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With which personality traits has the human monoamine oxidase A (MAOA) gene been associated?
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Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. These include antisocial and borderline personality disorders and antisocial aggression.
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['antisocial personality disorder', 'borderline personality disorder', 'antisocial aggression']
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[
"OBJECTIVE: Monoamine oxidase A is a mitochondrial enzyme involved in the \ndegradation of certain neurotransmitter amines: serotonin and norepinephrine. As \nfor its role in aggression, impulsivity, suicide and mood liability, monoamine \noxidase A can be considered a functional candidate in borderline personality \ndisorder.\nMETHODS: To test for this hypothesis we genotyped two polymorphic markers in \nmonoamine oxidase A gene, a promoter VNTR and an rs6323 (T941G) in exon 8, in \n111 Caucasian borderline personality disorder patients and 289 Caucasian healthy \ncontrols. Association analyses using individual marker and haplotype data were \nperformed by a program of COCAPHASE in UNPHASED (MRC Human Genome Mapping \nProject Resource Centre, Cambridge, UK).\nRESULTS: We found that the borderline personality disorder patients had a high \nfrequency of the high activity VNTR alleles (chi=4.696, P=0.03) and a low \nfrequency of the low activity haplotype (chi=5.089, P=0.02).\nCONCLUSION: These results show that the monoamine oxidase A gene may play an \nimportant role in the etiological development of the borderline personality \ndisorder.",
"Heritable factors account for approximately 40-60% of the total variance of \nliability to alcohol dependence. The present study tested whether a novel \nfunctional polymorphism in the promotor region of the X-chromosomal monoamine \noxidase A gene (MAOA) was related to antisocial and anxious-depressive traits in \nalcoholics. Due to the X-chromosomal localization of the MAOA gene, \npsychobiological traits were compared separately for both genders of 298 male \nand 66 female alcoholics. In males, 30 of 59 alcoholics with antisocial \npersonality disorder carried the low-activity 3-repeat allele in contrast to \nonly 7 of 31 anxious-depressive alcoholics (51% vs. 23%; p = 0.02). Likewise, \nfemale anxious-depressive alcoholics showed a trend towards a low frequency of \ngenotypes with the 3 repeat allele compared to female alcoholics without these \nsymptoms (29% vs. 53%; p = 0.09). Taken together, these findings suggest that \nthe 3-repeat allele of the MAOA polymorphism contributes modestly to the \ndimension of overand underreactive behaviors as possible antecedents of \nalcoholism.",
"Association studies suggest that the low activity variant of the monoamine \noxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances \nassociated with antisocial traits, particularly in males. Here, we assessed the \nlow (MAOA-L) activity variant in relation to both brain function and a \nbehavioral index of antisocial traits. From an initial sample of 290 healthy \nparticipants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. \nParticipants underwent a brief assessment of personality traits and \nevent-related potential (ERP) recording during an emotion-processing task. \nGenotype differences in ERPs were localized using LORETA. The MAOA-L genotype \nwas distinguished by elevated scores on the index of antisocial traits. These \ntraits were related to altered ERPs elicited 120-280ms post-stimulus, \nparticularly for negative emotion. Altered neural processing of anger in MAOA-L \ngenotypes was localized to medial frontal, parietal, and superior \ntemporo-occipital regions in males, but only to the superior occipital cortex in \nfemales. The MAOA low activity variant may increase susceptibility to antisocial \ntraits through alterations to the neural systems for processing threat-related \nemotion, especially for males. Monoamines such as noradrenalin and serotonin may \nmodulate these relationships, given that their metabolism varies according to \nMAOA variants, and that they modulate both emotional brain systems and \nantisocial aggression.",
"By conferring allele-specific transcriptional activity on the monoamine oxidase \nA (MAOA) gene in humans, length variation of a repetitive sequence [(variable \nnumber of tandem repeat (VNTR)] in the MAOA promoter influences a constellation \nof personality traits related to aggressive and antisocial behavior and \nincreases the risk of neurodevelopmental and psychiatric disorders. Here, we \nhave analyzed the presence and variability of this MAOA promoter repeat in \nseveral species of nonhuman primates. Sequence analysis of MAOA's \ntranscriptional control region revealed the presence of the VNTR in chimpanzee \n(Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla), orangutan \n(Pongo pygmaeus), rhesus macaque (Macaca mulatta) and Gelada baboon \n(Theropithecus gelada). The majority of P. troglodytes and P. paniscus showed a \nsingle repeat with a sequence identical to the VNTR sequence in humans. In \ncontrast, analyses of the remaining species revealed shorter sequences similar \nto the first 18 bp of human VNTR. Compared with other nonhuman primates, the \nVNTR sequence of M. mulatta showed the highest length variability with allele \nfrequencies of 35, 25 and 40% for the five, six and seven repeat variants, \nrespectively. The extent of variability of the MAOA promoter repeat in both \nrhesus monkeys and humans supports the notion that there may be a relationship \nbetween functional MAOA expression and aggression-related traits in humans and \nrhesus macaque populations.",
"Violent offending is elevated among individuals with antisocial personality \ndisorder (ASPD) and high psychopathic traits (PP). Morphological abnormalities \nof the amygdala and orbitofrontal cortex (OFC) are present in violent offenders, \nwhich may relate to the violence enacted by ASPD + PP. Among healthy males, \nmonoamine oxidase-A (MAO-A) genetic variants linked to low in vitro \ntranscription (MAOA-L) are associated with structural abnormalities of the \namygdala and OFC. However, it is currently unknown whether amygdala and OFC \nmorphology in ASPD relate to MAO-A genetic polymorphisms. We studied 18 ASPD \nmales with a history of violent offending and 20 healthy male controls. Genomic \nDNA was extracted from peripheral leukocytes to determine MAO-A genetic \npolymorphisms. Subjects underwent a T1-weighted MRI anatomical brain scan that \nprovided vertex-wise measures of amygdala shape and surface area and OFC \ncortical thickness. We found that ASPD + PP subjects with MAOA-L exhibited \ndecreased surface area in the right basolateral amygdala nucleus and increased \nsurface area in the right anterior cortical amygdaloid nucleus versus healthy \nMAOA-L carriers. This study is the first to describe genotype-related \nmorphological differences of the amygdala in a population marked by high \naggression. Deficits in emotional regulation that contribute to the violence of \nASPD + PP may relate to morphological changes of the amygdala under genetic \ncontrol.",
"BACKGROUND: Allelic variation of the monoamine oxidase A (MAOA) gene has been \nimplicated in conduct disorder and antisocial, aggressive behavior in humans \nwhen associated with early adverse experiences. We tested the hypothesis that a \nrepeat polymorphism in the rhesus macaque MAOA gene promoter region influences \naggressive behavior in male subjects.\nMETHODS: Forty-five unrelated male monkeys raised with or without their mothers \nwere tested for competitive and social group aggression. Functional activity of \nthe MAOA gene promoter polymorphism was determined and genotypes scored for \nassessing genetic and environmental influences on aggression.\nRESULTS: Transcription of the MAOA gene in rhesus monkeys is modulated by an \northologous polymorphism (rhMAOA-LPR) in its upstream regulatory region. High- \nand low-activity alleles of the rhMAOA-LPR show a genotype x environment \ninteraction effect on aggressive behavior, such that mother-reared male monkeys \nwith the low-activity-associated allele had higher aggression scores.\nCONCLUSIONS: These results suggest that the behavioral expression of allelic \nvariation in MAOA activity is sensitive to social experiences early in \ndevelopment and that its functional outcome might depend on social context.",
"AIMS: We analysed the MAOAuVNTR functional polymorphism in the promoter region \nof the X-chromosomal monoamine oxidase A (MAOA) gene. Genotypes with \nthree-repeat alleles were reported to be associated with antisocial as well as \nimpulsive traits.\nMETHODS: The repeat number (3-5) of the MAOA polymorphism was determined in 169 \nmale alcoholic subjects and 72 controls of German descent. Behavioural and \npersonality traits were evaluated using the Brown-Goodwin Assessment for History \nof Lifetime Aggression, the Buss Durkee Hostility Inventory, as well as the \nBarrat Impulsiveness Score. A median split in Brown-Goodwin, Buss Durkee \nIrritability, Buss Durkee Assault and Barrat Impulsiveness Score was conducted.\nRESULTS: High scores were found, i.e. 47.9% in Brown-Goodwin, 65.7% in Buss \nDurkee Irritability, 63.3% in Buss Durkee Assault and 59.8% in Barrat \nImpulsiveness Scale, indicating high impulsiveness, irritability and antisocial \nbehaviour. Based on the results of these questionnaires, we detected no \nsignificant differences between the frequency of the three-repeat allele and \nhigh or low scores in alcoholics and controls.\nCONCLUSIONS: Taken together, these findings suggest that the three-repeat allele \nof the MAOAuVNTR 30-bp polymorphism is not associated with impulsive and \naggressive personality traits.",
"Monoamine Oxidase A (MAOA) is a critical enzyme in the catabolism of \nmonoaminergic neurotransmitters. MAOA transcriptional activity is thought to be \nregulated by a well characterized 30 base pair (bp) variable nucleotide repeat \n(VNTR) that lies approximately ∼1000 bp upstream of the transcriptional start \nsite (TSS). However, clinical associations between this VNTR genotype and \nbehavioral states have been inconsistent. Herein, we describe a second, 10 bp \nVNTR that lies ∼1500 bp upstream of the TSS. We provide in vitro and in silico \nevidence that this new VNTR region may be more influential in regulating MAOA \ntranscription than the more proximal VNTR and that methylation of this CpG-rich \nVNTR is genotype dependent in females. Finally, we demonstrate that genotype at \nthis new VNTR interacts significantly with history of child abuse to predict \nantisocial personality disorder (ASPD) in women and accounts for variance in \naddition to that explained by the prior VNTR.",
