bluuebunny/crossref_metadata_2025_split huggingface dataset:
The hydrogen sulfide donor, GYY4137, exhibits anti‐atherosclerotic activity in high fat fed apolipoprotein E−/− mice
Authors: Liu Zhen , Han Yi , Li Ling , Lu Hui , Meng Guoliang , Li Xiaozhen , Shirhan Mohammed , Peh Meng Teng , Xie Liping , Zhou Suming , Wang Xiaowei , Chen Qi , Dai Weilu , Tan Choon‐Hong , Pan Shiyang , Moore Philip K , Ji Yong 
Published: May 2013

Background and PurposeAtherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow‐releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.Experimental ApproachRAW 264.7 cells and human blood monocyte‐derived macrophages were incubated with oxidized low density lipoprotein (ox‐LDL) with/without GYY4137. ApoE−/− mice were fed a high‐fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium‐dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real‐time PCR and Western blot.Key ResultsGYY4137 inhibited ox‐LDL‐induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin‐like ox‐LDL receptor‐1, iNOS, phosphorylated IκBα, NF‐κB, ICAM‐1, VCAM‐1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox‐LDL‐treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium‐dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM‐1, TNF‐α and IL‐6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down‐regulated the expression of LOX‐1.Conclusion and ImplicationsGYY4137 inhibits lipid accumulation induced by ox‐LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.
A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design
Authors: Kooistra A J , Kuhne S , de Esch I J P , Leurs R , de Graaf C 
Published: May 2013

Background and PurposeChemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G‐protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high‐resolution structural analyses of GPCR‐ligand complexes.Experimental ApproachIn this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high‐resolution structural analyses of (hist)aminergic GPCR‐ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular.Key ResultsOur investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by combining detailed analysis of crystallized or predicted protein‐ligand binding modes, receptor mutation studies, and ligand structure‐selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors.Conclusions and ImplicationsWe have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure‐selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design.Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
Feasibility of targeting ischaemia‐related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids
Authors: Andrag Ellen , Curtis Michael J 
Published: May 2013

Background and PurposeThe hypothesis that endocannabinoids protect hearts against ventricular fibrillation (VF) induced by myocardial ischaemia and reperfusion was examined, and the concept that cannabinoids may represent a new class of anti‐VF drug was tested.Experimental ApproachIn rat isolated hearts (Langendorff perfusion), VF evoked by reperfusion after 60 min regional ischaemia is known to be exacerbated by inhibitors of endogenous protectants such as nitric oxide. This preparation was used to assay the effects of cannabinoid agonists and antagonists, and the protocols were varied to examine mechanisms.Key ResultsReperfusion‐induced VF was not facilitated by relatively selective CB1 (1 μM AM251) or CB2 (1 μM AM630) antagonists. VF evoked during early (30 min) acute ischaemia was also unaffected. However, AM251 significantly increased the incidence of VF and the duration of VF episodes occurring during the later stage of acute ischaemia (30–60 min). AM630 had no such effects. In a separate study, cannabinoid perfusion (anandamide or 2‐arachidonoylglycerol, both 0.01‐1 μM) failed to reduce VF incidence concentration‐dependently during 30 min ischaemia. In all these studies, changes in ancillary variables (QT, PR, heart rate) were unrelated to changes in VF.Conclusions and ImplicationsEndocannabinoids are not endogenous anti‐VF mediators during reperfusion, but may have a weak protective effect during the late stages of ischaemia, mediated via CB1 agonism. This does not suggest endocannabinoids are important endogenous protectants in these settings, or that CB1 (or CB2) receptors are useful novel targets for developing drugs for VF.
Solid lipid nanoparticles of cholesteryl butyrate inhibit the proliferation of cancer cells in vitro and in vivo models
Authors: Minelli R , Occhipinti S , Gigliotti C L , Barrera G , Gasco P , Conti L , Chiocchetti A , Zara G P , Fantozzi R , Giovarelli M , Dianzani U , Dianzani C 
Published: May 2013

