bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia
Authors: Talbot S , Nelson R , Self W T 
Published: June 2008

Background and purpose:Arsenicals have been used medicinally for decades to treat both infectious disease and cancer. Arsenic trioxide (As2O3) is effective for treatment of acute promyelocytic leukaemia (APL), yet the mechanism of action of this drug is still widely debated. Recently, As2O3 was shown to inhibit the activity of the selenoenzyme thioredoxin reductase (TrxR). TrxR has been proposed to be required for selenium metabolism. The effect of inhibitors of TrxR on selenium metabolism has yet to be assessed. This study aims to determine whether chemotherapeutics that target selenocysteine within selenoenzymes may also affect the metabolism of selenium.Experimental approach:A lung cell line, A549, was used to assess the effect of TrxR inhibitors on selenium metabolism, using 75Se‐selenite. The level of mRNA encoding cytosolic TrxR (TrxR1) was determined using real‐time reverse transcriptase‐PCR. TrxR activity was determined in whole‐cell extracts.Key results:Exposure of cells to As2O3, arsenite or auranofin led to a concentration‐dependent reduction of selenium metabolism into selenoproteins. Knockdown of TrxR1, using small inhibitory RNA, did not affect selenium metabolism. Exposure of cells to monomethylarsonic acid, a potent inhibitor of TrxR, did not alter selenium metabolism but did inhibit enzyme activity.Conclusions and implications:As2O3 and auranofin block the metabolism of selenium in A549 cells. Because As2O3 is used to treat APL, our findings may reveal the mechanism of this therapeutic action and lead to further research targeting selenium metabolism to find novel chemotherapeutic agents for the treatment of APL.British Journal of Pharmacology (2008) 154, 940–948; doi:10.1038/bjp.2008.161; published online 21 April 2008
Sites of action of hydrogen peroxide on ion transport across rat distal colon
Authors: Schultheiss G , Hennig B , Diener M 
Published: June 2008

Background and purpose:The aim of this study was the identification of the mechanism of oxidant‐induced intestinal secretion.Experimental approach:The action of H2O2 on ion transport across rat distal colon was evaluated in Ussing chambers. Changes in cytosolic Ca2+ concentration were measured using fura‐2.Key results:H2O2 concentration‐dependently induced an increase in short‐circuit current (Isc), which was due to a stimulation of Cl− secretion. The effect of H2O2 was dependent on the presence of serosal Ca2+. It was inhibited after emptying of intracellular Ca2+ stores by cyclopiazonic acid or blockade of ryanodine receptors by ruthenium red, whereas a blocker of inositol 1,4,5‐trisphosphate receptors was less effective. Fura 2‐experiments confirmed an increase in the cytosolic Ca2+ concentration in the presence of H2O2. Measurements of Cl− currents across the apical membrane at basolaterally depolarized epithelia revealed the activation of a glibenclamide‐sensitive, SITS‐resistant Cl− conductance by the oxidant. The activation of this conductance was inhibited after blockade of protein kinases with staurosporine. When the apical membrane was permeabilized with nystatin, two sites of action of H2O2 were identified at the basolateral membrane. The oxidant stimulated a basolateral tetrapentylammonium‐sensitive K+ conductance and increased the current generated by the Na+–K+ pump. Pretreatment of the tissues with H2O2 reduced the action of subsequently administered Ca2+‐, cAMP‐ and cGMP‐dependent secretagogues demonstrating a long‐term downregulation after the initial secretory response evoked by the oxidant.Conclusions and implications:H2O2 affects colonic anion secretion by action sites at both the apical, as well as the basolateral membrane.British Journal of Pharmacology (2008) 154, 991–1000; doi:10.1038/bjp.2008.162; published online 21 April 2008
Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues
Authors: Behm D J , McAtee J J , Dodson J W , Neeb M J , Fries H E , Evans C A , Hernandez R R , Hoffman K D , Harrison S M , Lai J M , Wu C , Aiyar N V , Ohlstein E H , Douglas S A 
Published: June 2008

