bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the antinociceptive activity of two new NO‐releasing derivatives of the NSAID S‐ketoprofen in rats
Authors: Gaitan Gema , Ahuir F Javier , Soldato Piero Del , Herrero Juan F 
Published: October 2004

Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti‐inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)‐releasing NSAIDs resulted from this search.
We have compared the antinociceptive effectiveness of cumulative doses of two new NO‐releasing derivatives of S‐ketoprofen, HCT‐2037 and HCT‐2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration.
S‐ketoprofen and HCT‐2040 were equieffective in reducing responses to noxious mechanical stimulation after i.v. administration in anesthetized animals (ID50s: 1.3±0.1 and 1.6±0.2 μmol kg−1 respectively), but did not modify wind‐up. HCT‐2037 was two‐fold more potent (ID50 of 0.75±0.1 μmol kg−1) in responses to mechanical stimuli and very effective in reducing wind‐up (63±17% of control; P<0.01; MED: 0.4 μmol kg−1), indicating a greater activity than the parent compound.
In awake animals with inflammation, HCT‐2037 p.o. fully inhibited mechanical allodynia, 91±12% reduction, and hyperalgesia, 94±8% reduction. Equivalent doses of S‐ketoprofen only partially reduced either allodynia (50±11%) or hyperalgesia (40±4%). The effect on responses to noxious thermal stimulation was similar for the two compounds.
We conclude that the molecular changes made in the structure of S‐ketoprofen including an NO moiety in its structure, improve the antinociceptive profile of the compound opening new perspectives in a safer use of NSAIDs as analgesic drugs.

British Journal of Pharmacology (2004) 143, 533–540. doi:10.1038/sj.bjp.0705958
Acute wake‐promoting actions of JNJ‐5207852, a novel, diamine‐based H3 antagonist
Authors: Barbier A J , Berridge C , Dugovic C , Laposky A D , Wilson S J , Boggs J , Aluisio L , Lord B , Mazur C , Pudiak C M , Langlois X , Xiao W , Apodaca R , Carruthers N I , Lovenberg T W 
Published: October 2004

1‐[4‐(3‐piperidin‐1‐yl‐propoxy)‐benzyl]‐piperidine (JNJ‐5207852) is a novel, non‐imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ‐5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 μM.
JNJ‐5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg−1 in mice). In vitro autoradiography with 3H‐JNJ‐5207852 in mouse brain slices shows a binding pattern identical to that of 3H‐R‐α‐methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H‐JNJ‐5207852 was observed in brains of H3 receptor knockout mice.
In mice and rats, JNJ‐5207852 (1–10 mg kg−1 s.c.) increases time spent awake and decreases REM sleep and slow‐wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow‐wave delta power, is observed. The wake‐promoting effects of this H3 receptor antagonist are not associated with hypermotility.
A 4‐week daily treatment of mice with JNJ‐5207852 (10 mg kg−1 i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor.
JNJ‐5207852 is extensively absorbed after oral administration and reaches high brain levels.
The data indicate that JNJ‐5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake‐promoting effects of H3 receptor antagonists.

British Journal of Pharmacology (2004) 143, 649–661. doi:10.1038/sj.bjp.0705964
Impairment of the low‐affinity state β1‐adrenoceptor‐induced relaxation in spontaneously hypertensive rats
Authors: Mallem Mohamed Yassine , Toumaniantz Gilles , Serpillon Sabrina , Gautier Freddy , Gogny Marc , Desfontis Jean‐Claude , Gauthier Chantal 
Published: October 2004