Background and PurposeSolid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti‐cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti‐inflammatory and anti‐tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models.Experimental ApproachCholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti‐tumour activity was measured in two models of PC‐3 cell xenografts in SCID/Beige mice.Key ResultsCholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3‐Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC‐3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth.Conclusion and ImplicationsCholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug.
A single‐point mutation (Ala280Val) in the third intracellular loop alters the signalling properties of the human histamine H3 receptor stably expressed in CHO‐K1 cells
Authors: Flores‐Clemente Cecilia , Osorio‐Espinoza Angélica , Escamilla‐Sánchez Juan , Leurs Rob , Arias Juan‐Manuel , Arias‐Montaño José‐Antonio 
Published: May 2013

Background and PurposeAn alanine to valine exchange at amino acid position 280 (A280V) in the third intracellular loop of the human histamine H3 receptor was first identified in a patient suffering from Shy–Drager syndrome and later reported as a risk factor for migraine. Here, we have compared the pharmacological and signalling properties of wild‐type (hH3RWT) and A280V mutant (hH3RA280V) receptors stably expressed in CHO‐K1 cells.Experimental ApproachThe hH3RA280V cDNA was created by overlapping extension PCR amplification. Receptor expression and affinity were assessed by radioligand (N‐α‐[methyl‐3H]‐histamine) binding to cell membranes, and receptor function by the inhibition of forskolin‐induced cAMP accumulation and stimulation of ERK1/2 phosphorylation in intact cells, as well as stimulation of [35S]‐GTPγS binding to cell membranes.Key ResultsBoth receptors were expressed at similar levels with no significant differences in their affinities for H3 receptor ligands. Upon activation the hH3RWT was significantly more efficacious to inhibit forskolin‐induced cAMP accumulation and to stimulate [35S]‐GTPγS binding, with no difference in pEC50 estimates. The hH3RWT was also more efficacious to stimulate ERK1/2 phosphorylation, but this difference was not significant. The inverse agonist ciproxifan was more efficacious at hH3RWT to reduce [35S]‐GTPγS binding but, for both receptors, failed to enhance forskolin‐induced cAMP accumulation.Conclusions and ImplicationsThe A280V mutation reduces the signalling efficacy of the human H3 receptor. This effect may be relevant to the pathophysiology of disorders associated with the mutation.Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
High salt‐induced hypertension in B2 knockout mice is corrected by the ETA antagonist, A127722
Authors: Brochu I , Houde M , Desbiens L , Simard E , Gobeil F , Semaan W , Bkaily G , D'Orléans‐Juste P 
Published: May 2013

Background and PurposeThe contribution of endothelin‐1 (ET‐1) in a B2KO mouse model of a high salt‐induced arterial hypertension was investigated.Experimental ApproachWild‐type (WT) or B2KO mice receiving a normal diet (ND) or a high‐salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET‐1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L‐NG‐nitroarginine methyl ester (L‐NAME) in anaesthetized WT and B2KO mice.Key ResultsIn B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET‐1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg−1) reduced by 50% the pressor response to L‐NAME (2 mg·kg−1) in B2KO, but not WT mice under anaesthesia.Conclusions and ImplicationsOur results support the concept that functional B2 receptors oppose high salt‐induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.
Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long‐term outcomes in patients with locally advanced rectal cancers
Authors: Khan A. A. , Klonizakis M. , Shabaan A. , Glynne‐Jones R. 
Published: May 2013

