bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol Stimulates Activation of Snail, Epidermal Growth Factor Receptor Signaling, and Biomarkers of Epithelial–Mesenchymal Transition in Colon and Breast Cancer Cells
Authors: Forsyth Christopher B. , Tang Yueming , Shaikh Maliha , Zhang Lijuan , Keshavarzian Ali 
Published: October 2009

Background:  Alcohol consumption is associated with the risk of progressive cancers including colon and breast cancer. The mechanisms for the alcohol‐induced aggressive behavior of these epithelial cancer cells have not been fully identified. Epithelial–mesenchymal transition (EMT) is a developmental program recently shown to play a role in cancer progression and metastases. We hypothesized that alcohol might promote cancer progression by inducing EMT in cancer cells and tested this hypothesis by assessing alcohol‐stimulated changes in phenotypic markers of EMT as well as the EMT transcription factor Snail and its related cell signaling.Methods:  Colon and breast cancer cell lines and a normal intestinal epithelial cell line were tested as well as colonic mucosal biopsy samples from alcoholic subjects. Cells were treated with alcohol and assessed for EMT‐related changes using immunofluorescent microscopy, western blotting, reporter assays, RT‐PCR, and knockdown of Snail with siRNA.Results:  We show alcohol upregulated the signature EMT phenotypic marker vimentin as well as matrix metalloprotease (MMP)‐2, MMP‐7, and MMP‐9 and cell migration in colon and breast cancer cells—all characteristics of EMT. Alcohol also stimulated nuclear localization of Snail phosphorylated at Ser246, transcription from a Snail reporter plasmid, and Snail mRNA expression by RT‐PCR. Snail siRNA knockdown prevented alcohol‐stimulated vimentin expression. In vivo, Snail expression was significantly elevated in colonic mucosal biopsies from alcoholics. Also, we found alcohol stimulated activation of epidermal growth factor receptor (EGFR) signaling and an EGFR inhibitor blocked alcohol‐induced cell migration and Snail mRNA expression.Conclusions:  Collectively, our data support a novel mechanism for alcohol promoting cancer progression through stimulating the EMT program in cancer cells via an EGFR‐Snail mediated pathway. This study reveals new pathways for alcohol‐mediated promotion of cancer that could be targeted for therapy or prevention of alcohol‐related cancers.
Glycine Receptors Involved in Acamprosate’s Modulation of Accumbal Dopamine Levels: An In Vivo Microdialysis Study
Authors: Chau PeiPei , Stomberg Rosita , Fagerberg Anne , Söderpalm Bo , Ericson Mia 
Published: October 2009

Background:  Glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) have been suggested to be involved in the positive reinforcing and dopamine elevating effects of ethanol. Recent studies have also shown that ethanol high‐preferring rats substantially decrease their ethanol intake when treated with a glycine transporter 1 inhibitor (ORG 25935). Acamprosate, a drug used for relapse prevention in treatment of alcohol dependence, has also been demonstrated to elevate extracellular dopamine levels in the nAc. However, the underlying mechanism of action of acamprosate is not fully understood. Here we investigated whether acamprosate interferes with a neuronal circuitry that previously has been demonstrated to be involved in the dopamine elevating effects of ethanol and taurine.Methods:  In vivo microdialysis in freely moving rats was used to assess accumbal dopamine levels before and during local (nAc) or systemic administration of acamprosate.Results:  Perfusion of 0.5 mM acamprosate in the nAc significantly increased dopamine levels. Pretreatment either with 10 μM strychnine in the nAc or 100 μM mecamylamine in the VTA, completely antagonized the acamprosate‐induced elevation of accumbal dopamine levels. Also, systemic acamprosate administration elevated accumbal dopamine output, an effect that was abolished by local (nAc) pretreatment with 10 μM strychnine.Conclusions:  These results suggest that both systemic and local application of acamprosate elevate extracellular dopamine levels in the nAc by activating accumbal GlyRs, and, secondarily, tegmental nAChRs.
Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake‐Reducing Effect of Acamprosate
Authors: Chau PeiPei , Höifödt‐Lidö Helga , Löf Elin , Söderpalm Bo , Ericson Mia 
Published: October 2009