In hypertension, a decrease of the vascular β‐adrenergic relaxation has been described. However, the specific involvement of each β‐adrenoceptor (β‐AR) subtype, in particular the low‐affinity state of β1‐AR, has not yet been evaluated. We investigated whether the low‐affinity state of β1‐AR‐induced relaxation was impaired in Spontaneously Hypertensive Rats (SHR).
The relaxant responses to CGP 12177 and cyanopindolol, low‐affinity state β1‐AR agonists (with β1‐/β2‐AR antagonistic and partial β3‐AR agonistic properties) were evaluated on thoracic aortic rings isolated from 12‐weeks‐old Wistar Kyoto rats (WKY) and SHR.
In WKY, CGP 12177 and cyanopindolol produced an endothelium and nitric oxide (NO)‐independent relaxation. CGP 12177‐induced endothelium‐independent relaxation was not modified either by β1‐, β2‐AR (nadolol) or β3‐AR (L‐748337 or SR 59230A) antagonists but was significantly reduced by high concentrations of CGP 20712A (P<0.05). This relaxation was also reduced by adenylyl cyclase inhibitors, SQ 22536 or MDL 12330A.
In SHR, CGP 12177 produced mainly an endothelium and NO‐dependent relaxation. This effect was not modified by nadolol, but was strongly reduced by β3‐AR blockade. Endothelium‐independent relaxation to CGP 12177 was not altered by adenylyl cyclase inhibition, but was amplified in preparations from pertussis toxin‐pretreated SHR.
The immunohistochemical analysis revealed an upregulation of β3‐AR in the endothelial layer of SHR aorta, whereas the β3‐AR‐induced relaxation was not modified.
In conclusion, we demonstrated an impaired low‐affinity state of the β1‐AR‐induced relaxation and an upregulation of the β3‐AR in hypertension. Some clinical implications of those findings are discussed.

British Journal of Pharmacology (2004) 143, 599–605. doi:10.1038/sj.bjp.0705990
Do low‐affinity states of β‐adrenoceptors have roles in physiology and medicine?
Authors: Arch Jonathan R S 
Published: October 2004

The pharmacology once ascribed to the ‘β4‐adrenoceptor’ is now believed to be that of a low‐affinity state of the β1‐adrenoceptor. The β2‐adrenoceptor may also have a low‐affinity state or site, while the β3‐adrenoceptor – the original low‐affinity β‐adrenoceptor – can display more than one pharmacology. In this issue, Mallem et al. show that CGP‐12177 relaxes thoracic aorta rings from normal rats by stimulating vascular smooth muscle low‐affinity β1‐adrenoceptors, apparently linked in part to Gi protein. By contrast, in rings from hypertensive rats, CGP‐12177 acts mainly via endothelial β3‐adrenoceptors. This work raises the possibility that low‐affinity states of β‐adrenoceptors have physiological roles, and suggests that they might be drug targets.British Journal of Pharmacology (2004) 143, 517–518. doi:10.1038/sj.bjp.0705991
Tedisamil attenuates foetal transformation of myosin in the hypertrophied rat myocardium
Authors: Turcani Marian , Thormaehlen Dirk , Rupp Heinz 
Published: October 2004

Reduction in repolarizing potassium currents has controversial effects on hypertrophic responses in cardiomyocytes of transgenic models and cultured cardiomyocytes. It remains thus unknown whether a blockade of potassium channels with tedisamil (N,N′dicyclopropylmethylene‐9,9‐tetramethylene‐3,7‐diazabicyclo(3.3.1)nonane dihydrochloride) has any effects on cardiac growth during postnatal development or pressure overload.
To test the hypothesis that a treatment with tedisamil affects cardiac growth or protein phenotype, sham‐operated rats and rats with ascending aorta constriction were treated with tedisamil (36 mg kg day−1) for 7 weeks. Left ventricular mass and geometry, relative expression of myosin isoforms, hydroxyproline concentration and isovolumic ventricular function were assessed.
Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure–volume relationship was shifted to smaller volumes. The hydroxyproline concentration remained unaltered. The proportion of α‐myosin heavy chains was, however, reduced (P<0.05). Hypertrophied left ventricles manifested an enhanced overall performance but depressed myocardial contractility.
Administration of tedisamil was associated with decreased heart rate (P<0.05). In contrast, cardiac growth in sham‐operated rats and concentric left ventricular hypertrophy of pressure‐overloaded animals was not significantly altered. Hypertrophied hearts from rats treated with tedisamil expressed more α‐myosin heavy chains (65±4 versus 57±4%; P<0.05). Also, maximal rate of wall stress rise and decline was higher (P<0.05) in tedisamil‐treated pressure‐overloaded rats.
In the rat model of pressure‐overloaded hypertrophy, tedisamil had no effect on cardiac growth but partially corrected myocardial dysfunction. Postulated mechanism of this effect is the phenotype modification of myosin filaments in hypertrophied myocardium.