"BACKGROUND: Antisocial personality disorder (ASPD) is characterised by elevated \nimpulsive aggression and increased risk for criminal behaviour and \nincarceration. Deficient activity of the monoamine oxidase A (MAOA) gene is \nsuggested to contribute to serotonergic system dysregulation strongly associated \nwith impulsive aggression and antisocial criminality.\nAIMS: To elucidate the role of epigenetic processes in altered MAOA expression \nand serotonin regulation in a population of incarcerated offenders with ASPD \ncompared with a healthy non-incarcerated control population.\nMETHOD: Participants were 86 incarcerated participants with ASPD and 73 healthy \ncontrols. MAOA promoter methylation was compared between case and control \ngroups. We explored the functional impact of MAOA promoter methylation on gene \nexpression in vitro and blood 5-HT levels in a subset of the case group.\nRESULTS: Results suggest that MAOA promoter hypermethylation is associated with \nASPD and may contribute to downregulation of MAOA gene expression, as indicated \nby functional assays in vitro, and regression analysis with whole-blood \nserotonin levels in offenders with ASPD.\nCONCLUSIONS: These results are consistent with prior literature suggesting MAOA \nand serotonergic dysregulation in antisocial populations. Our results offer the \nfirst evidence suggesting epigenetic mechanisms may contribute to MAOA \ndysregulation in antisocial offenders.",
"OBJECTIVE: Impulsivity is a core feature of borderline personality disorder \n(BPD) and antisocial personality disorder (ASPD) that likely arises from \ncombined genetic and environmental influences. The interaction of the low \nactivity variant of the monoamine oxidase-A (MAOA-L) gene and early childhood \nadversity has been shown to predict aggression in clinical and non-clinical \npopulations. Although impulsivity is a risk factor for aggression in BPD and \nASPD, little research has investigated potential gene-environment (G×E) \ninfluences impacting its expression in these conditions. Moreover, G×E \ninteractions may differ by diagnosis.\nMETHODS: Full factorial analysis of variance was employed to investigate the \ninfluence of monoamine oxidase-A (MAO-A) genotype, childhood abuse, and \ndiagnosis on Barratt Impulsiveness Scale-11 (BIS-11) scores in 61 individuals: \n20 subjects with BPD, 18 subjects with ASPD, and 23 healthy controls.\nRESULTS: A group×genotype×abuse interaction was present (F(2,49)=4.4, p=0.018), \nsuch that the interaction of MAOA-L and childhood abuse predicted greater BIS-11 \nmotor impulsiveness in BPD. Additionally, BPD subjects reported higher BIS-11 \nattentional impulsiveness versus ASPD participants (t(1,36)=2.3, p=0.025).\nCONCLUSION: These preliminary results suggest that MAOA-L may modulate the \nimpact of childhood abuse on impulsivity in BPD. Results additionally indicate \nthat impulsiveness may be expressed differently in BPD and ASPD.",
"BACKGROUND: Monoamine oxidase A (MAOA) is an important enzyme that metabolizes \nmonoamines such as serotonin, norepinephrine and dopamine in the brain. In \nprefrontal cortex, low MAOA binding is associated with aggression and high \nbinding is associated with major depressive disorder (MDD) and also risk for \nrecurrence of depressive episodes. In rodent models, low MAOA levels are \nassociated with increased aggression and fear conditioning, and decreased social \nand exploratory investigative behaviors. Our objective was to measure MAOA \nbinding in prefrontal cortex and concurrently evaluate a broad range of \nvalidated personality traits. We hypothesized that prefrontal MAOA binding would \ncorrelate negatively with angry-hostility, a trait related to aggression/anger, \nand positively with traits intuitively related to adaptive investigative \nbehavior.\nMETHOD: Participants were aged 19-49 years, healthy and non-smoking. MAOA \nbinding was measured with [11C]harmine positron emission tomography (PET) in \nprefrontal brain regions and personality traits were measured with the NEO \nPersonality Inventory Revised (NEO PI-R).\nRESULTS: Prefrontal MAOA binding correlated negatively with angry-hostility \n(r=-0.515, p=0.001) and positively with deliberation (r=0.514, p=0.001). In a \ntwo-factor regression model, these facets explained 38% of variance in \nprefrontal MAOA binding. A similar relationship was found in prefrontal cortex \nsubregions.\nCONCLUSIONS: We propose a new continuum describing the relationship between \npersonality and MAOA: deliberate/thoughtful contrasting aggressive/impulsive. \nAdditionally, the association between high MAOA binding and greater deliberation \nmay explain why some people have moderately high levels of MAOA, although very \nhigh levels occur during MDD. In health, higher MAOA binding is associated with \nan adaptive personality facet.",
"Genetic variants of the monoamine oxidase A (MAOA) have been associated with \naggression-, anxiety-, and addiction-related behavior in several nonclinical and \nclinical populations. Here, we investigated the influence of allelic variation \nof MAOA activity on aggression-related personality traits and disease risk in \npatients with personality disorders. Personality disorders were diagnosed with \nthe Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, \nand C. Personality features were assessed by the revised NEO Personality \nInventory and the Tridimensional Personality Questionnaire. The genotype of the \nMAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients \nwith personality disorders and in 281 healthy controls. MAOA genotype was \nsignificantly associated with cluster B personality disorders (chi2=7.77, \np=0.005, df=1) but not with cluster C personality disorders. In total, 26.0% of \ncluster B patients were hemi- or homozygous for the low-activity variant of the \nMAOA genotype, compared to 16.4% in the control group. Associations between MAOA \nvariants and personality domains related to impulsivity and aggressiveness were \ninconsistent. Our findings further support the notion that allelic variation of \nMAOA activity contributes modestly to the balance of hyper- \n(impulsive-aggressive) and hyporeactive (anxious-depressive) traits.",
"Subjects with schizophrenia or conduct disorder display a lifelong pattern of \nantisocial, aggressive and violent behavior and agitation. Monoamine oxidase \n(MAO) is an enzyme involved in the degradation of various monoamine \nneurotransmitters and neuromodulators and therefore has a role in various \npsychiatric and neurodegenerative disorders and pathological behaviors. Platelet \nMAO-B activity has been associated with psychopathy- and aggression-related \npersonality traits, while variants of the MAOA and MAOB genes have been \nassociated with diverse clinical phenotypes, including aggressiveness, \nantisocial problems and violent delinquency. The aim of the study was to \nevaluate the association of platelet MAO-B activity, MAOB rs1799836 polymorphism \nand MAOA uVNTR polymorphism with severe agitation in 363 subjects with \nschizophrenia and conduct disorder. The results demonstrated significant \nassociation of severe agitation and smoking, but not diagnosis or age, with \nplatelet MAO-B activity. Higher platelet MAO-B activity was found in subjects \nwith severe agitation compared to non-agitated subjects. Platelet MAO-B activity \nwas not associated with MAOB rs1799836 polymorphism. These results suggested the \nassociation between increased platelet MAO-B activity and severe agitation. No \nsignificant association was found between severe agitation and MAOA uVNTR or \nMAOB rs1799836 polymorphism, revealing that these individual polymorphisms in \nMAO genes are not related to severe agitation in subjects with schizophrenia and \nconduct disorder. As our study included 363 homogenous Caucasian male subjects, \nour data showing this negative genetic association will be a useful addition to \nfuture meta-analyses.",
"AIMS: We have analysed the MAOA-uVNTR polymorphism in the promoter region of the \nX-chromosomal monoamine oxidase A (MAOA) gene. The first aim was to examine the \nassociation between the MAOA genotype and the alcoholic phenotype. In the second \npart of the paper we have analysed the association of the MAOA genotype with \nimpulsive and aggressive behaviour. Genotypes with 3 or 5-repeat alleles \n(MAOA-L-genotype) were reported to be associated with impulsive and aggressive \ntraits.\nMETHODS: The MAOA genotype was determined in 371 male alcohol-dependent subjects \nand 236 male controls all of German descent. Behavioural and personality traits \nwere evaluated using the self-report questionnaires Barratt Impulsiveness Scale \n(BIS), Buss Durkee Hostility Inventory (BDHI), Temperament and Character \nInventory (TCI) and NEO-Five Factor Inventory (NEO-FFI). A median split in BIS, \nBuss Durkee Physical Assault, Buss Durkee Irritability, TCI and NEO-FFI was \nconducted.\nRESULTS: No association could be detected between the MAOA genotype and the \nalcoholic phenotype. Based on the results of the BIS questionnaire, we were able \nto make out an association between the MAOA-L genotype and higher levels of \nimpulsivity (p = 0.043). Furthermore - without reaching statistical significance \n- we detected a very slight association between the MAOA-L genotype and higher \nscores in the BDHI subcategory physical aggression (p = 0.058).\nCONCLUSION: Taken together, these findings suggest that the MAOA-L genotype is \nto some extent associated with impulsive and antisocial personality traits in \nalcoholic men. Further studies on that question are needed.",
"The physiological changes of adolescence may promote risk-taking behaviors, \nincluding binge drinking. Approximately 40% of alcoholics were already drinking \nheavily in late adolescence. Most cases of alcoholism are established by the age \nof 30 years with the peak prevalence at 18-23 years of age. Therefore the key \ntime frame for the development, and prevention, of alcoholism lies in \nadolescence and young adulthood. Severe childhood stressors have been associated \nwith increased vulnerability to addiction, however, not all stress-exposed \nchildren go on to develop alcoholism. Origins of resilience can be both genetic \n(variation in alcohol-metabolizing genes, increased susceptibility to alcohol's \nsedative effects) and environmental (lack of alcohol availability, positive peer \nand parental support). Genetic vulnerability is likely to be conferred by \nmultiple genes of small to modest effects, possibly only apparent in \ngene-environment interactions. For example, it has been shown that childhood \nmaltreatment interacts with a monoamine oxidase A (MAOA) gene variant to predict \nantisocial behavior that is often associated with alcoholism, and an interaction \nbetween early life stress and a serotonin transporter promoter variant predicts \nalcohol abuse in nonhuman primates and depression in humans. In addition, a \ncommon Met158 variant in the catechol-O-methyltransferase (COMT) gene can confer \nboth risk and resilience to alcoholism in different drinking environments. It is \nlikely that a complex mix of gene(s)-environment(s) interactions underlie \naddiction vulnerability and development. Risk-resilience factors can best be \ndetermined in longitudinal studies, preferably starting during pregnancy. This \nkind of research is important for planning future measures to prevent harmful \ndrinking in adolescence.",
