bluuebunny/crossref_metadata_2025_split huggingface dataset:
Achieving signalling selectivity of ligands for the corticotropin‐releasing factor type 1 receptor by modifying the agonist's signalling domain
Authors: Beyermann M , Heinrich N , Fechner K , Furkert J , Zhang W , Kraetke O , Bienert M , Berger H 
Published: May 2007

Background and purpose:Most of the pharmaceuticals target G‐protein‐coupled receptors (GPCRs) which can generally activate different signalling events. The aim of this study was to achieve functional selectivity of corticotropin‐releasing factor receptor type 1 (CRF1) ligands.Experimental approach:We systematically substituted urocortin, a natural peptide agonist of CRF1, with bulky amino acids (benzoyl‐phenylalanine, naphthylalanine) and determined the effect of the analogues on coupling of CRF1 to Gs‐ and Gi‐protein in human embryonic kidney cells, using receptor binding, [35S]‐GTPγS binding stimulation, and cAMP accumulation assays.Key results:Native ligands stimulated Gs and Gi activation through CRF1, resulting in stimulation and then inhibition of cAMP accumulation. Single replacements in urocortin at positions 6–15 led, dependent on the position and nature of the substituent, to ligands that conserved Gs activity, but were devoid of Gi activity, only stimulating cAMP accumulation, and competitively antagonized the Gi activation by sauvagine. In contrast, analogues with substitutions outside this sequence non‐selectively activated Gs and Gi, as urocortin did.Conclusions and implications:Modifications in a specific region, which we have called the signalling domain, in the polypeptide agonist urocortin resulted in analogues that behaved as agonists and, at the same time, antagonists for the activation of different G‐proteins by CRF1. This finding implies significant differences between active conformations of the receptor when coupled to different G‐proteins. A similar structural encoding of signalling information in other polypeptide hormone receptor ligands would result in a general concept for the development of signalling‐selective drug candidates.British Journal of Pharmacology (2007) 151, 851–859; doi:10.1038/sj.bjp.0707293
Dexrazoxane prevents doxorubicin‐induced long‐term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats
Authors: Lebrecht D , Geist A , Ketelsen U‐P , Haberstroh J , Setzer B , Walker U A 
Published: May 2007

Background and purpose:Doxorubicin causes a chronic cardiomyopathy in which reactive oxygen species (ROS) accumulate over time and are associated with genetic and functional lesions of mitochondria. Dexrazoxane is a cardioprotective iron chelator that interferes with ROS production. We aim to analyze the effects of dexrazoxane on mitochondria in the prevention of doxorubicin‐induced chronic myocardial lesions.Experimental approach:Wistar rats (11 weeks of age) were injected with intravenous doxorubicin (0.8 mg kg‐1 weekly for 7 weeks) with or without simultaneous dexrazoxane (8 mg kg‐1). Animals were killed at 48 weeks. Cardiomyopathy was scored clinically and histologically and cardiac mitochondria were analyzed.Key results:Compared to control rats receiving saline, rats treated with doxorubicin alone developed a clinical, macroscopic, histological and ultrastructural cardiomyopathy with low cytochrome c‐oxidase (COX) activity (26% of controls). The expression of the mtDNA‐encoded COX II subunit was reduced (64% of controls). Myocardia exhibited a high production of ROS (malondialdehyde 338% and superoxide 787% of controls). Mitochondria were depleted of mitochondrial DNA (mtDNA copy number 46% of controls) and contained elevated levels of mtDNA deletions. Dexrazoxane co‐administration prevented all these effects of doxorubicin on mitochondria, except that hearts co‐exposed to doxorubicin and dexrazoxane had a slightly lower mtDNA content (81% of controls) and mtDNA deletions at low frequency.Conclusions and Implications:Dexrazoxane prevented doxorubicin induced late‐onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage.British Journal of Pharmacology (2007) 151, 771–778; doi:10.1038/sj.bjp.0707294
Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system
Authors: Mead E J , Maguire J J , Kuc R E , Davenport A P 
Published: May 2007

