inLeishmania
Authors: HOLZMULLER P. , BRAS-GONÇALVES R. , LEMESRE J.-L.
Published: October 2006

Nitric oxide (NO) has been demonstrated to be the principal effector molecule mediating intracellular killing ofLeishmania, bothin vitroandin vivo. We investigated the type of cell death process induced by NO for the intracellular amastigote stage of the protozoaLeishmania. Specific detection methods revealed a rapid and extensive cell death with morphological features of apoptosis in axenic amastigotes exposed to NO donors, in intracellular amastigotes insidein vitro– activated mouse macrophages and also in activated macrophages of regressive lesions in a leishmaniasis-resistant mouse model. We extended our investigations to the dog, a natural host-reservoir ofLeishmaniaparasites, by demonstrating that co-incubation of infected macrophages with autologous lymphocytes derived from dogs immunised with purified excreted-secreted antigens ofLeishmaniaresulted in a significant NO-mediated apoptotic cell death of intracellular amastigotes. From the biochemical point of view, NO-mediatedLeishmaniaamastigotes apoptosis did not seem to be controlled by caspase activity as indicated by the lack of effect of cell permeable inhibitors of caspases and cysteine proteases, in contrast to specific proteasome inhibitors, such as lactacystin or calpain inhibitor I. Moreover, addition of the products of two NO molecular targets,cis-aconitase and glyceraldehyde-3-phosphate dehydrogenase, also had an inhibitory effect on the cell death induced by NO. Interestingly, activities of these two enzymes plus 6-phosphogluconate dehydrogenase, parasitic enzymes involved in both glycolysis and respiration processes, are overexpressed in amastigotes selected for their NO resistance. This review focuses on cell death of the intracellular stage of the pathogenLeishmaniainduced by nitrogen oxides and gives particular attention to the biochemical pathways and the molecular targets potentially involved. Questions about the role ofLeishmaniaamastigotes NO-mediated apoptosis in the overall infection process are raised and discussed.
Apoptosis-like death as a feature of malaria infection in mosquitoes
Authors: HURD H. , GRANT K. M. , ARAMBAGE S. C.
Published: October 2006

Malaria parasites of the genusPlasmodiummake a hazardous journey through their mosquito vectors. The majority die in the process, many as a result of the action of mosquito defence mechanisms. The mosquito too is not unscathed by the encounter with these parasites. Tissue damage occurs as a result of mid-gut invasion and reproductive fitness is lost when many developing ovarian follicles are resorbed. Here we discuss some of the mechanisms that are involved in killing the parasite and in the self-defence mechanisms employed by the mosquito to repair the mid-gut epithelium and to manipulate resources altering the trade-off position that balances reproduction and survival. In all cases, cells die by apoptotic-like mechanisms. In the midgut cells, apoptosis-induction pathways are being elucidated, the molecules involved in apoptosis are being recognised andDrosophilahomologues sought. The death of ookinetes in the mosquito mid-gut lumen is associated with caspase-like activity and, although homologues of mammalian caspases are not present in the malaria genome, other cysteine proteases that are potential candidates have been discussed. In the ovary, apoptosis of patches of follicular epithelial cells is followed by resorption of the developing follicle and a subsequent loss of egg production in that follicle.
Measuring Adaptability: Psychological Examinations of Jewish Detainees in Cyprus Internment Camps
Authors: Zalashik Rakefet , Davidovitch Nadav
Published: October 2006