"BACKGROUND: Monoamine oxidase-A (MAO-A) is a treatment target in \nneurodegenerative illness and mood disorders that increases oxidative stress and \npredisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex \n(PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive \nbehavior and human studies of depressed moods. Extreme dysphoria is common in \nborderline personality disorder (BPD), especially when severe, and the molecular \nunderpinnings of severe BPD are largely unknown. We hypothesized that MAO-A \nlevels in PFC and ACC would be highest in severe BPD and would correlate with \nsymptom magnitude.\nMETHODS: [(11)C] Harmine positron emission tomography measured MAO-A total \ndistribution volume (MAO-A VT), an index of MAO-A density, in severe BPD \nsubjects (n = 14), moderate BPD subjects (n = 14), subjects with a major \ndepressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). \nAll subjects were female.\nRESULTS: Severe BPD was associated with greater PFC and ACC MAO-A VT compared \nwith moderate BPD, MDE, and healthy control subjects (multivariate analysis of \nvariance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT \nwere positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = \n.53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), \nwhile hippocampus MAO-A VT was negatively correlated with verbal memory (r = \n-.44, p = .023).\nCONCLUSIONS: These results suggest that elevated MAO-A VT is associated with \nmultiple indicators of BPD severity, including BPD symptomatology, mood \nsymptoms, suicidality, and neurocognitive impairment.",
"Author information:\n(1)Isabelle Ouellet-Morin, PhD, School of Criminology, Université de Montréal & \nResearch Center of the Montreal Mental Health University Institute, Montréal and \nResearch Group on Child Psychosocial Maladjustment, Université de Montréal, \nMontréal, Canada; Sylvana M. Côté, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Department of Social and \nPreventive Medicine, Université de Montréal, Montréal, Canada and International \nLaboratory for Child and Adolescent Mental Health Development, INSERM U669, \nParis, France; Frank Vitaro, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal and School of Psychoéducation, \nUniversité de Montréal, Montréal, Canada; Martine Hébert, PhD, Department of \nSexology, Université du Québec à Montréal, Montréal, Québec, Canada; René \nCarbonneau, PhD, Research Group on Child Psychosocial Maladjustment, Université \nde Montréal, Montréal, Canada;Éric Lacourse, PhD, School of Criminology, \nUniversité de Montréal & Research Center of the Montreal Mental Health \nUniversity Institute, Montréal, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Canada and Department of \nSociology, Université de Montréal & Research Center of the Sainte-Justine \nUniversity Hospital, Montréal, Canada; Gustavo Turecki, MD, PhD, The McGill \nGroup for Suicide Studies, Douglas Hospital Research Center, Montréal, Québec, \nCanada; Richard E. Tremblay, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Canada, International \nLaboratory for Child and Adolescent Mental Health Development, INSERM U669, \nParis, France, Department of Pediatrics, Psychiatry and Psychology, Université \nde Montréal, Montréal, Canada and School of Public Health, Physiotherapy and \nPopulation Science, University College Dublin, Ireland \nisabelle.ouellet-morin@umontreal.ca.\n(2)Isabelle Ouellet-Morin, PhD, School of Criminology, Université de Montréal & \nResearch Center of the Montreal Mental Health University Institute, Montréal and \nResearch Group on Child Psychosocial Maladjustment, Université de Montréal, \nMontréal, Canada; Sylvana M. Côté, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Department of Social and \nPreventive Medicine, Université de Montréal, Montréal, Canada and International \nLaboratory for Child and Adolescent Mental Health Development, INSERM U669, \nParis, France; Frank Vitaro, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal and School of Psychoéducation, \nUniversité de Montréal, Montréal, Canada; Martine Hébert, PhD, Department of \nSexology, Université du Québec à Montréal, Montréal, Québec, Canada; René \nCarbonneau, PhD, Research Group on Child Psychosocial Maladjustment, Université \nde Montréal, Montréal, Canada;Éric Lacourse, PhD, School of Criminology, \nUniversité de Montréal & Research Center of the Montreal Mental Health \nUniversity Institute, Montréal, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Canada and Department of \nSociology, Université de Montréal & Research Center of the Sainte-Justine \nUniversity Hospital, Montréal, Canada; Gustavo Turecki, MD, PhD, The McGill \nGroup for Suicide Studies, Douglas Hospital Research Center, Montréal, Québec, \nCanada; Richard E. Tremblay, PhD, Research Group on Child Psychosocial \nMaladjustment, Université de Montréal, Montréal, Canada, International \nLaboratory for Child and Adolescent Mental Health Development, INSERM U669, \nParis, France, Department of Pediatrics, Psychiatry and Psychology, Université \nde Montréal, Montréal, Canada and School of Public Health, Physiotherapy and \nPopulation Science, University College Dublin, Ireland.",
"The history of research on the association between platelet monoamine oxidase \n(MAO) activity and personality traits, such as sensation seeking and \nimpulsiveness, is reviewed. The effects of MAO-inhibiting compounds in cigarette \nsmoke for the interpretation of this association are discussed. Recent results \nconfirming a true association between platelet MAO activity and personality are \npresented. From a clinical point of view, this association has had its greatest \nimpact on the understanding of the nature of constitutional factors making \nindividuals vulnerable for e.g. substance abuse and the link between low \nplatelet MAO activity and type 2 alcoholism, recently confirmed on non-human \nprimates, is discussed. The molecular mechanisms underlying the association \nbetween platelet MAO and behaviour are discussed and evidence that common \ntranscriptional factors, e.g. within the AP-2 family, regulating both the \nexpression of platelet MAO and components of central monoaminergic systems, such \nas synthetizing enzymes, receptors and transporters, are presented. A hypothesis \nis put forward, that such common transcription factors may not directly regulate \nplatelet MAO expression, but rather mitochondrial number or outer membrane \nsurface."
] |
nan
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52d7b45e98d0239505000002
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19463607,
19006851,
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17636722,
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16026106,
22529180,
16542047
] |
train
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is pharmacological treatment of subclinical hypothyroidism effective in reducing cardiovascular events?
|
yesno
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whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.
|
no
|
[
"BACKGROUND: Some studies have proposed that subclinical hypothyroidism (SCH) has \nadverse effects on the cardiovascular system, but little is known about the \neffect on patients undergoing cardiovascular operations. We examined the \ninfluence of preoperative SCH on postoperative outcome in patients undergoing \ncoronary artery bypass grafting (CABG).\nMETHODS: Among patients who underwent CABG between July 2005 and June 2007 at \nSeoul National University Bundang Hospital, 224 with normal thyroid function and \n36 with SCH were enrolled. Preoperative risks and postoperative outcomes were \nevaluated prospectively without thyroid hormone replacement.\nRESULTS: There were no significant differences in primary outcomes (major \nadverse cardiovascular events) and secondary outcomes such as wound problems, \nmediastinitis, leg infection, respiratory complications, delirium, or \nreoperation during the same hospitalization. However, patients with SCH had a \nhigher incidence of postoperative atrial fibrillation than those with normal \nthyroid function after adjustment for age, gender, body mass index, and other \nindependent variables such as emergency operation, the use of cardiopulmonary \nbypass, combined valvular operation, preoperative creatinine levels, left \nventricular systolic dysfunction, and nonuse of beta-blockers (45.5% vs 29%; \nodds ratio, 2.552; 95% confidence interval, 1.117 to 5.830; p = 0.026).\nCONCLUSIONS: SCH appears to influence the postoperative outcome for patients by \nincreasing the development of postoperative atrial fibrillation. However, it is \nstill unproven whether preoperative thyroxine replacement therapy for patients \nwith SCH might prevent postoperative atrial fibrillation after CABG.",
"BACKGROUND: It has been suggested that low thyroid hormones levels may be \nassociated with increased mortality in patients with cardiovascular disease.\nAIM: To evaluate the prognostic role of thyroid function deficiency in patients \nwith chronic heart failure (CHF).\nMETHODS: We evaluated 338 consecutive outpatients with stable CHF receiving \nconventional therapy, all of whom underwent a physical examination, \nelectrocardiography and echocardiography. Blood samples were drawn to assess \nrenal function, and Na+, hemoglobin, NT-proBNPs, fT3, fT4 and TSH levels. \nPatients with hyperthyroidism were excluded.\nRESULTS: During the follow-up (15+/-8 months), heart failure progression was \nobserved in 79 patients (including 18 who died of heart failure after \nhospitalisation and six who underwent transplantation). Univariate regression \nanalysis showed that TSH (p<0.0001), fT3 (p<0.0001), fT4 (p=0.016) and fT3/fT4 \n(p<0.0001) were associated with heart failure progression but multivariate \nanalysis showed that only TSH considered as a continuous variable (p = 0.001) as \nwell as subclinical hypothyroidism (TSH > 5.5 mUI/l; p=0.014) remained \nsignificantly associated with the events.\nCONCLUSIONS: In CHF patients TSH levels even slightly above normal range are \nindependently associated with a greater likelihood of heart failure progression. \nThis supports the need for prospective studies aimed at clarifying the most \nappropriate therapeutic approach to sub-clinical hypothyroidism in such \npatients.",
"Cardiovascular consequences of thyroid diseases, their prevalence and treatment, \nparticularly in cases with subclinical hyper- and hypothyroidism. The aim of the \nstudy was to draw attention to an association between the thyroid and \ncardiovascular diseases. The main topic was to lay emphasis on the importance of \ncardiovascular diseases caused by subclinical hyper- and hypothyroidism in the \nrelation to the practice. The subclinical states precede the overt hyper- and \nhypothyroidism, and they are often present during their treatments. The changes \nin the levels of thyrotropin demonstrating subclinical thyroid diseases, could \nbe detected in different non-thyroid diseases and resulted from the effect of \nsome drugs. Particularly, the subclinical thyroid diseases become more frequent \nin older age. In the background of the high prevalences of atrial fibrillation, \nhypertension and psychosomatic events subclinical hyperthyroidism could be \nrevealed. Subclinical hypothyroidism is characterized by an increased prevalence \nof elevated serum lipid levels, atherosclerosis, ischemic heart disease and \nhypertension often associating with the presence of anti-thyroid antibodies. It \nis important to reveal subclinical thyroid diseases in time for the effective \ntreatment and for stopping of the cardiovascular damages before manifestations \nof cardiovascular diseases. The paper gives advice for the practice and the \nrational management. At the end, a survey of the association between thyroid and \nheart diseases in own department of internal medicine at the last three years is \ngiven.",