Orphan G‐protein‐coupled receptors that have recently been paired with their cognate ligand are an often untapped resource for novel drug development. The KISS1 receptor (previously designated GPR54) has been paired with biologically active cleavage peptides of the KiSS‐1 gene product, the kisspeptins (KP). The focus of this review is the emerging pharmacology and physiology of the KP. Genetic linkage analysis in humans revealed that mutations in KISS1 (GPR54, AXOR12 or hOT7T175) result in idiopathic hypogonadotrophic hypogonadism and knockout mouse studies confirmed this finding. Identification of KISS1 (GPR54) as a molecular switch for puberty subsequently led to the discovery that KP activate the GnRH cascade. Prior to the role of KISS1 (GPR54) in puberty being described, KP had been shown to be inhibitors of tumour metastasis across a range of cancers. Subsequently the mechanism of this inhibition has been suggested to be via altered cell motility and adhesiveness. PCR detected highest expression of KP and KISS1 (GPR54) in placenta, and changes in KP levels throughout pregnancy and expression in trophoblasts suggests a role in placentation. Placentation and metastasis are invasive processes that require angiogenesis. Investigation of KISS1 (GPR54) and KP in vasculature revealed discrete localisation of KISS1 (GPR54) to blood vessels prone to atherosclerosis and a potent vasoconstrictor action. A role for KP has also been shown in whole body homeostasis. KP are multifunctional peptides and further investigation is required to fully elucidate the complex pathways regulated by these peptides and how these pathways integrate in the whole body system.British Journal of Pharmacology (2007) 151, 1143–1153; doi:10.1038/sj.bjp.0707295
Size‐fractionated heparins have differential effects on human neutrophil function in vitro
Authors: Lever R , Lo W T , Faraidoun M , Amin V , Brown R A , Gallagher J , Page C P 
Published: May 2007

Background and purpose:Heparin is known to possess a range of activities, other than effects on blood coagulation, many of which are anti‐inflammatory. Effects with potential anti‐inflammatory applications include the inhibition of elastase release from neutrophils, as well as the adhesion of these cells to vascular endothelium. In the present study we aimed to investigate whether fractionation of heparin may yield molecules with enhanced or specific effects on human neutrophil function.Experimental approach:Fractions of defined molecular size were obtained from heparin by different methods and assessed for their effects on elastase release induced by formyl Met‐Leu‐Phe (fMLP), from neutrophils, in some cases following the priming of these cells with tumour necrosis factor‐α (TNF‐α). Effects of the fractions on neutrophil adhesion to interleukin‐1β (IL‐β)‐stimulated human umbilical vein endothelial cells (HUVECs) were also examined.Key results:Elastase release was inhibited by very low molecular weight fractions of heparin, with an apparent minimum chain length of 10 saccharides required for full effect. In contrast, neutrophil‐endothelial adhesion was unaffected by these fractionated heparins, suggesting that certain non‐anticoagulant actions of heparin may be lost by such an approach.Conclusions and implications:These data suggest that an optimum chain length of heparin possibly exists for certain non‐anticoagulant actions of heparin, which may prove to be useful in the design of novel drugs with specific anti‐inflammatory actions.British Journal of Pharmacology (2007) 151, 837–843; doi:10.1038/sj.bjp.0707298
Chemogenomic approaches to rational drug design
Authors: Rognan D 
Published: May 2007

Paradigms in drug design and discovery are changing at a significant pace. Concomitant to the sequencing of over 180 several genomes, the high‐throughput miniaturization of chemical synthesis and biological evaluation of a multiple compounds on gene/protein expression and function opens the way to global drug‐discovery approaches, no more focused on a single target but on an entire family of related proteins or on a full metabolic pathway. Chemogenomics is this emerging research field aimed at systematically studying the biological effect of a wide array of small molecular‐weight ligands on a wide array of macromolecular targets. Since the quantity of existing data (compounds, targets and assays) and of produced information (gene/protein expression levels and binding constants) are too large for manual manipulation, information technologies play a crucial role in planning, analysing and predicting chemogenomic data. The present review will focus on predictive in silico chemogenomic approaches to foster rational drug design and derive information from the simultaneous biological evaluation of multiple compounds on multiple targets. State‐of‐the‐art methods for navigating in either ligand or target space will be presented and concrete drug design applications will be mentioned.British Journal of Pharmacology (2007) 152, 38–52; doi:10.1038/sj.bjp.0707307
Influence of dietary fats on ecstasy‐induced hyperthermia
Authors: Mills E M , Weaver K L , Abramson E , Pfeiffer M , Sprague J E 
Published: May 2007