Background:  We have previously demonstrated that strychnine‐sensitive glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area are involved in mediating ethanol (EtOH)‐induced elevation of dopamine in the rat mesolimbic dopamine system. This neuronal circuitry was also demonstrated to mediate dopamine elevation in the nAc after both taurine, an endogenous agonist of GlyRs, and acamprosate, a synthetic derivate of homotaurine. The aim of this study was to investigate whether the EtOH intake‐reducing effect of acamprosate involves accumbal GlyRs.Methods:  For this purpose, we used a voluntary EtOH consumption model where EtOH medium‐ and high‐preferring rats were implanted with guide cannulae in the nAc. The animals received daily injections of acamprosate or 0.9% NaCl before accessing a bottle of 6% EtOH and a bottle of water. After 2 days, a microinjection of strychnine or vehicle preceded the daily systemic injection and bottle‐access period.Results:  Acamprosate, but not saline, decreased EtOH intake. Pretreatment with Ringer in the nAc did not influence EtOH intake in saline or acamprosate‐treated animals. Pretreatment with strychnine had no effect on EtOH intake in saline‐treated animals, whereas it completely reversed the EtOH intake‐reducing effect of acamprosate.Conclusions:  Based on current and previous results, we suggest that acamprosate primarily interacts with accumbal GlyRs and secondarily with ventral tegmental nAChRs, in a similar manner to that previously observed with EtOH and taurine. The interaction between acamprosate and GlyRs does not only influence dopamine output in the nAc but also EtOH consumption, giving further support for our hypothesis that GlyRs are of importance in EtOH reinforcement.
Alcohol Up‐Regulates TLR2 Through a NO/cGMP Dependent Pathway
Authors: Bailey Kristina L , Sisson Joseph H. , Romberger Debra J. , Robinson James E. , Wyatt Todd A. 
Published: October 2009

Background:  Heavy alcohol consumption is associated with severe bronchitis. This is likely related to increased inflammation in the airways of alcohol abusers. Toll‐like receptor 2 (TLR2) is an important mediator of inflammation in the airway epithelium. TLR2 initiates an inflammatory cascade in response to gram‐positive bacteria. We have previously shown that alcohol up‐regulates TLR2 in the airway epithelium. However, the mechanism of alcohol‐mediated up‐regulation of TLR2 has not been identified.Methods:  A human airway epithelial cell line, 16HBE14o−, was exposed to biologically relevant concentrations of alcohol (100 mM) in the presence and absence of Nω‐Nitro‐l‐arginine methyl ester hydrochloride, a nitric oxide (NO) synthase inhibitor; and Rp‐8‐Br‐cGMP‐S, an antagonist analogue of cGMP. TLR2 was measured using real‐time PCR and Western blots. In addition, 16HBE14o− cells were incubated with sodium nitroprusside (SNP), an NO donor, and 8‐Br‐cGMP, a cGMP analogue. TLR2 was measured using real‐time PCR.Results:  N
ω‐Nitro‐l‐arginine methyl ester hydrochloride blocked the alcohol‐mediated up‐regulation of TLR2. This indicates that NO plays a key role in alcohol’s up‐regulation of TLR2. SNP, a NO donor, up‐regulated TLR2. Rp‐8‐Br‐CGMP‐S attenuated alcohol’s up‐regulation of TLR2, suggesting that NO was working through cGMP/PKG. 8‐Br‐cGMP up‐regulated TLR2, also demonstrating the importance of cGMP/PKG.Conclusions:  Alcohol up‐regulates TLR2 through a NO/cGMP/PKG dependent pathway in the airway epithelium. This is an important observation in the understanding how alcohol modulates airway inflammation. In addition, this is the first time that cyclic nucleotides have been shown to play a role in the regulation of TLR2.
Alcohol, Cocaine, and Brain Stimulation‐Reward in C57Bl6/J and DBA2/J Mice
Authors: Fish Eric W. , Riday Thorfinn T. , McGuigan Megan M. , Faccidomo Sara , Hodge Clyde W. , Malanga C. J. 
Published: October 2009