British Journal of Pharmacology (2004) 143, 561–572. doi:10.1038/sj.bjp.0705992
Glucocorticoid hormone (cortisol) affects axonal transport in human cortex neurons but shows resistance in Alzheimer's disease
Authors: Dai Jiapei , Buijs Ruud , Swaab Dick 
Published: October 2004

The changes of tissue sensitivity to glucocorticoids are associated with many pathological states including neurological diseases. In the present study, using a novel in vitro post‐mortem tracing method on human brain slices, we demonstrated that cortisol, a major glucocorticoid hormone in humans, affected axonal transport both in the cortex neurons in four Alzheimer's disease (AD) patients and four nondemented controls.
Cortisol appeared to affect axonal transport of prefrontal cortex (PFC) and temporal cortex (TC) neurons in AD patients and controls in a dose‐dependent way at concentrations of 30, 60, 120 and 240 μg dl−1.
Higher doses of cortisol were needed for TC neurons to achieve a similar axonal transport effect as obtained in PFC neurons in AD patients. The maximum effect (Emax) on axonal transport was achieved in PFC slices at relatively low contraction (30–120 μg dl−1), while in TC slices, a maximum effect was only reached at relatively high concentrations (120–240 μg dl−1).
For PFC and TC slices from nondemented aging subjects, lower doses of cortisol (30–60 μg dl−1) on axonal transport were sufficient to achieve the maximum effect as compared to those used in AD brain slices, while levels of more than 60 μg dl−1 of cortisol mostly depressed axonal transport.
These results suggest that glucocorticoid resistance, which is thought to contribute to the pathogenesis of a number of common human disorders, may exist in AD brains and play an important role in neuropathological mechanisms and dementia.

British Journal of Pharmacology (2004) 143, 606–610. doi:10.1038/sj.bjp.0705995
Novel role for P2X receptor activation in endothelium‐dependent vasodilation
Authors: Harrington Louise S , Mitchell Jane A 
Published: October 2004

ATP is an important vasoactive mediator, which acts via two receptor classes: P2X and P2Y. Activation of P2X receptors has traditionally been associated with the well‐characterised vasoconstrictor properties of ATP.
In the current study, we have shown that the P2X1 & 3 receptor ligand, α, β methylene ATP, induces vasodilation of rat isolated mesenteric arteries and that P2X1 receptors are abundantly expressed in the endothelium of these vessels.
Second‐order rat mesenteric arteries were mounted in myographs and vasomotor responses recorded. Both ATP and α, β methylene ATP induced a constriction followed by a vasodilation. The dilator effects of either ATP or α, β methylene ATP were slower in onset than those induced by acetylcholine. By contrast, the traditional vasodilator P2Y ligand, ADP, induced vasodilation without contraction.
Vasodilation induced by α, β methylene ATP was endothelial dependent, but was not affected by treatment of the vessels with l‐NAME plus indomethacin alone. Dilation was, however, partially inhibited by the combination of apamin plus charybdotoxin and blocked by treating vessels with all four drugs.
Using confocal microscopy, P2X1 receptor immunoreactivity was localised to the endothelial, smooth muscle and adventitial layers of mesenteric vessels. P2X1 protein migrated as a primary band at around 50–60 kDa in vascular tissue.
These results show for the first time that P2X1 receptors are expressed on the endothelium and that a selective ligand of this receptor results in vasoconstriction followed by vasodilation. These observations have important implications for our understanding of the role of purines in biological responses.

British Journal of Pharmacology (2004) 143, 611–617. doi:10.1038/sj.bjp.0706004
Characterization of the cis-acting element directing perinuclear localization of the metallothionein-1 mRNA
Authors: Chabanon H. , Nury D. , Mickleburgh I. , Burtle B. , Hesketh J. 
Published: October 2004

Subcellular localization of mRNAs is a key mechanism for the synthesis of proteins close to their site of function. The mRNA encoding MT-1 (metallothionein-1) is localized in the perinuclear cytoplasm, where it is associated with cytoskeletal-bound polysomes. This localization relies on sequences present in the 3′-UTR (3′-untranslated region). The present study aims to characterize the cis-acting localization element(s) within the 3′-UTR. Using transfected cells expressing tagged MT-1 differing in their 3′-UTRs (deleted or mutated), the section(s) of this region required for directing MT-1 transcripts to the perinuclear cytoplasm has been investigated. Different 3′-UTRs were also used in UV cross-linking experiments that highlighted two distinct regions (nt 26–30 and 66–76) necessary for the binding of a protein of approx. 50 kDa, presumably involved in the mRNA targeting. The poor sequence homology between the MT-1 3′-UTR of various species, together with the bipartite nature of the required cis-element, indicates the involvement of a particular structure in the localization signal. The secondary structure of the MT-1 3′-UTR was investigated using enzymic and chemical probing. Current structural analysis of mutant 3′-UTRs will allow the critical structural features of the MT-1 mRNA perinuclear localization signal to be defined.
Transcriptional regulation by the Wilms' tumour suppressor protein WT1
Authors: Wagner K.J. , Roberts S.G.E. 
Published: October 2004