Background and purpose:Studies were designed to examine the effects of dietary fats on metabolic effects of 3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy). These effects included hyperthermia, expression of uncoupling protein (UCP1 and 3) in brown adipose tissue or skeletal muscle and plasma free fatty acid (FFA) levels.Experimental approach:Male Sprague‐Dawley rats were fed either a high‐fat diet (HFD, 60% kcal) or a lower fat isocaloric controlled diet (LFD, 10% kcal) for 28 days before MDMA challenge.Key results:No significant differences were observed between LFD and HFD groups in terms of body weight, plasma thyroxine (T4) levels and expression of brown fat UCP1 or skeletal muscle UCP3 protein. HFD significantly raised levels of circulating FFA and potentiated the thermogenesis induced by MDMA (10 mg kg−1, s.c.), compared to the effects of the LFD. Moreover, 30 and 60 min after MDMA administration, plasma FFA levels decreased in HFD animals, but were markedly elevated in the LFD group.Conclusions and implications:These results indicate that high‐fat feeding regulates MDMA‐induced thermogenesis by augmenting the activation of UCP rather than its expression.British Journal of Pharmacology (2007) 151, 1103–1108; doi:10.1038/sj.bjp.0707312
Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity‐prone HLA‐DRB1*0301 transgenic mice
Authors: Flynn Jeffrey C. , Gilbert Jacqueline A. , Meroueh Chady , Snower Daniel P. , David Chella S. , Kong Yi‐chi M. , Paul Banga J. 
Published: May 2007

SummaryWe have examined the induction of autoimmunity and the maintenance of sustained hyperthyroidism in autoimmunity‐prone human leucocyte antigen (HLA) DR3 transgenic non‐obese diabetic (NOD) mice following chronic stimulation of the thyrotropin receptor (TSHR) by monoclonal thyroid‐stimulating autoantibodies (TSAbs). Animals received weekly injections over the course of 9 weeks of monoclonal antibodies (mAbs) with strong thyroid‐stimulating properties. Administration of the mAbs KSAb1 (IgG2b) or KSAb2 (IgG2a), which have similar stimulating properties but different TSH‐binding blocking activity, resulted in significantly elevated serum thyroxine (T4) levels and thyroid hyperplasia. After the first injection, an initial surge then fall in serum T4 levels was followed by sustained elevated levels with subsequent injections for at least 63 days. Examination of KSAb1 and KSAb2 serum bioactivity showed that the accumulation of the TSAbs in serum was related to their subclass half‐lives. The thyroid glands were enlarged and histological examination showed hyperplastic follicles, with minimal accompanying thyroid inflammation. Our results show that chronic in vivo administration of mAbs with strong thyroid‐stimulating activity resulted in elevated T4 levels, suggesting persistent stimulation without receptor desensitization, giving a potential explanation for the sustained hyperthyroid status in patients with Graves' disease. Moreover, despite the presence of HLA disease susceptibility alleles and the autoimmune prone NOD background genes, chronic stimulation of the thyroid gland did not lead to immune cell‐mediated follicular destruction, suggesting the persistence of immunoregulatory influences to suppress autoimmunity.
Periodontitis is characterized by elevated PAI‐1 activity
Authors: Bizzarro S. , Van Der Velden U. , Ten Heggeler J. M. A. G. , Leivadaros E. , Hoek F. J. , Gerdes V. E. A. , Bakker S. J. L. , Gans R. O. B. , Ten Cate H. , Loos B. G. 
Published: May 2007