Background: Pleasure and reward are critical features of alcohol drinking that are difficult to measure in animal studies. Intracranial self‐stimulation (ICSS) is a behavioral method for studying the effects of drugs directly on the neural circuitry that underlies brain reward. These experiments had 2 objectives: first, to establish the effects of alcohol on ICSS responding in the C57Bl6/J (C57) and DBA2/J (DBA) mouse strains; and second, to compare these effects to those of the psychostimulant cocaine.Methods: Male C57 and DBA mice were implanted with unipolar stimulating electrodes in the lateral hypothalamus and conditioned to spin a wheel for reinforcement by the delivery of rewarding electrical stimulation (i.e., brain stimulation‐reward or BSR). Using the curve‐shift method, the BSR threshold (θ0) was determined immediately before and after oral gavage with alcohol (0.3, 0.6, 1.0, 1.7 g/kg) or water. Blood alcohol concentration (BAC) was measured to determine the influence of alcohol metabolism on BSR threshold. Separately, mice were administered cocaine (1.0, 3.0, 10.0, 30.0 mg/kg) or saline intraperitoneally.Results: In C57 mice, the 0.6 g/kg dose of alcohol lowered BSR thresholds by about 20%, during the rising (up to 40 mg/dl), but not falling, phase of BAC. When given to the DBA mice, alcohol lowered BSR thresholds over the entire dose range; the largest reduction was by about 50%. Cocaine lowered BSR thresholds in both strains. However, cocaine was more potent in DBA mice than in C57 mice as revealed by a leftward shift in the cocaine dose–response curve. For both alcohol and cocaine, effects on BSR threshold were dissociable from effects on operant response rates.Conclusions: In C57 and DBA mice, reductions in BSR threshold reflect the ability of alcohol to potentiate the neural mechanisms of brain reward. The DBA mice are more sensitive to the reward‐potentiating effects of both alcohol and cocaine, suggesting that there are mouse strain differences in the neural mechanisms of brain reward that can be measured with the ICSS technique.
CB1 Receptor Blockade Decreases Ethanol Intake and Associated Neurochemical Changes in Fawn‐Hooded Rats
Authors: Femenía Teresa , García‐Gutiérrez María S. , Manzanares Jorge 
Published: October 2009

Background: This study was undertaken to identify the neurochemical changes underlying the attenuation of voluntary ethanol intake induced by the cannabinoid CB1 receptor antagonist AM251 in fawn‐hooded rats.Methods: Rats were exposed to the 2‐bottle‐choice paradigm (ethanol 10% v/v or water) for 15 days. After this period, rats received AM251 (3 to 6 mg/kg, i.p.) or vehicle.Results: Voluntary ethanol intake decreased (30%) with the administration of incremental dosages of AM251 (3 mg/kg, 5 days and 6 mg/kg, 5 days) in rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/d). Ethanol intake significantly decreased proopiomelanocortin expression in the arcuate nucleus (38.31%) and μ‐opioid‐DAMGO‐stimulated [35S]‐GTPγ binding in the caudate‐putamen (40%), nucleus accumbens core (AccC) (32.87%), and shell (AccS) (34.21%). Moreover, ethanol intake increased tyrosine hydroxylase (TH) gene expression in the substantia nigra (24%) and ventral tegmental area (23%) and corticotrophin‐releasing gene expression in the paraventricular hypothalamic nucleus (41.6%). The reduction of ethanol intake induced by AM251 was associated with blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. Interestingly, treatment with AM251 reduced (20%) TH gene expression in rats drinking only water. In this respect, the action of AM251 in reducing TH gene expression may not be specific.Conclusion: Taken together, these results revealed that blockade of cannabinoid CB1 receptors (CB1r) decreased voluntary ethanol intake in ethanol‐habituated rats by normalizing the neurochemical alterations induced by ethanol.
Heavy Episodic Drinking and Alcohol Consumption in French Colleges: The Role of Perceived Social Norms
Authors: França Lionel Riou , Dautzenberg Bertrand , Reynaud Michel 
Published: October 2009

Background:  The effect of normative perceptions (social norms) on heavy episodic drinking (HED) behavior is well known in the U.S. college setting, but little work is available in other cultural contexts. The objective of this study is therefore to assess whether social norms of alcohol use are related to HED in France, taking account of other influential predictors.Methods:  A cross‐sectional survey was carried out among 731 second‐year university students in the Paris region to explore the role of 29 potential alcohol use risk factors. The probability of heavy episodic drinking and the frequency of HED among heavy episodic drinkers were modeled independently. Monthly alcohol consumption was also assessed.Results:  Of the students, 56% overestimate peer student prevalence of HED (37% for alcohol drinking prevalence). HED frequency rises with perceived peer student prevalence of HED. Other social norms associated with HED are perceived friends’ approval of HED (increasing both HED probability and HED frequency) and perceived friend prevalence of alcohol drinking (increasing HED probability only). Cannabis and tobacco use, academic discipline, gender, and the number of friends are also identified as being associated with HED.Conclusions:  Overestimation of peer student prevalence is not uncommon among French university students. Furthermore, perceived peer student prevalence of HED is linked to HED frequency, even after adjusting for other correlates. Interventions correcting misperceived prevalences of HED among peer students have therefore the potential to reduce the frequency of HED in this population.
Recipient‐derived HPA‐1a antibodies: a cause of prolonged thrombocytopenia after unrelated donor stem cell transplantation
Authors: Lucas Geoff , Culliford Steven , Green Frances , Sidra Gamal , Calvert Anthony , Green Ann , Harrison Penny , Harvey John , Allen Dave , Smillie David , Masurekar Ashish , Marks David , Russell Nigel , Massey Edwin 
Published: October 2009