"CONTEXT: The negative impact of subclinical hypothyroidism (sHT) on \ncardiovascular risk, widely recognized in young adults (aged <55-60 y), is still \ndebated in the elderly (>65 y), especially in the oldest olds (>80 y).\nEVIDENCE ACQUISITION: We searched Medline for reports published with the \nfollowing search terms: \"hypothyroidism,\" \"subclinical hypothyroidism,\" \n\"ageing,\" \"elderly,\" \"L-thyroxin,\" \"thyroid,\" \"guidelines,\" \"treatment,\" \n\"quality of life,\" \"cardiovascular risk,\" \"heart failure,\" \"coronary heart \ndisease\" (CHD), \"atherosclerosis,\" and \"endothelial dysfunction.\" We limited our \nsearch to reports in English published after 1980, although we incorporated some \nreports published before 1980. We supplemented the search with records from \npersonal files, textbooks, and relevant articles. Analyzed parameters included \nthe epidemiology of thyroid failure, the effect of thyroid hormone on the aging \nprocess, cardiovascular function, and CHD risk factors. We also included the \npotential benefits of L-T4 therapy on the quality of life, cardiovascular \nevents, and survival.\nEVIDENCE SYNTHESIS: TSH levels increase with age, even in older people without \nthyroid disease. Most longitudinal studies show an increased risk for CHD events \nand mortality in sHT participants. This increase is less evident in the elderly, \nmainly in cases of serum TSH values above 10 mIU/L. Lower mortality rate in a \ncohort of the oldest olds (>85 y) has been reported.\nCONCLUSIONS: sHT in older people should be not regarded as a unique condition, \nand moderately old patients (aged <70-75 y) could be considered clinically \nsimilar to the adult population, albeit with a higher optimal TSH target value. \nConversely, the oldest old subjects should be carefully followed with a \nwait-and-see strategy, generally avoiding hormonal treatment. The decision to \ntreat elderly people is still an unresolved clinical challenge--first, due to a \nlack of appropriately powered randomized controlled trials of L-T4 in sHT \npatients, examining cardiovascular hard endpoints in various classes of age; and \nsecond, because of the negative effects of possible overtreatment.",
"CONTEXT: Although the negative impact of subclinical hypothyroidism (sHT) in \nterms of cardiovascular risk in young adults is mostly acknowledged it remains \nto be established in the elderly, especially in the oldest old.\nEVIDENCE ACQUISITION: We searched Medline for reports published with the \nfollowing search words: hypothyroidism, sHT, ageing, elderly, L-thyroxin, \nthyroid, guidelines, treatment, quality of life, cardiovascular risk, heart \nfailure (HF), ischemic heart disease (IHD), endothelial dysfunction. The search \nwas restricted to reports published in English since 1980, but some reports \npublished before 1980 were also incorporated. We supplemented the search with \nrecords from personal files and references of relevant articles and textbooks. \nParameters analyzed included epidemiology of sHT and thyroid failure the effect \nof thyroid hormone on ageing process and cardiovascular function as well as the \npotential benefits of L-thyroxin therapy on quality of life, HF progression and \nevents.\nEVIDENCE SYNTHESIS: TSH levels increase with age, even in older patients without \nthyroid disease, in whom higher TSH value might favor longevity; better quality \nof life and lower IHD mortality in the oldest old population has been reported \nyet. However, at odds with the relationship between sHT and IHD risk and \nmortality, which shows a clear age dependent feature, vanishing in the last \ndecades of life, the detrimental effect of sHT on HF progression and events \nremains evident also in older patients, although no data are available in the \noldest old population.\nCONCLUSIONS: The lack of specific randomized trials enrolling either old or very \nold subjects, aimed at evaluate the efficacy of hormonal replacement on overall \nsurvival and cardiovascular risk reduction along with the negative effects of \npossible over-treatment, makes the decision to treat older people a still \nunresolved clinical challenge. Moreover, the possibility that restoring \neuthyroidism may be harmful in the elderly should be always taken into account.",
"There is ongoing debate whether subclinical hypothyroidism may exert deleterious \neffects on the cardiovascular system with the consequences of increased \nmorbidity and mortality. To elucidate this problem many epidemiological studies \nhave been performed, however, these studies have not given an unambiguous answer \nso far. Many confounding elements are influencing the evaluation of these \ninvestigations which must be taken into consideration. Authors argue for the use \nof age specific reference limits for TSH (especially in older age, where TSH \nlevel is often shifted to a higher level) to avoid significant misclassification \nof patients with abnormal TSH who may or may not have thyroid dysfunction. \nFurthermore, recent studies have shown that subclinical hypothyroidism is \nassociated with increased ischemic heart disease risk, mainly in individuals \nunder the age of 65 years. In the future, well designed prospective randomized \nstudies with age stratified groups and vascular events as the primary endpoint \nare required and it is anticipated that these studies will give the proper \nanswer whether early substitution therapy with thyroxin will be able to reverse \nthe ischemic heart disease risk in affected patients.",
"BACKGROUND: Subclinical hypothyroidism is defined as an elevated serum \nthyroid-stimulating hormone (TSH) level with normal free thyroid hormones \nvalues. The prevalence of subclinical hypothyroidism is 4% to 8% in the general \npopulation, and up to 15% to 18% in women who are over 60 years of age. There is \nconsiderable controversy regarding the morbidity, the clinical significance of \nsubclinical hypothyroidism and if these patients should be treated.\nOBJECTIVES: To assess the effects of thyroid hormone replacement for subclinical \nhypothyroidism.\nSEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE and LILACS. \nOngoing trials databases, reference lists and abstracts of congresses were \nscrutinized as well.\nSELECTION CRITERIA: All studies had to be randomised controlled trials comparing \nthyroid hormone replacement with placebo or no treatment in adults with \nsubclinical hypothyroidism. Minimum duration of follow-up was one month.\nDATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality \nand extracted data. We contacted study authors for missing or additional \ninformation.\nMAIN RESULTS: Twelve trials of six to 14 months duration involving 350 people \nwere included. Eleven trials investigated levothyroxine replacement with \nplacebo, one study compared levothyroxine replacement with no treatment. We did \nnot identify any trial that assessed (cardiovascular) mortality or morbidity. \nSeven studies evaluated symptoms, mood and quality of life with no statistically \nsignificant improvement. One study showed a statistically significant \nimprovement in cognitive function. Six studies assessed serum lipids, there was \na trend for reduction in some parameters following levothyroxine replacement. \nSome echocardiographic parameters improved after levothyroxine replacement \ntherapy, like myocardial relaxation, as indicated by a significant prolongation \nof the isovolumic relaxation time as well as diastolic dysfunction. Only four \nstudies reported adverse events with no statistically significant differences \nbetween groups.\nAUTHORS' CONCLUSIONS: In current RCTs, levothyroxine replacement therapy for \nsubclinical hypothyroidism did not result in improved survival or decreased \ncardiovascular morbidity. Data on health-related quality of life and symptoms \ndid not demonstrate significant differences between intervention groups. Some \nevidence indicates that levothyroxine replacement improves some parameters of \nlipid profiles and left ventricular function.",
"No consensus exists whether subclinical thyroid disease should be treated or \njust observed. Untreated overt thyroid disease is associated with increased risk \nof cardiovascular disease, and this study was conducted to assess the risk of \ncardiovascular events in subclinical thyroid disease. The population-based \nprospective study was conducted in Denmark. A total of 609 subjects from general \npractice aged 50 years or above with normal left ventricular function were \nexamined. During a median of 5 years of follow-up, major cardiovascular events \nwere documented. In subjects with abnormal TSH at baseline, information about \npotential thyroid treatment during follow-up was obtained from case reports and \nmailings. At baseline, 549 (90.7%) were euthyroid (TSH 0.40-4.00 mU/l), 31 \n(5.1%) were subclinical hypothyroid (TSH>4.00 mU/l), and 25 (4.1%) were \nsubclinical hyperthyroid (TSH<0.40 mU/l). 1 overt hyperthyroid and 3 overt \nhypothyroid participants were excluded from the analyses. At baseline, the \nlevels of NT-proBNP were inversely associated with the levels of TSH; the lower \nthe levels of TSH, the higher the NT-proBNP concentration. During follow-up, 88 \nparticipants died, 81 had a major cardiovascular event, and 28 had a stroke. The \nincidence of stroke was increased among subjects with subclinical \nhyperthyroidism, HR 3.39 (95% CI 1.15-10.00, p=0.027) after adjusting for sex, \nage, and atrial fibrillation. Subclinical hypothyroidism was not related with \nany of the outcome measurements. Subclinical hyperthyroidism seems to be a risk \nfactor of developing major cardiovascular events, especially stroke in older \nadults from the general population with normal left ventricular function.",
"AIM: To study the time course changes in the parameters of endothelial \ndysfunction in patients with type 2 diabetes mellitus (DM) and subclinical \nhypothyroidism (SH) in the natural course of SH and during replacement therapy.\nSUBJECTS AND METHODS: All the examined patients were divided into 2 groups: 1) \n67 patients received replacement therapy with euthyrox in a dose of 25 to 100 \nmicrog/day; 2) 60 patients were followed up.\nRESULTS: At the moment of study inclusion, there was a close direct correlation \nbetween the levels of cholesterol and the aggregate intima-media thickness (IMT) \n(r = 0.7) and between IMT and the levels of sICAM-1 (r = 0.71) and sVCAM-1 (r = \n0.8). In the dynamics of the disease (following a year), the above correlations \nbecame weaker due to the performed treatment. A weak positive correlation was \nfound between the aggregate IMT and the levels of sICAM-1 (r = 0.2) and sVCAM-1 \n(r = 0.3).\nCONCLUSION: In patients with type 2 DM, the presence of SH serves as an \nadditional risk factor for endothelial dysfunction. Replacement therapy will be \nable to considerably retard the progression of the disease and to reduce the \nincidence of vascular events.",
"Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid \nstimulating hormone (TSH) with normal levels of free thyroid hormones, is common \nin adults, especially in women over 60 years of age. Among individuals with this \ncondition, up to two-thirds have serum TSH levels between 5-10 mU/L and thyroid \nautoantibodies; almost half of them may progress to overt thyroid failure, the \nannual percent risk increasing with serum TSH level. There is evidence that \nelevated TSH levels in patients with SH do not reflect pituitary compensation to \nmaintain euthyroidism, but a mild tissue hypothyroidism sensu strictu. When \nlasting more than 6-12 months, SH may be associated with an atherogenic lipid \nprofile, a hypercoagulable state, a subtle cardiac defect with mainly diastolic \ndysfunction, impaired vascular function, and reduced submaximal exercise \ncapacity. The deviation from normality usually increases with serum TSH level \n('dosage effect' phenomenon). Restoration of euthyroidism by levothyroxine (LT4) \ntreatment may correct the lipid profile and cardiac abnormalities, especially in \npatients with an initially higher deviation from normality and higher serum TSH \nlevels. Importantly, a strong association between SH and atherosclerotic \ncardiovascular disease, independent of the traditional risk factors, has been \nrecently reported in a large cross-sectional survey (the Rotterdam Study). \nHowever, whether SH confers a high risk for cardiovascular disease, and whether \nLT4 therapy has a long-term benefit that clearly outweighs the risks of \noverzealous treatment in these individuals, remain topics of controversy. \nTherefore, until randomized, controlled, prospective, and adequately powered \ntrials provide unequivocal answers to these critical questions, it is advisable \nto prescribe LT4 therapy on a case-by-case basis, taking into account the risk \nof progressive thyroid failure and the risk of cardiovascular events.",
"BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic \nheart disease (IHD); however, it is unknown whether treatment of SCH with \nlevothyroxine sodium will reduce the risk of IHD. The aim of this study was to \ninvestigate the association between levothyroxine treatment of SCH with IHD \nmorbidity and mortality. METHODS We used the United Kingdom General Practitioner \nResearch Database to identify individuals with new SCH (serum thyrotropin levels \nof 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with \noutcomes analyzed until March 2009. All analyses were performed separately for \nyounger (40-70 years) and older (>70 years) individuals. Hazard ratios (HRs) \nfor IHD events (fatal and nonfatal) were calculated after adjustment for \nconventional IHD risk factors, baseline serum thyrotropin levels, and initiation \nof levothyroxine treatment as a time-dependent covariate. RESULTS Subclinical \nhypothyroidism was identified in 3093 younger and 1642 older individuals. For a \nmedian follow-up period of 7.6 years, 52.8% and 49.9% of younger and older \npatients with SCH were treated with levothyroxine, respectively. There were 68 \nincident IHD events in 1634 younger patients treated with levothyroxine (4.2%) \nvs 97 IHD events in 1459 untreated individuals (6.6%) (multivariate-adjusted HR, \n0.61; 95% CI, 0.39-0.95). In contrast, in the older group there were 104 events \nin 819 treated patients (12.7%) vs 88 events in 823 untreated individuals \n(10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with \nlevothyroxine was associated with fewer IHD events in younger individuals, but \nthis was not evident in older people. An appropriately powered randomized \ncontrolled trial of levothyroxine in SCH examining vascular outcomes is now \nwarranted.",
"Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating \nhormone (TSH) level in the face of normal free thyroid hormone values. The \noverall prevalence of subclinical hypothyroidism is 4-10% in the general \npopulation and up to 20% in women aged >60 years. The potential benefits and \nrisks of therapy for subclinical hypothyroidism have been debated for 2 decades, \nand a consensus is still lacking. Besides avoiding the progression to overt \nhypothyroidism, the decision to treat patients with subclinical hypothyroidism \nrelies mainly on the risk of metabolic and cardiovascular alterations. \nSubclinical hypothyroidism causes changes in cardiovascular function similar to, \nbut less marked than, those occurring in patients with overt hypothyroidism. \nDiastolic dysfunction both at rest and upon effort is the most consistent \ncardiac abnormality in patients with subclinical hypothyroidism, and also in \nthose with slightly elevated TSH levels (>6 mIU/L). Moreover, mild thyroid \nfailure may increase diastolic blood pressure as a result of increased systemic \nvascular resistance. Restoration of euthyroidism by levothyroxine replacement is \ngenerally able to improve all these abnormalities. Early clinical and autopsy \nstudies had suggested an association between subclinical hypothyroidism and \ncoronary heart disease, which has been subsequently confirmed by some, but not \nall, large cross-sectional and prospective studies. Altered coagulation \nparameters, elevated lipoprotein (a) levels, and low-grade chronic inflammation \nare regarded to coalesce with the hypercholesterolemia of untreated patients \nwith subclinical hypothyroidism to enhance the ischemic cardiovascular risk. \nAlthough a consensus is still lacking, the strongest evidence for a beneficial \neffect of levothyroxine replacement on markers of cardiovascular risk is the \nsubstantial demonstration that restoration of euthyroidism can lower both total \nand low-density lipoprotein-cholesterol levels in most patients with subclinical \nhypothyroidism. However, the actual effectiveness of thyroid hormone \nsubstitution in reducing the risk of cardiovascular events remains to be \nelucidated. In conclusion, the multiplicity and the possible reversibility of \nsubclinical hypothyroidism-associated cardiovascular abnormalities suggest that \nthe decision to treat a patient should depend on the presence of risk factors, \nrather than on a TSH threshold. On the other hand, levothyroxine replacement \ntherapy can always be discontinued if there is no apparent benefit. \nLevothyroxine replacement therapy is usually safe providing that excessive \nadministration is avoided by monitoring serum TSH levels. However, the \npossibility that restoring euthyroidism may be harmful in the oldest of the \nelderly population of hypothyroid patients has been recently raised, and should \nbe taken into account in making the decision to treat patients with subclinical \nhypothyroidism who are aged >85 years."
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train
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is there an increase in ultrasound comets after intense exercise?
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yesno
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Strenuous exercise and exercise perfomed in extreme conditions provoke increase in interstitial pulmonary water content as shown by the increased number of ultrasuond comets
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yes
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[
"High altitude pulmonary edema is a life-threatening condition that remains a \nconcern for climbers and clinicians alike. Within the last decade, studies have \nshown ultrasonography to be valuable in the accurate diagnosis of a variety of \nlung pathologies, including cardiogenic pulmonary edema, pleural effusion, \npneumothorax, and lung consolidation. Recently, studies conducted in remote \nareas have demonstrated that ultrasound lung comets can be used as a measure of \nsubacute pulmonary edema and high altitude pulmonary edema in climbers ascending \nto altitude. This clinical review article provides an overview of lung \nultrasonography and its relevance as a diagnostic aid to respiratory pathology. \nIn addition, we describe a standardized technique for identifying ultrasound \nlung comets and its utility in recognizing the presence of extravascular lung \nwater, as well as the results of studies that have used this approach at sea \nlevel and high altitude.",
"There are several pieces of evidence showing occurrence of pulmonary edema (PE) \nin healthy subjects in extreme conditions consisting of extreme psychophysical \ndemand in normal environment and psychophysical performances in extreme \nenvironment. A combination of different mechanisms, such as mechanical, \nhemodynamic, biochemical, and hypoxemic ones, may underlie PE leading to an \nincrease in lung vascular hydrostatic pressure and lung vascular permeability \nand/or a downregulation of the alveolar fluid reabsorption pathways. PE can be \nfunctionally detected by closing volume measurement and lung diffusing capacity \ntest to different gases or directly visualized by multiple imaging techniques. \nAmong them chest ultrasonography can detect and quantify the extravascular lung \nwater, creating \"comet-tail\" ultrasound artefacts (ULCs) from water-thickened \npulmonary interlobular septa. In this paper the physiopathological mechanisms of \nPE, the functional and imaging techniques applied to detect and quantify the \nphenomenon, and three models of extreme conditions, that is, ironman athletes, \nclimbers and breath-hold divers, are described.",
"An increasing number of recreational self-contained underwater breathing \napparatus (SCUBA) divers use trimix of oxygen, helium, and nitrogen for dives \ndeeper than 60 m of sea water. Although it was seldom linked to the development \nof pulmonary edema, whether SCUBA diving affects the extravascular lung water \n(EVLW) accumulation is largely unexplored.\nMETHODS: Seven divers performed six dives on consecutive days using compressed \ngas mixture of oxygen, helium, and nitrogen (trimix), with diving depths ranging \nfrom 55 to 80 m. The echocardiographic parameters (bubble grade, lung comets, \nmean pulmonary arterial pressure (PAP), and left ventricular function) and the \nblood levels of the N-terminal part of pro-brain natriuretic peptide (NT-proBNP) \nwere assessed before and after each dive.\nRESULTS: Venous gas bubbling was detected after each dive with mean probability \nof decompression sickness ranging from 1.77% to 3.12%. After each dive, several \nultrasonographically detected lung comets rose significantly, which was \nparalleled by increased pulmonary artery pressure (PAP) and decreased left \nventricular contractility (reduced ejection fraction at higher end-systolic and \nend-diastolic volumes) as well as the elevated NT-proBNP. The number of \nultrasound lung comets and mean PAP did not return to baseline values after each \ndive.\nCONCLUSIONS: This is the first report that asymptomatic SCUBA dives are \nassociated with accumulation of EVLW with concomitant increase in PAP, \ndiminished left ventricular contractility, and increased release of NT-proBNP, \nsuggesting a significant cardiopulmonary strain. EVLW and PAP did not return to \nbaseline during repetitive dives, indicating possible cumulative effect with \nincreasing the risk for pulmonary edema.",