Background and purpose:The recent development of the UT ligand palosuran (1‐[2‐(4‐benzyl‐4‐hydroxy‐piperidin‐1‐yl)‐ethyl]‐3‐(2‐methyl‐ quinolin‐4‐yl)‐urea sulphate salt) has led to the proposition that urotensin‐II (U‐II) plays a significant pathological role in acute and chronic renal injury in the rat.Experimental approach:In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays.Key results:Palosuran functioned as a ‘primate‐selective’ UT ligand in recombinant cell membranes (monkey and human UT Ki values of 4±1 and 5±1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline Ki values >1 μM). Paradoxically, however, palosuran lost significant (10‐ to 54‐fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (Ki values of 50±3 and 276±67 nM). In accordance, palosuran also exhibited diminished activity in hUT (human urotensin‐II receptor)‐CHO (Chinese hamster ovary) cells (IC50 323±67 nM) and isolated arteries (Kb>10 μM in rat aorta; Kb>8.5 μM in cat arteries; Kb>1.6 μM in monkey arteries; Kb 2.2±0.6 μM in hUT transgenic mouse aorta). Relative to recombinant binding Ki values, palosuran was subjected to a 392‐ to 690‐fold reduction in functional activity in monkey isolated arteries. Such phenomena were peculiar to palosuran and were not apparent with an alternative chemotype, SB‐657510 (2‐bromo‐N‐[4‐chloro‐3‐((R)‐1‐methyl‐ pyrrolidin‐3‐yloxy)‐phenyl]‐4,5‐dimethoxybenzenesulphonamide HCl).Conclusions and implications:Collectively, such findings suggest that caution should be taken when interpreting data generated using palosuran. The loss of UT affinity/activity observed in intact cells and tissues cf. membranes offers a potential explanation for the disappointing clinical efficacy reported with palosuran in diabetic nephropathy patients. As such, the (patho)physiological significance of U‐II in diabetic renal dysfunction remains uncertain.British Journal of Pharmacology (2008) 155, 374–386; doi:10.1038/bjp.2008.266; published online 30 June 2008
Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea‐pig model
Authors: Yao X , Anderson D L , Ross S A , Lang D G , Desai B Z , Cooper D C , Wheelan P , McIntyre M S , Bergquist M L , MacKenzie K I , Becherer J D , Hashim M A 
Published: June 2008

Background and purpose:Drug‐induced prolongation of the QT interval can lead to torsade de pointes, a life‐threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans.Experimental approach:Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a‐go‐go‐related gene) patch‐clamp assay and an anaesthetized guinea‐pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea‐pigs were determined using liquid chromatography‐mass spectrometry.Key results:Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea‐pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model.Conclusions and implications:Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea‐pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.British Journal of Pharmacology(2008)154, 1446–1456; doi:10.1038/bjp.2008.267; published online 30 June 2008
Somatostatin inhibits colon cancer cell growth through cyclooxygenase‐2 downregulation
Authors: Colucci R , Blandizzi C , Ghisu N , Florio T , Del Tacca M 
Published: June 2008

Background and purpose:Cyclooxygenase‐2 (COX‐2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E2 (PGE2) production. This study investigated the effects of somatostatin‐14 on COX‐2 expression, PGE2 production and proliferation in colon cancer cells.Experimental approach:Human colon adenocarcinoma cell lines Caco‐2, HT‐29 and HCT116 were used. The following techniques were employed: colourimetric assay for cell growth; 5‐bromo‐2′‐deoxyuridine assay for DNA synthesis; enzyme immunoassay for PGE2; COX‐2 mRNA silencing; RT–PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated‐ERK‐1/ERK‐2 and phosphorylated‐Akt.Key results:HT‐29 and Caco‐2 cells expressed COX‐2 and somatostatin receptors (sst3/4/5 and sst3/5, respectively). HCT116 cells did express somatostatin receptors (sst2/3/5), but not COX‐2. Somatostatin‐14 inhibited basal COX‐2 expression, PGE2 production, DNA synthesis and growth in Caco‐2 cells and these effects were prevented by BN81658 (sst3 receptor antagonist). Basal proliferation of HT‐29, HCT116 and COX‐2‐silenced Caco‐2 cells was not affected by somatostatin‐14. Stimulation of HT‐29 cells with gastrin‐17 elicited increments of ERK‐1/ERK‐2 and Akt phosphorylation, COX‐2 expression, PGE2 production, DNA synthesis and cell growth, which were all counteracted by somatostatin‐14. Somatostatin‐14‐induced inhibition of COX‐2 expression, PGE2 production and DNA synthesis were blocked by BIM23056 (sst5 receptor antagonist).Conclusions and implications:Somatostatin decreases COX‐2 expression and function in colon cancer cells via activation of sst3 or sst5 receptors, and these effects contribute to the inhibitory action of somatostatin on cell proliferation. These findings can be relevant to the development of therapeutic strategies based on the modulation of the COX‐2 pathway.British Journal of Pharmacology (2008) 155, 198–209; doi:10.1038/bjp.2008.268; published online 30 June 2008
Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase
Authors: Oppermann M , Dao V T‐V , Suvorava T , Bas M , Kojda G 
Published: June 2008