Wilms' tumour is a paediatric malignancy of the kidneys and is the most common solid tumour found in children. The Wilms' tumour suppressor protein WT1 is mutated in approx. 15% of Wilms' tumours, and is aberrantly expressed in many others. WT1 can manifest both tumour suppressor and oncogenic activities, but the reasons for this are not yet clear. The Wilms' tumour suppressor protein WT1 is a transcriptional activator, the function of which is under cell-context-specific control. We have previously described a small region at the N-terminus of WT1 (suppression domain) that inhibits the transcriptional activation domain by contacting a co-suppressor protein. We recently identified BASP1 as one of the components of the co-suppressor. Here, we analyse the mechanism of action of the WT1 suppression domain, and discuss its function in the context of the role of WT1 as a regulator of development.
Genes controlling the metabolic switch in hibernating mammals
Authors: Andrews M.T. 
Published: October 2004

Hibernating mammals have the ability to decrease their metabolic rate and survive up to 6 months without food in an inactive state where body temperatures approach 0°C. In hibernating 13-lined ground squirrels (Spermophilus tridecemlineatus), oxygen consumption holds at 1/30 to 1/50 of the aroused condition and heart rates are as low as 3–10 beats/min, compared with 200–300 beats/min when the animal is active. This seasonal adaptation requires a metabolic shift away from the oxidation of carbohydrates and towards the combustion of stored fatty acids as the primary source of energy. A key element in this fuel switch is the differential expression of the gene encoding pyruvate dehydrogenase kinase isoenzyme 4. Pyruvate dehydrogenase kinase isoenzyme 4 inhibits pyruvate dehydrogenase and thus minimizes carbohydrate oxidation by preventing the flow of glycolytic products into the tricarboxylic acid cycle. Hibernators also exploit the low-temperature activity of PTL (pancreatic triacylglycerol lipase) in both heart and white adipose tissue. Lipolytic activity at body temperatures associated with hibernation was examined using recombinant ground squirrel and human PTL expressed in yeast. Enzymes from both humans and ground squirrel displayed high activity at temperatures as low as 0°C and showed Q10=1.2–1.5 over the temperature range 37–7°C. These studies indicate that low-temperature lipolysis is a general property of PTL and does not require protein modifications unique to mammalian cells and/or the hibernating state.
Small GTP-binding protein-coupled receptors
Authors: Bhattacharya M. , Babwah A.V. , Ferguson S.S.G. 
Published: October 2004

Heterotrimeric GPCRs (G-protein-coupled receptors) form the largest group of integral membrane receptor proteins and mediate diverse physiological processes. In addition to signalling via heterotrimeric G-proteins, GPCRs can also signal by interacting with various small G-proteins to regulate downstream effector pathways. The small G-protein superfamily is structurally classified into at least five families: the Ras, Rho/Rac/cdc42, Rab, Sar1/Arf and Ran families. They are monomeric G-proteins with molecular masses over the range 20–30 kDa, which function as molecular switches to control many eukaryotic cell functions. Several studies have provided evidence of crosstalk between GPCRs and small G-proteins. It is well documented that GPCR signalling through heterotrimeric G-proteins can lead to the activation of Ras and Rho GTPases. In addition, RhoA, Rabs, ARFs and ARF GEFs (guanine nucleotide-exchange factors) can associate directly with GPCRs, and GPCRs may also function as GEFs for small GTPases. In this review, we summarize the recent progress made in understanding the interaction between GPCRs and small GTPases, focusing on understanding how the association of small G-proteins with GPCRs and GPCR-regulatory proteins may influence GPCR signalling and intracellular trafficking.
An enzyme mechanism language for the mathematical modeling of metabolic pathways
Authors: Yang Chin-Rang , Shapiro Bruce E. , Mjolsness Eric D. , Hatfield G. Wesley 
Published: October 2004