Argument

Two medical delegations, one from Palestine and one from the United States, were sent to detainment camps in Cyprus in the summer of 1947. The British Mandatory government had set up these camps in the summer of 1946 to stem the flow of Jewish immigrants into Palestine after World War II. The purpose of the medical delegations was to screen the camps' inhabitants and to propose a mental-health program for their life in Palestine. We examine the activities of these two delegations within the context of their scientific interest in the psycho-pathology of displaced persons after World War II and as part of a broader project of mental hygiene. According to the delegations, the detainees would be a potential source of strength for building a new society if they adapted to life in Palestine. However, they would become a burden if they failed to be absorbed. At the same time, the medical delegations also saw the detainee camps as a potential “living laboratory” for scientific exploration. The case of the two medical delegations in Cyprus is also a story about constructing and transgressing medical borders. Apart from the obvious fact that this case study deals with movement of people, refugees as well as health-care workers, it is also about the transmission of knowledge and professions across the ocean.
Measuring the bulk density of meteorites nondestructively using three‐dimensional laser imaging
Authors: Smith D. L. , Samson C. , Herd R. , Deslauriers A. , Sink J.‐E. , Christie I. , Ernst R. E.
Published: October 2006

The fragile and unique nature of meteoritic material requires a method of density measurement that is accurate yet nondestructive. This is difficult to achieve using conventional methods. In this study, the bulk density of eleven meteorite fragments which vary in shape, size, surface roughness, porosity, and reflectance has been determined using three‐dimensional (3‐D) laser imaging. An auto‐synchronized laser camera raster scanned the surface features of each meteorite without contact and to a high degree of precision. Visualization software was used to align several scans into a closed model and to compute its volume. The mass having been predetermined, the density was then easily computed. Three‐dimensional laser imaging is the least invasive method of density measurement currently in use. The precision of the approach is less than 1%. The densities determined using 3‐D laser imaging compare very well with previously published values, based on a variety of different measurement techniques. The average difference is 3.4% and can be attributed to the presence of heterogeneities and to the limited amount of comparative data available. For nine out of the eleven samples studied, the densities determined using 3‐D laser imaging are higher than previously published results. Friction between fluid and container, and bead compaction might have led to an overestimation of the volume measured using Archimedean methods. In addition to volume measurements, 3‐D images of rock samples can yield detailed information on surface properties from a distance. The technique could be used for semiautonomous planetary geological exploration.
Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A‐841720, a novel non‐competitive mGluR1 receptor antagonist
Authors: El‐Kouhen O , Lehto S G , Pan J B , Chang R , Baker S J , Zhong C , Hollingsworth P R , Mikusa J P , Cronin E A , Chu K L , McGaraughty S P , Uchic M E , Miller L N , Rodell N M , Patel M , Bhatia P , Mezler M , Kolasa T , Zheng G Z , Fox G B , Stewart A O , Decker M W , Moreland R B , Brioni J D , Honore P
Published: October 2006

Background and purpose:

To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain.

Experimental approach:

We characterized the effects of A‐841720, a novel, potent and non‐competitive mGluR1 antagonist in models of pain and of motor and cognitive function.

Key results:

At recombinant human and native rat mGluR1 receptors, A‐841720 inhibited agonist‐induced calcium mobilization, with IC50 values of 10.7±3.9 and 1.0±0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A‐841720 potently reduced complete Freund's adjuvant‐induced inflammatory pain (ED50=23 μmol kg−1) and monoiodoacetate‐induced joint pain (ED50=43 μmol kg−1). A‐841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5‐L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50=28 and 27 μmol kg−1, respectively). Electrophysiological studies demonstrated that systemic administration of A‐841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A‐841720 also impaired cognitive function in the Y‐maze and the Water Maze tests.

Conclusions and implications.

The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre‐clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

British Journal of Pharmacology (2006) 149, 761–774. doi:10.1038/sj.bjp.0706877
Antidystonic effects of Kv7 (KCNQ) channel openers in thedtszmutant, an animal model of primary paroxysmal dystonia
Authors: Richter A , Sander S E , Rundfeldt C
Published: October 2006

Background and purpose:

Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined.

Experimental approach:

In the present study, we therefore examined the effects of the activators of neuronal Kv7.2/7.3 channels retigabine (5, 7.5, 10 mg kg−1i.p. and 10, 20 mg kg−1p.o.) and flupirtine (10, 20 mg kg−1i.p.) and of the channel blocker 10,10‐bis(4‐pyridinylmethyl)‐9(10H)‐anthracenone (XE‐991, 3 and 6 mg kg−1i.p.) in thedtszmutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress.