Background and purpose:The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment.Experimental approach:We investigated whether high dose isosorbide mononitrate (ISMN) or pentaerythrityl tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg−1 d−1 for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg−1 d−1 for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite.Key results:Western blots of rabbit aortic rings showed similar protein levels of sGC α1‐ (P=0.2790) and β1‐subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN‐treated mice (P=0.0961 for α1 and P=0.3709 for β1). The activities of isolated sGC in response to SNAP (1 μM–1 mM) were identical in aortae of ISMN‐treated rabbits (P=0.0775) and lungs of PETN‐treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN.Conclusions and implications:These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo.British Journal of Pharmacology (2008) 155, 335–342; doi:10.1038/bjp.2008.269; published online 30 June 2008
Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice
Authors: Zarbock A , Allegretti M , Ley K 
Published: June 2008

Background and purpose:Acute lung injury (ALI) remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of ALI. The main chemokine receptor on neutrophils is CXCR2, which regulates neutrophil recruitment and vascular permeability, but no small molecule CXCR2 inhibitor has been demonstrated to be effective in ALI or animal models of ALI. To investigate the functional relevance of the CXCR2 inhibitor Reparixin in vivo, we determined its effects in two models of ALI, induced by either lipopolysaccharide (LPS) inhalation or acid instillation.Experimental approach:In two ALI models in mice, we measured vascular permeability by Evans blue and evaluated neutrophil recruitment into the lung vasculature, interstitium and airspace by flow cytometry.Key results:Pharmacological inhibition of CXCR2 by Reparixin reduced CXCL1‐induced leukocyte arrest in the microcirculation of the cremaster muscle, but did not influence arrest in response to leukotriene B4 (LTB4) demonstrating specificity. Reparixin (15 μg g−1) reduced neutrophil recruitment in the lung by approximately 50% in a model of LPS‐induced ALI. A higher dose did not provide additional reduction of neutrophil recruitment. This dose also reduced accumulation of neutrophils in the interstitial compartment and vascular permeability in LPS‐induced ALI. Furthermore, both prophylactic and therapeutic application of Reparixin improved gas exchange, and reduced neutrophil recruitment and vascular permeability in a clinically relevant model of acid‐induced ALI.Conclusions and implications:Reparixin, a non‐competitive allosteric CXCR2 inhibitor attenuates ALI by reducing neutrophil recruitment and vascular permeability.British Journal of Pharmacology (2008) 155, 357–364; doi:10.1038/bjp.2008.270; published online 30 June 2008
Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt‐dependent mechanisms
Authors: Xia L , Wang X X , Hu X S , Guo X G , Shang Y P , Chen H J , Zeng C L , Zhang F R , Chen J Z 
Published: June 2008

Background and purpose:Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity.Experimental approach:After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic β‐galactosidase staining. The bromo‐deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting.Key results:Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre‐treatment with the PI3K inhibitor, LY294002, significantly attenuated resveratrol‐induced telomerase activity.Conclusions and implications:Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K‐Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.British Journal of Pharmacology (2008) 155, 387–394; doi:10.1038/bjp.2008.272; published online 30 June 2008
Dorsal Nucleus Raphé
Authors:   Allen Institute for Brain Science, Royall Josh , Ng Lydia , Morris John 
Published: July 2008

AbstractThis report contains a gene expression summary of the dorsal nucleus raphé (DR), derived from the Allen Brain Atlas (ABA) in-situ hybridization (ISH) mouse data set. The structure’s location and morphological characteristics in the mouse brain are described using the Nissl data found in the Allen Reference Atlas. Using an established algorithm, the expression values of the DR were compared to the values of the macro/parent-structure, in this case the midbrain, for the purpose of extracting regionally specific gene expression data. The highest ranking ratios were then manually curated and verified. The 50 Select Genes were compiled for expression characterization. The experimental data for each gene may be accessed via the links provided; complementary sagittal data may also be accessed using the ABA. Correlation between gene expression in the DR and the rest of the brain, across all genes in the coronal dataset (~4300 genes), were derived computationally and are presented below. A gene ontology table (derived from DAVID Bioinformatics Resources 2007) is also included, highlighting possible functions of these 50 Select Genes.
Effect of a Program to Reduce Hospital Ciprofloxacin Use on Nosocomial Pseudomonas aeruginosa Susceptibility to Quinolones and Other Antimicrobial Agents
Authors: Cook Paul P. , Das Titu D. , Gooch Michael , Catrou Paul G. 
Published: June 2008