AbstractObjectives: Periodontitis is a chronic infectious disease and has been associated with cardiovascular diseases (CVD). We investigated whether plasma levels of markers of a prothrombotic state were elevated in patients with periodontitis in comparison with healthy controls.Materials and methods: Untreated patients with moderate (n=53) and severe periodontitis (n=38) and healthy controls (n=39) were recruited. Levels of von Willebrand factor (vWF), prothrombin fragment 1+2 (F1+2), plasminogen activator inhibitor‐1 (PAI‐1) activity and D‐dimer were measured as markers of a prothrombotic state.Results: The erythrocyte sedimentation rate (ESR), plasma C‐reactive protein (CRP) and leucocyte counts (WBC) were significantly higher in patients with periodontitis. No statistically significant difference was found among the three groups for vWF (p=0.264), F1+2 (p=0.295) and D‐dimer (p=0.572). However, PAI‐1 was clearly elevated in the severe periodontitis group (p=0.001), even after adjusting for potential confounding factors (padj=0.004). Moreover, more patients than controls were having vWF and PAI‐1 levels above the respective population medians.Conclusions: In periodontitis, elevated levels of PAI‐1 activity are observed compared with healthy controls. This may increase the potential for impaired fibrinolysis, a condition that results in a prothrombotic state. We suggest that this state, if left untreated, may contribute to an increased risk for CVD.
Effect of an essential oil‐containing antimicrobial mouthrinse on specific plaque bacteria in vivo
Authors: Fine Daniel H. , Markowitz Kenneth , Furgang David , Goldsmith Deborah , Charles Christine H. , Lisante Toni Anne , Lynch Michael C. 
Published: May 2007

AbstractAim: This study was conducted to investigate the effect of rinsing with an essential oil‐containing mouthrinse on levels of specific supra and subgingival bacteria in subjects with gingivitis.Material and Methods: Fifteen subjects meeting entry criteria completed this randomized, controlled, double‐blind, crossover study. Subjects were required to have 1000 target organisms per millilitre in pooled samples from two subgingival sites. Following sampling of supra and subgingival plaque, subjects began twice‐daily rinsing for 14 days with either an essential oil‐containing mouthrinse (Cool Mint Listerine® Antiseptic) or a negative control. Supra and subgingival plaque was again sampled on day 15, and the procedure repeated after a 1‐week washout period with subjects using the alternate rinse.Results: Compared with the negative control, the essential oil mouthrinse produced significant reductions in supragingival plaque levels of Veillonella sp., Capnocytophaga sp., Fusobacterium nucleatum, and total anaerobes ranging from 52.3 to 88.5% (p<0.001 except for Veillonella, p=0.002); respective reductions in subgingival plaque ranged from 54.1 to 69.1% (p<0.001).Conclusions: Rinsing with the essential oil mouthrinse can have an impact on the subgingival plaque flora. This study provides additional evidence indicating that reduction in supragingival plaque can reduce levels of subgingival plaque.
Subjective intensity of pain during ultrasonic supragingival calculus removal
Authors: Braun Andreas , Jepsen Søren , Krause Felix 
Published: May 2007

AbstractObjective: To assess subjective intensities of pain during supragingival calculus removal employing ultrasonic scaler tips of two different shapes.Material and Methods: Twenty patients were treated using a piezoelectric ultrasonic device (Sirosonic L) and two different scaler tips representing a conventional (Instrument No. 3) and a slim‐line style (Perio Pro Line Instrument SI‐11) in a split‐mouth design. Pain was recorded during calculus removal at intervals of 0.5 s employing an inter‐modal intensity comparison. Additionally, a visual analogue scale was used for evaluation directly after the treatment procedure. Treatment time was recorded to assess the efficiency of calculus removal.Results: Pain assessment during treatment showed that the slim‐line scaler tip (median pain score: 1.4 [U], maximum: 3.5 [U], minimum: 0 [U]) caused less pain than the conventional device (median pain score: 7.8 [U], maximum: 14.7 [U], minimum: 0 [U]) (p<0.05). These results could be confirmed by the visual analogue scale. Treatment with the slim‐line tip took significantly longer than treatment with the conventional tip (p<0.05).Conclusions: Using slim‐line‐styled ultrasonic scaler tips for supragingival calculus removal, painful sensations can be reduced compared with conventional ultrasonic devices. Thus, it might be possible to increase the patient's compliance during dental treatment with oscillating instruments.
Preterm delivery but not intrauterine growth retardation is associated with young maternal age among primiparae in rural Nepal
Authors: Stewart Christine P. , Katz Joanne , Khatry Subarna K. , LeClerq Steven C. , Shrestha Sharada Ram , West Keith P. , Christian Parul 
Published: May 2007