Key results:

Retigabine (10 mg kg−1i.p., 20 mg kg−1p.o.) and flupirtine (20 mg kg−1i.p.) significantly improved dystonia, while XE‐991 caused a significant aggravation in thedtszmutant. The antidystonic effect of retigabine (10 mg kg−1i.p.) was counteracted by XE‐991 (3 mg kg−1i.p.).

Conclusions and Implications:

These data indicate that dysfunctions of neuronal Kv7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in thedtszmutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia‐associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.

British Journal of Pharmacology(2006)149, 747–753. doi:10.1038/sj.bjp.0706878
Inhibition of cardiac voltage‐gated sodium channels by grape polyphenols
Authors: Wallace C H R , Baczkó I , Jones L , Fercho M , Light P E
Published: October 2006

Background and purpose:

The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including quercetin, catechin and resveratrol. Inhibition of cardiac voltage‐gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic VGSC inhibitors, we hypothesised that VGSC inhibition may contribute to cardioprotection by these polyphenols.

Experimental approach:

The whole‐cell voltage‐clamp technique was used to record peak and late VGSC currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field‐stimulated. Either calcium transients or contractility were measured using the calcium‐sensitive dye Calcium‐Green 1AM or video edge detection, respectively.

Key results:

The red grape polyphenols quercetin, catechin and resveratrol blocked peak INa with IC50s of 19.4 μM, 76.8 μM and 77.3 μM, respectively. In contrast to lidocaine, resveratrol did not exhibit any frequency‐dependence of peak INa block. Late INa induced by the VGSC long QT mutant R1623Q was reduced by resveratrol and quercetin. Resveratrol and quercetin also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 μM and 24.9 μM, respectively. In field‐stimulated myocytes, ATXII‐induced increases in diastolic calcium were prevented and reversed by resveratrol. ATXII‐induced contractile dysfunction was delayed and reduced by resveratrol.

Conclusions and implications:

Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products.

British Journal of Pharmacology (2006) 149, 657–665. doi:10.1038/sj.bjp.0706897
Baclofen, an agonist at peripheral GABABreceptors, induces antinociceptionviaactivation of TEA‐sensitive potassium channels
Authors: Reis G M L , Duarte I D G
Published: October 2006

Background and Purpose:

Central anti‐nociceptive actions of baclofen involve activation of K+channels. Here we assessed what types of K+channel might participate in the peripheral anti‐nociception induced by baclofen.

Experimental approach:

Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E2.(PGE2) to induce hyperalgesia were measured 3h after PGE2injection. Other agents were also given by intraplantar injection

Key results:

Baclofen elicited a dose‐dependent (15 ‐ 240 μg per paw) anti‐nociceptive effect. An intermediate dose of baclofen (60 μg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABABreceptor antagonist saclofen (12.5 ‐ 100 μg per paw) antagonized, in a dose‐dependent manner, peripheral antinociception induced by baclofen (60 μg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABAAreceptor antagonist (80 μg per paw), or by (1,2,5,6 tetrahydropyridin‐4‐yl) methylphosphinic acid, GABACreceptor antagonist (20 μg per paw). The peripheral antinociception induced by baclofen (60 μg) was reversed, in a dose‐dependent manner, by the voltage‐dependent K+channel blockers tetraethylammonium (7.5 ‐ 30 μg per paw) and 4‐aminopyridine (2.5 ‐ 10 μg per paw). The blockers of other K+channels, glibenclamide (160 μg), tolbutamide (320 μg), charybdotoxin (2 μg), dequalinium (50 μg) and caesium (500 μg) had no effect.