Objective.We evaluated the effect of an antimicrobial management effort to decrease ciprofloxacin use on the antibiotic susceptibility of nosocomial Pseudomonas aeruginosa isolates.Design.Retrospective, observational study.Setting.Tertiary care teaching hospital with 731 beds.Methods.The study was conducted between January 1, 2001, and December 31, 2007. Linear regression analyses and Student t tests were used to determine significant changes in drug use among patients and antimicrobial susceptibility patterns among nosocomial P. aeruginosa isolates during the 84-month period.Results.Following implementation of a program to reduce oral and intravenous use of ciprofloxacin in 2005, there was a 56.6% reduction in ciprofloxacin use (P < .001). Significant reductions in the mean percentage of nosocomial P. aeruginosa isolates that were resistant to ciprofloxacin (from 45.0% to 35.2%; P < .002) and the mean incidence of ciprofloxacin resistance (from 0.77 to 0.67 isolates recovered per 1,000 patient-days; P = .03) were noted after implementation of this program. The total quantity of antipseudomonal antibiotics consumed decreased, but the use of certain antipseudomonal antibiotics (ie, cefepime and imipenem/meropenem) increased. Among nosocomial P. aeruginosa isolates, the prevalence of imipenem/meropenem resistance increased, whereas the prevalence of cefepime resistance did not. During the 84 months of the study, there was a significant association between ciprofloxacin use and the percentage of nosocomial P. aeruginosa isolates that were resistant to ciprofloxacin (p = 0.47; P = .011), but there was no correlation between ciprofloxacin use and the incidence of ciprofloxacin resistance (p = 0.21; P = .26).Conclusions.Major reductions in ciprofloxacin use were associated with small but significant improvements in the rate of ciprofloxacin susceptibility among nosocomial P. aeruginosa isolates. The impact of the program on other antipseudomonal agents was variable.
An evaluation of conscious sedation using propofol and remifentanil for tension‐free vaginal tape insertion
Authors: Winton A. L. , Eastwood J. , Powell M. C. , Norris A. M. 
Published: July 2008

SummaryTension‐free vaginal tape insertion is a recommended treatment for stress incontinence. There is evidence that intra‐operative testing of continence by asking patients to cough may improve outcomes, but an optimal sedation regimen has not been determined. We prospectively evaluated the effectiveness of propofol and remifentanil infusions in 25 patients using pre‐ and post‐sedation peak cough pressures and pain scores. Patient satisfaction was assessed using the Iowa Satisfaction with Anaesthesia Score (ISAS). Post‐sedation cough pressures were improved compared to baseline, with a mean peak pressure increase of 24 mmHg (95% CI 15.5–32.5; p < 0.001). Pain scores (median, IQR [range]) were low for local anaesthetic infiltration (0, [0–1]) and first (0, [0–1]) and second (0, [0–3.5]) needle insertions. Of the 19 patients completing the ISAS, all felt safe and satisfied. Sedation using propofol and remifentanil provides acceptable analgesia, satisfaction and effective continence testing.
Effects of soil disturbance, seed rate, nitrogen fertilizer and subsequent cutting treatment on establishment of Bromus inermis seedlings on degraded steppe grassland in China
Authors: Liu G. X. , Mao P. S. , Huang S. Q. , Sun Y. C. , Han J. G. 
Published: July 2008

AbstractEstablishment of seedlings of Bromus inermis, a native grass species of China, into a degraded steppe grassland was studied in an experiment with a factorial combination of different soil disturbance (control and harrowing), cutting post‐sowing (control and cutting), nitrogen (N) fertilizer application (0 and 100 kg KNO3 hm−2) and seed rate (400, 800 and 1200 seeds m−2) treatments. Seedling emergence and survival rates, and plant performance, were followed over 2 years. Seedling emergence was increased by soil disturbance (harrowing). Cutting post‐sowing and N fertilizer application did not increase seedling emergence. Seedling survival rates at the end of first growing season were strongly influenced by harrowing and the use of higher seed rates. Seedling height was higher in the harrowing and the N fertilizer application treatments and at the higher seed rates. Seedling survival rates in the second growing season were low but much higher with harrowing than the other treatments. Soil disturbance by harrowing may have increased contact between seed and soil, and reduced competition from established plants. It is concluded that, for the restoration of degraded semi‐arid grassland in China by re‐seeding, soil surface disturbance is necessary for successful seedling establishment, and modest seeding rates should be used to control costs.