AbstractAimThe study was carried out to investigate whether pretreatment haemoglobin (Hb) levels act as a biomarker in the management of patients with locally advanced rectal cancer.MethodWe prospectively collected data on all patients within our cancer network with localized low rectal cancer treated with preoperative radiotherapy/chemoradiotherapy at Mount Vernon Centre for Cancer Treatment between March 1994 and July 2008. Pretreatment Hb level was assessed as an independent variable for the whole study sample and dichotomised at a value of 12 g/dl. A multivariate analysis of covariance (MANCOVA) was conducted on parameters that had significant association on univariate analysis of covariance (ANCOVA) and correlational (Kendall tau/Pearson) analyses. Kaplan–Meier survival analysis and Cox proportional hazard models were used to determine significant prognostic markers. Statistical significance was set at 0.05.Results463 patients (male/female 2:1; median age = 66 years, interquartile range = 56.5–73.0) were included in the analysis. There was significant tumour response of T stage (P < 0.001) and N stage (P < 0.001), with 17.6% of patients achieving a pathological complete response. Pretreatment Hb value was inversely related to the craniocaudal vertical tumour length (P = 0.02) and pretreatment T stage of the tumour (P = 0.01). Patients with Hb levels of < 12 g/dl and moderately differentiated adenocarcinoma were less responsive. Local recurrence was more common in patients with a pretreatment Hb of < 12 g/dl (hazard ratio = 1.78) over a median follow up of 24 months, but this was not statistically significant (P = 0.08).ConclusionThe pretreatment Hb level might be used as a biomarker of rectal tumour morphology, response to neoadjuvant chemoradiation and risk of local recurrence.
Learning to look: probabilistic variation and noise guide infants' eye movements
Authors: Tummeltshammer Kristen Swan , Kirkham Natasha Z. 
Published: May 2013

AbstractYoung infants have demonstrated a remarkable sensitivity to probabilistic relations among visual features (Fiser & Aslin, 2002; Kirkham et al., 2002). Previous research has raised important questions regarding the usefulness of statistical learning in an environment filled with variability and noise, such as an infant's natural world. In an eye‐tracking experiment, 8‐month‐old infants viewed sequences of spatio‐temporal events with three different transitional probabilities (1.0‐Deterministic, 0.75‐High probability, and 0.5‐Low probability). Across two between‐subjects conditions, the sequences were presented with or without competing visual distracters. Results show that as transitional probability decreased, infants distributed less attention to the predictable locations and their anticipations were less often correct. With no distraction, infants had faster saccadic latencies to the high probability events; however, with distracters present in the stimulus environment, infants' eye movements shifted to favour the deterministic relations. These findings suggest that infants integrate multiple sources of variability to guide visual attention and facilitate the detection and learning of statistically reliable events.
Domain‐specific impulsivity in school‐age children
Authors: Tsukayama Eli , Duckworth Angela Lee , Kim Betty 
Published: May 2013

AbstractImpulsivity is a salient individual difference in children with well‐established predictive validity for life outcomes. The current investigation proposes that impulsive behaviors vary systematically by domain. In a series of studies with ethnically and socioeconomically diverse samples of middle school students, we find that schoolwork‐related and interpersonal‐related impulsivity, as observed by teachers, parents, and the students themselves, are distinct, moderately correlated behavioral tendencies. Each demonstrates differentiated relationships with dimensions of childhood temperament, Big Five personality factors, and outcomes, such as report card grades. Implications for theoretical conceptions of impulsivity as well as for practical applications (e.g. domain‐specific interventions) are discussed.
Diabetes Attitudes, Wishes and Needs second study (DAWN2™): Cross‐national benchmarking of diabetes‐related psychosocial outcomes for people with diabetes
Authors: Nicolucci A. , Kovacs Burns K. , Holt R. I. G. , Comaschi M. , Hermanns N. , Ishii H. , Kokoszka A. , Pouwer F. , Skovlund S. E. , Stuckey H. , Tarkun I. , Vallis M. , Wens J. , Peyrot M. ,   the DAWN2 Study Group
Published: May 2013

AbstractAimsThe second Diabetes Attitudes, Wishes and Needs (DAWN2) study aimed to assess psychosocial outcomes in people with diabetes across countries for benchmarking.MethodsSurveys included new and adapted questions from validated questionnaires that assess health‐related quality of life, self‐management, attitudes/beliefs, social support and priorities for improving diabetes care. Questionnaires were conducted online, by telephone or in person.ResultsParticipants were 8596 adults with diabetes across 17 countries. There were significant between‐country differences for all benchmarking indicators; no one country's outcomes were consistently better or worse than others. The proportion with likely depression [WHO‐5 Well‐Being Index (WHO‐5) score ≤ 28] was 13.8% (country range 6.5–24.1%). Diabetes‐related distress [Problem Areas in Diabetes Scale 5 (PAID‐5) score ≥ 40] was reported by 44.6% of participants (17.2–67.6%). Overall quality of life was rated ‘poor’ or ‘very poor’ by 12.2% of participants (7.6–26.1%). Diabetes had a negative impact on all aspects investigated, ranging from 20.5% on relationship with family/friends to 62.2% on physical health. Approximately 40% of participants (18.6–64.9%) reported that their medication interfered with their ability to live a normal life. The availability of person‐centred chronic illness care and support for active involvement was rated as low. Following self‐care advice for medication and diet was most common, and least common for glucose monitoring and foot examination, with marked country variation. Only 48.8% of respondents had participated in diabetes educational programmes/activities to help manage their diabetes.ConclusionsCross‐national benchmarking using psychometrically validated indicators can help identify areas for improvement and best practices to drive changes that improve outcomes for people with diabetes.
The Moral Economy Is a Double‐edged Sword: Explaining Farmers’ Earnings and Self‐exploitation in Community‐Supported Agriculture
Authors: Galt Ryan E. 
Published: May 2013