"BACKGROUND: Data regarding the effect of high altitude on heart function are \nsparse and conflicting. We aimed to assess the right and left ventricular \nresponses to altitude-induced hypoxia and the occurrence of subclinical \npulmonary edema.\nMETHODS: Echocardiography was performed according to protocol on 14 subjects \nparticipating in an expedition in Nepal, at 3 altitude levels: Montreal (30 m), \nNamche Bazaar (3450 m), and Chukkung (4730 m). Systematic lung ultrasound was \nperformed to detect ultrasound lung comets.\nRESULTS: Pulmonary artery systolic pressure increased in all subjects between \nMontreal and Chukkung (mean 27.4 ± 5.4 mm Hg vs. 39.3 ± 7.7 mm Hg; P < 0.001). \nRight ventricular (RV) myocardial performance index (MPI) increased \nsignificantly (0.32 ± 0.08 at 30 m vs. 0.41 ± 0.10 at 4730 m; P = 0.046). A \ntrend toward deteriorated RV free wall longitudinal strain was observed between \nMontreal and Chukkung (-25.9 [5.3%] vs. -21.9 [6.4%]; P = 0.092). The left \nventricular early diastolic inflow velocity/atrial mitral inflow velocity and \nearly diastolic inflow velocity/mean of the maximal early diastolic mitral \nannulus tissue doppler velocities ratios remained unchanged. At 4730 m, \nultrasound lung comets were seen in all subjects except 1. None had clinical \ncriteria for high-altitude pulmonary edema (HAPE). All altered parameters \nnormalized after return to sea level.\nCONCLUSION: Subclinical HAPE is frequent in healthy lowlander climbers. This is \nthe first study to document a trend towards decreased RV free wall strain and \nMPI increment at high altitude. Whether rising RV MPI is a physiologic adaptive \nmechanism to hypoxia or a pathologic response identifying HAPE-susceptible \nsubjects needs further study.",
"Ultrasound lung comet images (ULC) are useful for the noninvasive assessment of \nextravascular lung water (EVLW). We investigated the modification of EVLW, its \nrelation to indices of left ventricular systolic and diastolic function, and \nnoninvasively determined pulmonary capillary wedge pressure (PCWP) (PCWP = 1.24 \nratio of early diastolic mitral inflow velocity to early diastolic velocity of \nthe mitral annulus [E/Em] + 1.9) at rest and its variation during exercise \nechocardiography. A total of 72 patients (mean age 66.4 +/- 8.4 years) with mean \nejection fraction of 41.2 +/- 14.4% underwent symptoms-limited exercise \nechocardiography. The sum of the ULC yielded a score of EVLW. The ULC increased \nsignificantly from baseline to postexercise (5.9 +/- 14.9 vs 11 +/- 20.7, P = \n.0001). Positive linear correlations were found between baseline ULC score and \nbaseline ejection fraction (r = -0.37, P = .002), systolic pulmonary artery \npressure (r = 0.69, P = .0001), E/Em (r = 0.70, P = .0001), and estimated PCWP \n(r = 0.69, P = .0001). The variation between postexercise and baseline ULC score \ncorrelated significantly with the variation between peak stress and rest PCWP (r \n= 0.62, P = .0001), systolic pulmonary artery pressure (r = 0.44, P = .0001), \nwall-motion score index (r = 0.30, P = .01), and peak stress E/Em (r = 0.71, P = \n.0001), whereas no significant correlations were found between variations of ULC \nscore and ejection fraction. This study shows that ULC represents a simple way \nto assess the presence of excess EVLW. Increased EVLW is associated with \nestimated PCWP and indices of left ventricular systolic and diastolic \ndysfunction. The additional exercise-induced increase of PCWP, the worsening of \nleft ventricular diastolic function, and extensive wall-motion abnormalities \ncorrelate with variations of EVLW.",
"Can ultrasound be of any help in the diagnosis of alveolar-interstitial \nsyndrome? In a prospective study, we examined 250 consecutive patients in a \nmedical intensive care unit: 121 patients with radiologic alveolar-interstitial \nsyndrome (disseminated to the whole lung, n = 92; localized, n = 29) and 129 \npatients without radiologic evidence of alveolar-interstitial syndrome. The \nantero-lateral chest wall was examined using ultrasound. The ultrasonic feature \nof multiple comet-tail artifacts fanning out from the lung surface was \ninvestigated. This pattern was present all over the lung surface in 86 of 92 \npatients with diffuse alveolar-interstitial syndrome (sensitivity of 93.4%). It \nwas absent or confined to the last lateral intercostal space in 120 of 129 \npatients with normal chest X-ray (specificity of 93.0%). Tomodensitometric \ncorrelations showed that the thickened sub-pleural interlobular septa, as well \nas ground-glass areas, two lesions present in acute pulmonary edema, were \nassociated with the presence of the comet-tail artifact. In conclusion, presence \nof the comet-tail artifact allowed diagnosis of alveolar-interstitial syndrome.",
"Pulmonary edema has been reported in breath-hold divers during fish-catching \ndiving activity. The present study was designed to detect possible increases in \nextravascular lung water (EVLW) in underwater fishermen after a competition. \nThirty healthy subjects were studied. They participated in two different 5-h \nfish-catching diving competitions: one organized in the winter (10 subjects) and \none organized in the autumn (20 subjects). A questionnaire was used to record \nunderwater activity and note respiratory problems. An increase in EVLW was \ninvestigated from the detection of ultrasound lung comets (ULC) by chest \nultrasonography. Complementary investigations included echocardiography and \npulmonary function testing. An increase in EVLW was detected in three out of 30 \nunderwater fishermen after the competition. No signs of cardiovascular \ndysfunction were found in the entire population and in divers with an increase \nin the ULC score. Two divers with raised ULC presented respiratory disorders \nsuch as cough or shortness of breath. Impairment in spirometric parameters was \nrecorded in these subjects. An increase in EVLW could be observed after a \nfish-catching diving competition in three out of 30 underwater fishermen. In two \nsubjects, it was related to respiratory disorders and impairment in pulmonary \nflow.",
"The \"comet-tail\" is an ultrasound sign detectable with ultrasound chest \ninstruments; this sign consists of multiple comet-tails fanning out from the \nlung surface. They originate from water-thickened interlobular septa and would \nbe ideal for nonradiologic bedside assessment of extravascular lung water. To \nassess the feasibility and value of ultrasonic comet signs, we studied 121 \nconsecutive hospitalized patients (43 women and 78 men; aged 67 +/- 12 years) \nadmitted to our combined cardiology-pneumology department (including cardiac \nintensive care unit); the study was conducted with commercially available \nechocardiographic systems including a portable unit. Transducer frequencies \n(range 2.5 to 3.5 MHz) were used. In each patient, the right and left chest was \nscanned by examining predefined locations in multiple intercostal spaces. \nExaminers blinded to clinical diagnoses noted the presence and numbers of lung \ncomets at each examining site. A patient lung comet score was obtained by \nsumming the number of comets in each of the scanning spaces. Within a few \nminutes, patients underwent chest x-ray, with specific assessment of \nextravascular lung water score by 2 pneumologist-radiologists blinded to \nclinical and echo findings. The chest ultrasound scan was obtained in all \npatients (feasibility 100%). The imaging time per examination was always <3 \nminutes. There was a linear correlation between echocardiographic comet score \nand radiologic lung water score (r = 0.78, p <0.01). Intrapatient variations (n \n= 15) showed an even stronger correlation between changes in echocardiographic \nlung comet and radiologic lung water scores (r = 0.89; p <0.01). In 121 \nconsecutive hospitalized patients, we found a linear correlation between \nechocardiographic comet scores and radiologic extravascular lung water scores. \nThus, the comet-tail is a simple, non-time-consuming, and reasonably accurate \nchest ultrasound sign of extravascular lung water that can be obtained at \nbedside (also with portable echocardiographic equipment) and is not restricted \nby cardiac acoustic window limitations.",
"BACKGROUND: Ultrasound lung comets (ULCs) detected by chest sonography are a \nsimple, noninvasive, semiquantitative sign of increased extravascular lung \nwater. Pulmonary edema may occur in elite apnea divers, possibly triggered by \ncentralization of blood flow from the periphery to pulmonary vessels. We \nassessed the prevalence of ULCs in top-level breath-hold divers after immersion.\nMETHODS: We evaluated 31 consecutive healthy, top-level, breath-hold divers (10 \nfemale, 21 male; age 31 +/- 5 years) participating in a yearly international \napnea diving contest in Sharm-el-Sheik, Egypt, November 1 to 3, 2007. We \nperformed chest and cardiac sonography with a transthoracic probe (2.5-3.5 MHz, \nEsaote Mylab) in all divers, both on the day before and 10 +/- 9 minutes after \nimmersion. In a subset of 4 divers, chest scan was also repeated at 24 hours \nafter immersion. ULCs were evaluated on the anterior and posterior chest at 61 \npredefined scanning sites. An independent sonographer, blind to both patient \nidentity and status (pre- or post-diving), scored ULCs.\nRESULTS: Diving depth ranged from 31 to 112 m. Duration of immersion ranged from \n120 to 225 seconds. The ULC score was 0.5 +/- 1.5 at baseline and 13 +/- 21 \nafter diving (P = .012). At individual patient analysis, ULCs appeared in 14 \nathletes (45%) after diving. Of these 14 athletes, 4 were asymptomatic, 6 showed \naspecific symptoms with transient loss of motor control (\"Samba\"), 2 had \npalpitations with frequent premature ventricular contractions, and 2 had \npersistent cough with hemoptysis and pulmonary crackles. In a subset of 4 \nathletes with post-diving ULCs in whom late follow-up study also was available, \nchest sonography findings fully normalized at 24 hours of follow-up.\nCONCLUSION: In top-level breath-hold divers, chest sonography frequently reveals \nan increased number of ULCs after immersion, indicating a relatively high \nprevalence of (often subclinical) reversible extravascular lung water \naccumulation.",