Conclusions and Implications:

This study provides evidence that the peripheral antinociceptive effect of the GABABreceptor agonist baclofen results from the activation of tetraethylammonium‐sensitive K+channels. Other K+channels appear not to be involved.

British Journal of Pharmacology(2006)149, 733–739. doi:10.1038/sj.bjp.0706898
Inhibition of glycogen synthase kinase‐3β attenuates the development of carrageenan‐induced lung injury in mice
Authors: Cuzzocrea S , Crisafulli C , Mazzon E , Esposito E , Muià C , Abdelrahman M , Di Paola R , Thiemermann C
Published: October 2006

Background and purpose:

Glycogen synthase kinase‐3 (GSK‐3) is a ubiquitous serine‐threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK‐3β inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD‐8, a potent and selective GSK‐3β inhibitor, in a mouse model of carrageenan‐induced pleurisy.

Experimental approach:

Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2(PGE2), tumour necrosis factor‐α, (TNF‐α) and interleukin‐1β (IL‐1β). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM‐1 and P‐selectin, iNOS, COX‐2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues.

Key results:

Administration of TDZD‐8 (1, 3 or 10 mg kg−1, i.p.), 30 min prior to injection of carrageenan, caused a dose‐dependent reduction in all the parameters of inflammation measured.

Conclusions and Implications:

Thus, based on these findings we propose that inhibitors of the activity of GSK‐3β, such as TDZD‐8, may be useful in the treatment of various inflammatory diseases.

British Journal of Pharmacology(2006)149, 687–702. doi:10.1038/sj.bjp.0706902
Inhalation of activated protein C inhibits endotoxin‐induced pulmonary inflammation in mice independent of neutrophil recruitment
Authors: Slofstra S H , Groot A P , Maris N A , Reitsma P H , Cate H ten , Spek C A
Published: October 2006

Background and purpose:

Intravenous administration of recombinant human activated protein C (rhAPC) is known to reduce lipopolysaccharide (LPS)‐induced pulmonary inflammation by attenuating neutrophil chemotaxis towards the alveolar compartment. Ideally, one would administer rhAPC in pulmonary inflammation at the site of infection to minimize the risk of systemic bleeding complications. In this study, we therefore assessed the effect of inhaled rhAPC in a murine model of acute lung injury.

Experimental approach:

Mice were exposed to LPS (0.5 mg kg‐1: intranasally) to induce acute lung injury. 30 minutes before and 3 hours after LPS exposure mice were subjected to vehicle or rhAPC inhalation (25 or 100 μg per mouse in each nebulization). In order to establish whether rhAPC inhalation affects neutrophil recruitment, neutrophil migration was determined in vitro using a trans‐well migration assay.

Key results:

rhAPC inhalation dose‐dependently decreased LPS‐induced coagulation and inflammation markers in bronchoalveolar lavage fluid (BALF), reduced protein leakage into the alveolar space and improved lung function. In contrast, rhAPC did not prevent LPS‐induced neutrophil recruitment into the alveolar space.

Neutrophil migration in vitro towards FCS or interleukin (IL)‐8 was significantly inhibited by pretreatment with rhAPC (0.01‐10 μg ml‐1], whereas rhAPC (10 μg ml‐1) added to the chemoattractant (modelling for topical rhAPC administration) did not affect neutrophil migration towards FCS or IL‐8.

Conclusions and Implications:

rhAPC inhalation significantly diminished LPS‐induced pulmonary inflammation. The benefit of inhaled rhAPC appeared not to involve attenuation of neutrophil recruitment, in contrast to its effects after intravenous administration.

British Journal of Pharmacology (2006) 149, 740–746. doi:10.1038/sj.bjp.0706915
The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba2+ currents in guinea‐pig vascular smooth muscle
Authors: Zhu H‐L , Tomoda T , Aishima M , Ito Y , Teramoto N
Published: October 2006

Background and purpose:

Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage‐dependent L‐type Ca2+ channels were investigated in guinea‐pig portal vein.