Abstract
Motivation: As a first step toward the elucidation of the systems biology of complex biological systems, it was our goal to mathematically model common enzyme catalytic and regulatory mechanisms that repeatedly appear in biological processes such as signal transduction and metabolic pathways.
Results: We describe kMech, a Cellerator language extension that describes a suite of enzyme mechanisms. Each enzyme mechanism is parsed by kMech into a set of fundamental association–dissociation reactions that are translated by Cellerator into ordinary differential equations that are numerically solved by Mathematica™. In addition, we present methods that use commonly available kinetic measurements to estimate rate constants required to solve these differential equations.
Availability: A Mathematica™ executable kMech.m file is available at the University of California, Irvine, Institute for Genomics and Bioinformatics website, http://www.igb.uci.edu/servers/sb.html. Cellerator, free of charge to academic, US government, and other non-profit organizations, can be obtained at the Cellerator website, (http://www-aig.jpl.nasa.gov/public/mls/cellerator/feedback.html).
Contact: Biology correspondence should be addressed to gwhatfie@uci.edu. Computation correspondence should be addressed to emj@uci.edu.
Supplementary information: http://www.igb.uci.edu/servers/sb.html.
Profile-based detection of microRNA precursors in animal genomes
Authors: Legendre Matthieu , Lambert André , Gautheret Daniel 
Published: October 2004

Abstract
Motivation: MicroRNAs (miRNA) are essential 21–22 nt regulatory RNAs produced from larger hairpin-like precursors. Local sequence alignment tools such as BLAST are able to identify new members of known miRNA families, but not all of them. We set out to estimate how many new miRNAs could be recovered using a profile-based strategy such as that implemented in the ERPIN program.
Results: We constructed alignments for 18 miRNA families and performed ERPIN searches on animal genomes. Results were compared to those of a WU-BLAST search at the same E-value cutoff. The two combined approaches produced 265 new miRNA candidates that were not found in miRNA databases. About 17% of hits were ERPIN specific. They showed better structural characteristics than BLAST-specific hits and included interesting candidates such as members of the miR-17 cluster in Tetraodon. Profile-based RNA detection will be an important complement of similarity search programs in the completion of miRNA collections.
Contact: gautheret@esil.univ-mrs.fr
Statistical analysis of domains in interacting protein pairs
Authors: Nye Tom M. W. , Berzuini Carlo , Gilks Walter R. , Babu M. Madan , Teichmann Sarah A. 
Published: October 2004

Abstract
Motivation: Several methods have recently been developed to analyse large-scale sets of physical interactions between proteins in terms of physical contacts between the constituent domains, often with a view to predicting new pairwise interactions. Our aim is to combine genomic interaction data, in which domain–domain contacts are not explicitly reported, with the domain-level structure of individual proteins, in order to learn about the structure of interacting protein pairs. Our approach is driven by the need to assess the evidence for physical contacts between domains in a statistically rigorous way.
Results: We develop a statistical approach that assigns p-values to pairs of domain superfamilies, measuring the strength of evidence within a set of protein interactions that domains from these superfamilies form contacts. A set of p-values is calculated for SCOP superfamily pairs, based on a pooled data set of interactions from yeast. These p-values can be used to predict which domains come into contact in an interacting protein pair. This predictive scheme is tested against protein complexes in the Protein Quaternary Structure (PQS) database, and is used to predict domain–domain contacts within 705 interacting protein pairs taken from our pooled data set.
Contact: thomas.nye@mrc-bsu.cam.ac.uk
LabArray: real-time imaging and analytical tool for microarrays
Authors: Ng Johnson Kian-Kok , Liu Wen-Tso 
Published: October 2004

Abstract
Summary: Microarrays have been used to perform high-throughput genetic analyses such as single-nucleotide polymorphisms detection and microbial genome analysis. Some of these analyses require real-time monitoring of the hybridization signals with respect to a varying experimental condition, such as temperature. However, current microarray imaging and analysis packages typically do not possess such real-time capabilities. Therefore, microarray image analyses are often time-consuming and labour-intensive. LabArray was developed to expedite such processes by enabling real-time monitoring of microarray signals.
Availability: LabArray is available at http://www.eng.nus.edu.sg/civil/Labarray/labarray.htm
Contact: cveliuwt@nus.edu.sg
Supplementary information: Screenshots and instructions for use are available at the above website.