AbstractPregnancy during adolescence is associated with adverse birth outcomes, including preterm delivery and low birthweight. The nutrient availability to the fetus may be limited if the mother is still growing. This research aims to study the effects of pregnancy during adolescence in a nutritionally poor environment in rural Nepal. This study utilized data from a randomized controlled trial of micronutrient supplementation during pregnancy in south‐eastern Nepal. Women of parity 0 or 1 and of age ≤ 25 years who gave birth to a singleton liveborn infant who was measured within 72 h of delivery were included (n = 1393). There was no difference in the risk of low birthweight (OR = 0.96; 95% CI = 0.90–1.02) or small for gestational age (OR = 1.01; 95% CI = 0.94–1.08) per year of increasing maternal age among primiparae. Young maternal age did not affect the anthropometry or gestational age of the offspring of parity 1 women. Each year of increasing maternal age among primiparae was associated with increases in birth length (0.07 cm; 95% CI = −0.01 to 0.16), head (0.05 cm; 95% CI = 0.01–0.09) and chest circumference (0.07 cm; 95% CI = 0.01–0.12), but not weight (9.0 g; 95% CI = −2.1 to 21.8) of their offspring. Young maternal age was associated with an increased risk of preterm delivery among primiparae (OR = 2.07; 95% CI = 1.26–3.38) that occurred at an age cut‐off of ≤18 years relative to those 19–25 years. Thus, we conclude that young maternal age (≤18 years) increased the risk of preterm delivery, but not intrauterine growth retardation, for the first but not second liveborn infant.
THIS ARTICLE HAS BEEN RETRACTED  Exergy as an ecological application used in the recovery process of benthic communities
Authors: ZHANG Feijun , TONG Chunfu , XIE Zhifa , LU Jianjian 
Published: May 2007

AbstractExergy, the thermodynamic function that represents the distance of an open system from equilibrium, is proposed as an ecological indicator for summarizing the complex dynamics occurring in a disturbed community during its recovery processes. These complex dynamics can be difficult to capture by using classical indices. In this study, we sampled macrobenthos using the BACI scheme (before versus after; control versus impact) in tidal wetlands of west Chongming Island, China, an area that has been disturbed by ecological engineering measures. Exergy storage is estimated for benthic communities. The control area is proposed as dynamic reference for estimating local exergy storage of the benthic community. Three different methods were used for estimating exergy on the basis of coefficients: (a) taken for taxa groups; (b) estimated from coding genes given for broad taxonomic groups; and (c) estimated from genome size taken as close as possible to the taxonomic level of the species, providing a basis for inferring similarities. We found a decrease of local exergy content in the disturbed area 9 days after the disturbance. Subsequently, the reference exergy of the benthic community increased (i.e. in the surrounding control area) in accordance with the proposed hypothesis regarding the dynamics of exergy storage during a system's development. Estimates of local exergy arrived at using the three methods provided comparable results. Based on this, we then discuss the feasibility of using the more readily available genome size data for estimating exergy. This result may have important implications for broader application of this indicator to biological systems. Moreover, the adjacent control samples seem to represent an appropriate dynamic reference for estimating the local exergy of disturbed communities. We found that exergy was a useful indicator that integrates the processes underlying the recovery of the benthic community after disturbance.
Conservation status of Chinese species: (1) Overview
Authors: XIE Yan , SUNG Wang 
Published: May 2007

AbstractThe first comprehensive evaluation of more than 10 000 species in China based on the IUCN Red List Criteria and Regional Guidelines is complete. More than 100 experts have been involved in this evaluation, which covers a wide range of species, including invertebrates, vertebrates, gymnosperms and angiosperms. The present paper summarizes the major conclusions of the project. The number of threatened species in China was found to be much high than previously expected. In the past, the estimated percentages of species in each phylum that were endangered was 2‐30%. In this comprehensive evaluation, the percentages of threatened species were found to be 7.4‐100%. Compared with the status of threatened species worldwide (IUCN Red List 2006), groups such as fish, mammals and gymnosperms face much higher levels of threat in China then they do globally, and other groups, such as crustaceans, reptiles and birds, face lower levels of threat. Given the dire conclusions of this study, we recommend that more research be done on the threats faced by those groups of organisms that are most threatened.