"Assessment of extravascular lung water is a challenging task for the clinical \ncardiologist and an elusive target for the echocardiographer. Today chest x-ray \nis considered the best way to assess extravascular lung water objectively, but \nthis requires radiology facilities and specific reading expertise, uses ionizing \nenergy, and poses a significant logistic burden. Recently, a new method was \ndeveloped using echocardiography (with cardiac probes) of the lung. An increase \nin extravascular lung water-as assessed independently by chest computed \ntomography, chest x-ray, and thermodilution techniques-is mirrored by appearance \nof ultrasound lung comets (ULCs). ULCs consist of multiple comet tails \noriginating from water-thickened interlobular septa and fanning out from the \nlung surface. The technique requires ultrasound scanning of the anterior right \nand left chest, from the second to the fifth intercostal space. It is simple \n(with a learning curve of < 10 examinations) and fast to perform (requiring < 3 \nminutes). ULC assessment is independent of the cardiac acoustic window, because \nthe lung on the anterior chest is scanned. It requires very basic 2-D technology \nimaging, even without a second harmonic or Doppler. ULCs probably represent an \nultrasonic equivalent of radiologic Kerley B-lines. On still-frame assessment, \ncardiogenic watery comets can be difficult to distinguish from pneumogenic \nfibrotic comets, although the latter are usually more localized and are not \ndissolved by an acute diuretic challenge. Functionally, ULCs are a sign of \ndistress of the alveolar-capillary membrane, often associated with reduced \nejection fraction and increased pulmonary wedge pressure. The ULC sign is \nquantitative, reproducible, and ideally suited to complement conventional \nechocardiography in the evaluation of heart failure patients in the emergency \ndepartment (for the differential diagnosis of dyspnea), in-hospital evaluation \n(for tailoring diuretic therapy), home care (with portable ultrasound), and \nstress echocardiography lab (as a sign of acute pulmonary congestion during \nstress). In conclusion, ULCs represent a useful, practical, and appealingly \nsimple way to image directly extravascular lung water.",
"Whether prolonged strenuous exercise performed by athletes at sea level can \nproduce interstitial pulmonary edema is under debate. Chest sonography allows to \nestimate extravascular lung water, creating ultrasound lung comet-tail (ULC) \nartifacts. The aim of the study was to determine whether pulmonary water content \nincreases in Ironmen (n = 31) during race at sea level and its correlation with \ncardiopulmonary function and systemic proinflammatory and cardiac biohumoral \nmarkers. A multiple factor analysis approach was used to determine the relations \nbetween systemic modifications and ULCs by assessing correlations among \nvariables and groups of variables showing significant pre-post changes. All \nathletes were asymptomatic for cough and dyspnea at rest and after the race. \nImmediately after the race, a score of more than five comet tail artifacts, the \nthreshold for a significant detection, was present in 23 athletes (74%; 16.3 ± \n11.2; P < 0.01 ULC after the race vs. rest) but decreased 12 h after the end of \nthe race (13 athletes; 42%; 6.3 ± 8.0; P < 0.01 vs. soon after the race). \nMultiple factor analysis showed significant correlations between ULCs and \ncardiac-related variables and NH(2)-terminal pro-brain natriuretic peptide. \nHealthy athletes developed subclinical increase in pulmonary water content \nimmediately after an Ironman race at sea level, as shown by the increased number \nof ULCs related to cardiac changes occurring during exercise. Hemodynamic \nchanges are one of several potential factors contributing to the mechanisms of \nULCs.",
"The purpose of the study was to analyze the ultrasound lung comets (ULCs) \nvariation, which are a sign of extra-vascular lung water. Forty-two healthy \nindividuals performed breath-hold diving in different conditions: dynamic \nsurface apnea; deep variable-weight apnea and shallow, face immersed without \neffort (static maximal and non-maximal). The number of ULCs was evaluated by \nmeans of an ultrasound scan of the chest, before and after breath-hold diving \nsessions. The ULC score increased significantly from baseline after dynamic \nsurface apnea (p = 0.0068), after deep breath-hold sessions (p = 0.0018), and \nafter static maximal apnea (p = 0.031). There was no statistically significant \ndifference between the average increase of ULC scores after dynamic surface \napnea and deep breath-hold diving. We, therefore, postulate that extravascular \nlung water accumulation may be due to other factors than (deep) immersion alone, \nbecause it occurs during dynamic surface apnea as well. Three mechanisms may be \nresponsible for this. First, the immersion-induced hydrostatic pressure gradient \napplied on the body causes a shift of peripheral venous blood towards the \nthorax. Second, the blood pooling effect found during the diving response \nRedistributes blood to the pulmonary vascular bed. Third, it is possible that \nthe intense involuntary diaphragmatic contractions occurring during the \n\"struggle phase\" of the breath-hold can also produce a blood shift from the \npulmonary capillaries to the pulmonary alveoli. A combination of these factors \nmay explain the observed increase in ULC scores in deep, shallow maximal and \nshallow dynamic apneas, whereas shallow non-maximal apneas seem to be not \"ULC \nprovoking\".",
"Recently, an increase in extravascular lung water (EVLW) accumulation with \ndiminished left ventricular contractility within 60 min after SCUBA diving was \nreported. We have observed previously that diving was associated with reduced \ndiffusing lung capacity for carbon monoxide (DLCO) and arterial oxygen pressure \nfor up to 60-80 min postdive. Here we investigated whether increased EVLW \npersists 2-3h after successive deep dives in a group of seven male divers. The \nechocardiographic indices of pulmonary water accumulation (ultrasound lung \ncomets (ULC)) and left ventricular function, respiratory functional measurements \nand arterial oxygen saturation (SaO(2)) were assessed 2-3h post diving, while \nvenous gas bubbles (VGB) and the blood levels of NT-proBNP and proANP were \nanalyzed 40 min after surfacing. Spirometry values, flow-volume, DLCO, SaO(2) \nand ULC were unchanged after each dive, except for significant increase in ULC \nafter the second dive. Left ventricular function was reduced, while NT-proBNP \nand proANP levels were significantly elevated after majority of dives, \nsuggesting a cardiac strain."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D020552', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014463', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016477', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015444', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D056352']
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train
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what is the effect of Bisphenol A in the body?
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summary
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Bisphenol A (BPA) is an endocrine-disruptor compound that exhibits estrogenic activit
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Bisphenol A (BPA) is an endocrine-disruptor compound that exhibits estrogenic activit
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[
"Inflammatory bowel disease is a complex collection of disorders. Microbial \ndysbiosis as well as exposure to toxins including xenoestrogens are thought to \nbe risk factors for inflammatory bowel disease development and relapse. \nBisphenol-A has been shown to exert estrogenic activity in the colon and alter \nintestinal function, but the role that xenoestrogens, such as bisphenol-A , play \nin colonic inflammation has been previously described but with conflicting \nresults. We investigated the ability of bisphenol-A to exacerbate colonic \ninflammation and alter microbiota metabolites derived from aromatic amino acids \nin an acute dextran sulfate sodium-induced colitis model. Female C57BL/6 mice \nwere ovariectomized and exposed to bisphenol-A daily for 15 days. Disease \nactivity measures include body weight, fecal consistency, and rectal bleeding. \nColons were scored for inflammation, injury, and nodularity. Alterations in the \nlevels of microbiota metabolites derived from aromatic amino acids known to \nreflect phenotypic changes in the gut microbiome were analyzed. Bisphenol-A \nexposure increased mortality and worsened disease activity as well as \ninflammation and nodularity scores in the middle colon region following dextran \nsulfate sodium exposure. Unique patterns of metabolites were associated with \nbisphenol-A consumption. Regardless of dextran sulfate sodium treatment, \nbisphenol-A reduced levels of tryptophan and several metabolites associated with \ndecreased inflammation in the colon. This is the first study to show that \nbisphenol-A treatment alone can reduce microbiota metabolites derived from \naromatic amino acids in the colon which may be associated with increased colonic \ninflammation and inflammatory bowel disease. Impact statement As rates of \ninflammatory bowel disease rise, discovery of the mechanisms related to the \ndevelopment of these conditions is important. Environmental exposure is \nhypothesized to play a role in etiology of the disease, as are alterations in \nthe gut microbiome and the metabolites they produce. This study is the first to \nshow that bisphenol-A alone alters tryptophan and microbiota metabolites derived \nfrom aromatic amino acids in a manner consistent with autoimmune diseases, \nspecifically inflammatory bowel diseases, regardless of dextran sulfate sodium \ntreatment. These findings indicate a potential mechanism by which bisphenol-A \nnegatively affects gut physiology to exacerbate inflammation.",
"BACKGROUND: Bisphenol A (BPA) is a well-known endocrine disruptor that affects \nmale fertility. However, the main biological events through which BPA affects \nspermatogenesis remain to be identified.\nMETHODS: Adult male mice were treated by feeding with drinking water containing \nBPA (0.2 μg/ml, 20 μg/ml, 200 μg/ml, respectively) for two months. Testes were \ncollected for protein extraction or for immunohistochemical analysis. Epididymal \nspermatozoa were collected for sperm quality evaluation and male fertility assay \nby in vitro fertility (IVF). Serums were collected for detection of testosterone \nlevels. Proteins associated with germ cell proliferation, meiosis, blood-testis \nbarrier, and steroidogenesis production were examined in BPA-treated and control \nmice testes. CCK8 assay was used to detect the effect of BPA on the \nproliferation of GC-1 and GC-2 cells.\nRESULTS: The BPA-treated mice were characterized by decreased sperm quality, \nserum testosterone levels and, sub-fertile phenotype characterizing with low \npregnancy rates and reduced fertilization efficiency. In lower BPA (0.2 μg/ml) \ntreatment, PCNA and PLZF were down-expressed that indicated impaired germ cell \nproliferation. SYCP3 was down-expressed in BPA-treated mice, but expressions of \nother proteins associated with meiosis and blood-testis barrier were not \nsignificantly altered. CYP11A1 and HSD3B1 were down-expressed in BPA-treated \nmice that demonstrated reduced steroidogenesis activity. BPA has a \nconcentration-dependent inhibition effect on the proliferation of GC-1 and \nGC-2 cells. Conclusively, low doses BPA exposure reduced mice sperm quality \nmainly by impairing germ cell proliferation, leading to reduced male fertility. \nThe study would provide relevant information for investigation on molecular \nmechanisms and protective strategy on male production.",