Experimental approach:

The inhibitory potency of azelnidipine on spontaneous contractions in guinea‐pig portal vein was compared with those of other dihydropyridine (DHP)‐derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage‐dependent nifedipine‐sensitive inward Ba2+ currents (I
Ba) in smooth muscle cells dispersed from guinea‐pig portal vein were investigated by use of a conventional whole‐cell patch‐clamp technique.

Key results:

Spontaneous contractions in guinea‐pig portal vein were reduced by all of the Ca antagonists (azelnidipine, K

i=153 nM; amlodipine, K

i=16 nM; nifedipine, K

i=7 nM). In the whole‐cell experiments, azelnidipine inhibited the peak amplitude of I
Ba in a concentration‐ and voltage‐dependent manner (‐60 mV, K

i=282 nM; −90 mV, K

i=2 μM) and shifted the steady‐state inactivation curve of I
Ba to the left at −90 mV by 16 mV. The inhibitory effects of azelnidipine on I
Ba persisted after 7 min washout at −60 mV. In contrast, I
Ba gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of I
Ba at ‐90 mV. Only nifedipine appeared to interact competitively with S(‐)‐Bay K 8644.

Conclusions and implications:

These results suggest that azelnidipine induces long‐lasting vascular relaxation by inhibiting voltage‐dependent L‐type Ca2+ channels in vascular smooth muscle.

British Journal of Pharmacology (2006) 149, 786–796. doi:10.1038/sj.bjp.0706919
Prostaglandin E2receptor distribution and function in the gastrointestinal tract
Authors: Dey I , Lejeune M , Chadee K
Published: October 2006

Prostaglandin E2(PGE2) is one of the most important biologically active prostanoids found throughout the gastrointestinal tract. Despite the fact that PGE2regulates many physiological functions of the gut including mucosal protection, gastrointestinal secretion and motility, it is implicated in the pathophysiology of inflammatory bowel diseases (IBD) and colorectal neoplasia. The varied biological functions exerted by PGE2are through the pharmacologically distinct, G‐protein coupled plasma membrane receptors termed EP receptors. Disruptions of various prostanoid receptor genes have helped in unravelling the physiological functions of these receptors. To date, all four subtypes of EP receptors have been individually knocked out in mice and various phenotypes have been reported for each subtype. Similarly,in vitroandin vivostudies using EP receptor agonists and antagonists have helped in uncoupling the diverse functions of PGE2signalling involving distinct EP receptors in the gut. In this review, we will summarize and conceptualize the salient features of EP receptor subtypes, their regional functions in the gut and how expressions of EP receptors are altered during disease states.

British Journal of Pharmacology(2006)149, 611–623. doi:10.1038/sj.bjp.0706923
Effects of nitric oxide synthase inhibition with or without cyclooxygenase‐2 inhibition on resting haemodynamics and responses to exendin‐4
Authors: Gardiner S M , March J E , Kemp P A , Bennett T
Published: October 2006

Background and purpose:

Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase‐2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with N
G‐nitro‐L‐arginine methyl ester (L‐NAME)), on resting cardiovascular variables and on responses to the glucagon‐like peptide 1 agonist, exendin‐4, which causes regionally‐selective vasoconstriction and vasodilatation.

Experimental approach:

Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L‐NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin‐4 was given 60 min after the onset of L‐NAME infusion.

Key results:

Parecoxib had no effect on resting cardiovascular variables or on responses to L‐NAME. Exendin‐4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin‐4, but L‐NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L‐NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response.

Conclusions and implications:

Cyclooxygenase‐2‐derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L‐NAME on the hindquarters vasodilator and tachycardic effects of exendin‐4 are consistent with a previous study that showed those events to be β‐adrenoceptor mediated. The additional effect of parecoxib on responses to exendin‐4 in the presence of L‐NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced.

British Journal of Pharmacology (2006) 149, 802–809. doi:10.1038/sj.bjp.0706931