BACKGROUND:Patients with human platelet antigen (HPA) specific antibodies in cases of neonatal alloimmune thrombocytopenia and platelet (PLT) refractoriness derive clinical benefit from the use of HPA‐selected PLTs.STUDY DESIGN AND METHODS:This study describes three patients with underlying diagnoses of acute myeloid leukemia, chronic lymphocytic leukemia, and myelodysplasia, respectively, who underwent allogeneic bone marrow transplantation (BMT) with unrelated donors matched at the HLA‐A, B, C, Dr, and DQ loci but who failed to achieve an adequate PLT count. Investigation using PLT immunofluorescence test, monoclonal antibody immobilization of PLT antigens assay, and genotyping revealed the presence of recipient‐derived HPA‐1a antibodies.RESULTS:In two patients, anti‐HPA‐1a was detected post‐BMT and in the third patient, anti‐HPA‐1a was detected during pre‐BMT chemotherapy. Despite apparent 100% engraftment of donor cells, the patients' PLT counts failed to recover 9‐10 months posttransplant. The patients remained PLT‐transfusion dependent and failed to achieve satisfactory increments following random donor or HLA‐matched PLT transfusions. After the identification of HPA‐1a antibodies, the patients were supported by HPA‐1a(‐) PLTs and satisfactory posttransfusion PLT increments were obtained. These cases illustrate that HPA‐1a antibodies may remain detectable for 10 months following apparently successful donor engraftment and the disappearance of recipient‐derived HLA antibodies. The prolonged persistence of recipient‐derived PLT‐specific antibodies following BMT has to our knowledge not been described previously.CONCLUSION:HPA‐1a antibodies were associated with protracted PLT‐transfusion dependence and significant hemorrhagic complications. Appropriate and timely laboratory investigation for HPA‐specific antibodiesfollowed by transfusion support with HPA‐selected PLTs provided the cornerstone of the hemostatic management in these cases.
The Identification of a Human Skull Recovered from an eBay Sale
Authors: Seidemann Ryan M. , Stojanowski Christopher M. , Rich Fredrick J. 
Published: October 2009

Abstract: A human skull seized by the State of Louisiana from an eBay sale is analyzed. Bioarchaeological analyses of age‐at‐death, sex, and population affinity suggest the individual represented by the skull was a middle‐aged Native American female. The presence of intentional cranial modification independently supports the population affinity assessment while confounding the metric analyses. However, no further specificity as to population affinity could be inferred using existing methods and comparative databases. Sedimentological and palynological analyses were attempted to redress this impasse. The presence of fine‐grained charcoal, abundant fungal remains, and small angular quartz grains suggestive of burial in loess, as well as the lack of pollen, pteridophyte spores, and microscopic algae, suggest a likely upland burial location from somewhere in the lower Mississippi Valley. The sedimentological and palynological analyses, while not conclusive, show promise for use in future affiliation analyses of human remains recovered during the course of forensic investigations. The results are reviewed within the broader context of the legal debate over the repatriation of human remains.
Preservation of TSPO by chronic intermittent hypobaric hypoxia confers antiarrhythmic activity
Authors: Li Jun , Xu Jiahong , Xiao Junjie , Zhang Hong , Liang Dandan , Liu Yi , Zhang Yangyang , Liu Ying , Wen Wei , Hu Yaer , Yu Zhuo , Yan Biao , Jiang Bing , Zhou Zhao‐Nian , Chen Yi‐Han 
Published: October 2009

AbstractAbnormal activation of mitochondrial translocator protein (TSPO) contributes to arrhythmogenesis during cardiac metabolic compromise; however, its role in the antiarrhythmic activities of chronic hypoxia adaptation remains unclear. Our results demonstrated that 80% of normoxic rats developed ischaemic VF, whereas this condition was seldom observed in rats with 14 days of chronic intermittent hypobaric hypoxia (CIHH). TSPO stimulation or inhibition affected the arrhythmias incidence in normoxic rats, but did not change the CIHH‐mediated antiarrhythmic effects. Abrupt and excessive elevation of TSPO activity was positively linked to ischaemic VF, and CIHH preserved TSPO activity during ischaemia. The preservation of TSPO activity by CIHH also contributed to the maintenance of intracellular Ca homeostasis. These results suggest that the blunt sensitivity of TSPO to ischaemic stress may be responsible for the antiarrhythmic effects by CIHH.
Lipid droplet growth by fusion: insights from freeze‐fracture imaging
Authors: Robenek Horst , Severs Nicholas J. 
Published: October 2009