AbstractIn this articleIdevelop a political economic understanding of community‐supported agriculture (CSA). I first develop the relevance of three concepts—economic rents, self‐exploitation, and social embeddedness—toCSAand then introduce a framework that relatesCSAfarmers’ earnings to the average rate of profit, economic rents, and self‐exploitation. I then examine qualitative and quantitative data from a study of 54CSAsin California's Central Valley and surrounding foothills to explain the wide range of farmers’ earnings in relation to the characteristics of production ofCSAs, the social embeddedness ofCSAs, and the farmers’ motivations and rationalities. Qualitative data from interviews are used to interpret the results of an ordinary least squares regression analysis showing that (1) farmers’ age, number of employees, and type ofCSAstrongly shape farmers' earnings; (2) the moral economy ofCSAcuts both ways economically, allowing for the capture of economic rents but more often resulting in self‐exploitation because of farmers’ strong sense of obligation to their members; and (3) farmers’ motivations are diverse, but tend toward low and moderate instrumentalism, meaning that earning an income is often not a high priority relative to other values. The conclusion recommends the need to recognize alternative rationalities but also to discuss and confront strong self‐exploitation in alternative food networks because of the broader political economic context in which they exist.
Differential sources of host species heterogeneity influence the transmission and control of multihost parasites
Authors: Streicker Daniel G. , Fenton Andy , Pedersen Amy B. 
Published: May 2013

AbstractControlling parasites that infect multiple host species often requires targeting single species that dominate transmission. Yet, it is rarely recognised that such ‘key hosts’ can arise through disparate mechanisms, potentially requiring different approaches for control. We identify three distinct, but not mutually exclusive, processes that underlie host species heterogeneity: infection prevalence, population abundance and infectiousness. We construct a theoretical framework to isolate the role of each process from ecological data and to explore the outcome of different control approaches. Applying this framework to data on 11 gastrointestinal parasites in small mammal communities across the eastern United States reveals variation not only in the magnitude of transmission asymmetries among host species but also in the processes driving heterogeneity. These differences influence the efficiency by which different control strategies reduce transmission. Identifying and tailoring interventions to a specific type of key host may therefore enable more effective management of multihost parasites.
Relationship between natural teeth and memory in a healthy elderly population
Authors: Hansson Patrik , Sunnegårdh‐Grönberg Karin , Bergdahl Jan , Bergdahl Maud , Nyberg Lars , Nilsson Lars‐Göran 
Published: May 2013

The relationship between mastication and cognitive function remains unclear, but both animal and experimental human studies suggest a possible causal relationship. In the present study it was hypothesized that natural teeth are of importance for hippocampus‐based cognitive processes, such as episodic long‐term memory. A population‐based sample of 273 participants (55–80 yr of age; 145 women) was investigated in a cross‐sectional study. The participants underwent health assessment, completed a battery of cognitive tests, and took part in an extensive clinical oral examination. The number of natural teeth contributed uniquely and significantly to explaining variance (3–4%) in performance on measures of episodic memory and semantic memory over and above individual differences in age, years of education, gender, occupation, living conditions, and medical history. The number of natural teeth did not have an influence on the performance of measures of working memory, visuospatial ability, or processing speed. Within the limitations of the current study, a small, but significant, relationship between episodic memory and number of natural teeth is evident.