AbstractAn understanding of how lipid droplets grow in the cell is important to current human health issues. Homotypic fusion of small lipid droplets to create larger ones is one proposed mechanism though the evidence for this process continues to be debated. By applying the technique of freeze‐fracture electron microscopy to cells that have been stimulated to accumulate lipid droplets, we here present images which suggest that at least some large lipid droplets may indeed result from amalgamation of multiple smaller ones. These visual data add significantly to the notion that fusion contributes to lipid droplet growth.
Tissue inhibitor of metalloproteinases‐1‐induced scattered liver metastasis is mediated by host‐derived urokinase‐type plasminogen activator
Authors: Schrötzlmair Florian , Kopitz Charlotte , Halbgewachs Birgit , Lu Fei , Algül Hana , Brünner Nils , Gänsbacher Bernd , Krüger Achim 
Published: October 2009

AbstractParadoxically, not only proteinases but also their inhibitors can correlate with bad prognosis of cancer patients, underlining the evolving concept of the protease web as the complex interplay between proteinases, their inhibitors and effector molecules. Elevated levels of tissue inhibitor of metalloproteinases‐1 (TIMP‐1) render the liver more susceptible to metastasis by triggering urokinase plasminogen activator (uPA) expression as well as hepatocyte growth factor (HGF) signalling, thereby leading to the fatal scattered infiltration of metastasizing tumour cells throughout the parenchyma of the target organ. Here, we investigated whether host uPA is a crucial protagonist for the TIMP‐1‐induced modulation of a pro‐metastatic microenvironment in the liver. Indeed, in livers of uPA‐ablated mice elevated TIMP‐1 levels did not trigger HGF signalling and did not promote metastasis of a murine T‐lymphoma cell line. In contrast, lack of tumour cell‐derived uPA induced by gene silencing did not interfere with this pro‐metastatic pathway. Furthermore, host uPA was necessary for the recruitment of neutrophilic granulocytes and the associated increase of HGF in livers with elevated TIMP‐1 levels. This newly identified co‐operation between TIMP‐1 and host uPA suggests that therapies, simultaneously interfering with pro‐ and anti‐proteolytic pathways may be beneficial for patients with metastatic disease.
Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes
Authors: Sharabi Kfir , Lecuona Emilia , Helenius Iiro Taneli , Beitel Greg J. , Sznajder Jacob Iasha , Gruenbaum Yosef 
Published: October 2009

Abstract

CO2 transport into cells
CO2 sensing in cells and organisms
Physiological effects of elevated CO2
Molecular response to elevated CO2 levels

Carbon dioxide (CO2) is an important gaseous molecule that maintains biosphere homeostasis and is an important cellular signalling molecule in all organisms. The transport of CO2 through membranes has fundamental roles in most basic aspects of life in both plants and animals. There is a growing interest in understanding how CO2 is transported into cells, how it is sensed by neurons and other cell types and in understanding the physiological and molecular consequences of elevated CO2 levels (hypercapnia) at the cell and organism levels. Human pulmonary diseases and model organisms such as fungi, C. elegans, Drosophila and mice have been proven to be important in understanding of the mechanisms of CO2 sensing and response.
A Dominant Negative Mutant of Pma1 Interferes with the Folding of the Wild Type Enzyme
Authors: Eraso Pilar , Mazón María J. , Portillo Francisco 
Published: October 2009

Abstract Misfolded proteins are usually arrested in the endoplasmic reticulum (ER) and degraded by the ER‐associated degradation (ERAD) machinery. Several mutant alleles of PMA1, the gene coding for the plasma membrane H +‐ATPase, render misfolded proteins that are subjected to ERAD. A subset of misfolded PMA1 mutants exhibits a dominant negative effect on yeast growth since, when co‐expressed with the wild type allele, both proteins are retained in the ER and degraded. We have used a PMA1‐D378T dominant lethal allele to analyse the mechanism underlying the retention of the wild type enzyme by the dominant negative mutant. A genetic screen was performed for isolation of intragenic suppressors of PMA1‐D378T allele. This analysis pointed to transmembrane helix 10 (TM10) as an important element in the establishment of the dominant lethality. Deletion of the TM10 was able to suppress not only the PMA1‐D378T but all the dominant lethal alleles tested. Biochemical analyses suggest that dominant lethal proteins obstruct, through TM10, the correct folding of the wild type enzyme leading to its retention and degradation by ERAD.