"Bisphenol A is a widely used industrial chemical with many potential sources of \nhuman exposure. Bisphenol A is a weak estrogen and has been implicated as an \n\"endocrine disruptor\". This term is used for a variety of chemicals encountered \nin the environment which have estrogenic activity. It has been postulated that \nhuman exposure to these chemicals may elicit unwanted estrogenic effects in \nhumans such as reduced fertility, altered development and cancer. Up to now the \nbody burden of bisphenol A in humans is unknown. Therefore, we investigated the \nmetabolism and toxicokinetics of bisphenol A in humans exposed to low doses \nsince systemic bioavailability has a major influence on possible estrogenic \neffects in vivo. Human subjects (three males and three females, and four males \nfor detailed description of blood kinetics) were administered d(16)-bisphenol A \n(5 mg). Blood and urine samples were taken in intervals (up to 96 h), \nmetabolites formed were identified by GC/MS and LC-MS/MS and quantified by \nGC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of \nd(16)-bisphenol A detected in urine and blood samples, and concentrations of \nfree d(16)-bisphenol A were below the limit of detection both in urine (6 nM) \nand blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human \nblood and excreted with urine with terminal half-lives of less than 6 h; the \napplied doses were completely recovered in urine as d(16)-bisphenol A \nglucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide \n(approximately 800 nM) were measured 80 min after oral administration of \nd(16)-bisphenol A (5 mg). The obtained data indicate major species differences \nin the disposition of bisphenol A. Enterohepatic circulation of bisphenol A \nglucuronide in rats results in a slow rate of excretion, whereas bisphenol A is \nrapidly conjugated and excreted by humans due to the absence of enterohepatic \ncirculation. The efficient glucuronidation of bisphenol A and the rapid \nexcretion of the formed glucuronide result in a low body burden of the \nestrogenic bisphenol A in humans following oral absorption of low doses.",
"Bisphenol A, one of the industrial chemicals used in plastics and in the coating \nof dishes and medical equipment, behaves as an endocrine disruptor in the human \nbody. Bisphenol A can bind directly to several types of nuclear receptors, \nincluding steroid and xenobiotic receptor (SXR). SXR plays an important role in \nbone metabolism through the activation of osteoblasts in vitro, but SXR protein \nlocalization has not been reported in bone tissues. Additionally, it is not \nknown whether bisphenol A acts on osteoblasts through SXR activation. Therefore, \nin this study, we first examined the immunolocalization of the SXR protein in \nhuman adult and fetal bone tissues. We then examined the effects of bisphenol A \non human osteoblasts in vitro. SXR immunoreactivity was detected in osteoblasts, \nbut not in osteoclasts, of both adult and fetal bone tissues. In fetal bone \ntissues, the mesenchymal cells or fetal connective tissue were also positive for \nSXR immunoreactivity. Expression of SXR target genes (tsukushi, matrilin-2, and \nCYP3A4) and SXR response element-luciferase activity were increased by bisphenol \nA treatment in normal osteoblasts transfected with SXR (hFOB/SXR) and in \nosteoblast-like cells (MG-63). Bisphenol A also stimulated cell proliferation \nand collagen accumulation in hFOB/SXR cells. These results suggest that, as in \nother tissues, SXR plays important roles in bone metabolism and fetal bone \ndevelopment and that bisphenol A may disturb bone homeostasis in both adult and \nfetus through SXR.",
"Bisphenol A [BPA, 2,2-bis(4-hydoxyphenyl)propane], an industrial chemical used \nin the production of polycarbonate, epoxide resin, and polyarylate, is \nconsidered to be an endocrine-disrupting chemical. BPA may be present in some \nhollow-fiber dialyzers used in hemodialysis. In this study, we tested the \namounts of BPA eluted from various hollow fibers. Furthermore, we measured the \nBPA concentration in the sera of 22 renal disease predialysis patients, as well \nas 15 patients who were receiving hemodialysis, to see if there is BPA \naccumulation in these patients. The elution test of BPA showed that a much \nlarger amount of BPA was eluted from polysulfone (PS), and \npolyester-polymeralloy hollow fibers. Among renal disease patients who had not \nundergone hemodialysis, the serum BPA concentration increased as the renal \nfunction deteriorated, showing a significant negative association. In a \ncrossover test between PS and cellulose (Ce) dialyzers, the predialysis serum \nBPA concentration of PS dialyzer users decreased after changing to a Ce \ndialyzer, and the serum BPA increased again after switching back to PS \ndialyzers. In patients who were using PS dialyzers, the BPA level significantly \nincreased after a dialysis session. However, in the Ce dialyzer users, the BPA \nlevel decreased. Since accumulation of BPA could affect the endocrine or \nmetabolic system of the human body, it is important to perform further \ninvestigations on dialysis patients.",
"Bisphenol A, an environmental contaminant, widely used as a monomer in \npolycarbonate plastics, has been shown to cause abnormalities in liver of rats \nand mice. The nature and mechanism of action of bisphenol A on liver is not \nclear. The aim of the present study was to investigate if bisphenol A induces \noxidative stress in the liver of rats and if co-administration of vitamin C, an \nantioxidant, can prevent oxidative stress. Bisphenol A (0.2, 2.0 and 20 micro \ng/kg body weight per day) and bisphenol A+vitamin C (0.2, 2.0, 20 micro g+40 \nmg/kg body weight per day) was orally administered to rats for 30 days. After 24 \nh of the last treatment, rats were killed using overdose of anesthetic ether. \nBody weights of the animals and the weights of liver showed no significant \nchanges. The activities of antioxidant enzymes, superoxide dismutase, catalase, \nglutathione reductase and glutathione peroxidase were decreased in mitochondrial \nand microsome-rich fractions of liver. The levels of hydrogen peroxide and lipid \nperoxidation increased in the treated rats when compared with the corresponding \ngroup of control animals. Activity of alanine transaminase, a marker enzyme of \nhepatic injury remained unchanged in the treated rats as compared with the \ncorresponding control rats. Co-administration of bisphenol A and vitamin C \nshowed no changes in the activities of superoxide dismutase, catalase, \nglutathione reductase and glutathione peroxidase and in the levels of hydrogen \nperoxide and lipid peroxidation as compared with the corresponding control \ngroups. The results indicated that bisphenol A induces oxidative stress in the \nliver of rats by decreasing the antioxidant enzymes. Co-administration of \nvitamin C reversed the effects of bisphenol A-induced oxidative stress in the \nliver of rats.",
"Bisphenol A is an environment-polluting industrial chemical able to interfere \nwith the endocrine system. An obesogenic effect in perinatally exposed rodents \nhas been described as estrogenic activity. We exposed male mice to Bisphenol A \nduring fetal-perinatal period (from 10 days post coitum to 31 days post partum) \nand investigated the effects of this early-life exposure at 78 days of age. Body \nweight, food intake, fat mass, and hypothalamic signals related to anorexigenic \ncontrol of food intake were analyzed. Results show that Bisphenol A exposure \nreduced body weight and food intake. In addition, the exposure decreased \nepididymal fat mass and adiposity, acting negatively on adipocyte volume. At \nhypothalamic level, Bisphenol A exposure reduced the expression of the \ncannabinoid receptor 1 and induced gene expression of cocaine and \namphetamine-regulated transcript-1. This observation suggests that Bisphenol A \ninduces activation of anorexigenic signals via down-regulation of the \nhypothalamic cannabinoid receptor 1 with negative impact on food intake.",
"Bisphenol A (BPA) is an endocrine-disruptor compound that exhibits estrogenic \nactivity. BPA is used in the production of materials such as polycarbonate \nplastics, epoxy resins and dental sealants. Whereas, the endocrine modulating \nactivity of BPA and its effects on reproductive health have been widely studied, \nits effects on the function of the immune system are poorly characterized. This \nmight be attributable to the different BPA doses used in a diversity of animal \nmodels. Moreover, most studies of the effect of BPA on the immune response are \nlimited to in vitro and in vivo studies that have focused primarily on the \nimpact of BPA on the number and proportion of immune cell populations, without \nevaluating its effects on immune function in response to an antigenic challenge \nor infectious pathogens. In this review, we discuss the current literature on \nthe effects of BPA on the function of immune system that potentially increases \nthe susceptibility to infections by the virtue of acting as a pro-inflammatory \nmolecule. Thus, it appears that BPA, while by such an impact might be useful in \nthe control of certain disease states that are helped by an inflmmatory \nresponse, it can worsen the prognosis of diseases that are adversely affected by \ninflammation.",
"Bisphenol A (BPA), a compound used in the manufacturing of plastics and epoxy \nresins, is an endocrine disruptor with significant adverse impact on the human's \nhealth. Here, we review the animal models and clinical studies as well as the \nmolecular and cellular mechanisms that show that BPA alters the normal function \nof the reproductive system, metabolism, brain function and behavior and \ncontributes to the development of certain neurodevelopmental disorders including \nautism spectrum and attention-deficit and hyperactivity disorders. BPA also \ncauses aberrant cognitive function, behavioral disturbances, and \nneurodegenerative diseases, including Parkinson's disease, amyotrophic lateral \nsclerosis (ALS), and multiple sclerosis. It has recently been proposed that \nexposure to BPA may be associated with the development of certain \nneurodegenerative diseases and neurodevelopmental disorders; however, it is a \nline of research that is just emerging. This work aims to review the available \ninformation about the association between exposure to BPA and cognitive \nfunction, behavioral disturbances, neurodegenerative diseases (Parkinson�s \nDisease, Amyotrophic lateral sclerosis, Multiple Sclerosis), and \nneurodevelopmental disorders (Autism Spectrum and \nAttention-Deficit/Hyperactivity Disorders). Likewise, the molecular and cellular \nmechanisms that may be involved with these pathological conditions will be \nanalyzed.",
"The relationship between exposure to endocrine-disrupting chemicals (EDs) and \nrisk to reproductive organs is well documented, but the influence of EDs on \nbehavioral development has not been studied. In this study we evaluated the \neffect of fetal exposure to bisphenol A, which mimics estrogenic activity, on \naggressive behavior and hormonal change in male mice. On gestation days 11-17, \nfemale mice were fed bisphenol A at 2 ng/g or 20 ng/g of body weight \n(environmentally relevant concentration). Aggression rating and blood sampling \nof the offspring were done at 8, 12, and 16 weeks of age. Aggression scores \nincreased significantly (p < 0.01) at 8 weeks of age in male mice exposed to \nbisphenol A at both the 2 ng/g and 20 ng/g concentrations compared with a \ncontrol group, but no difference was found after 12 weeks. Relative testis \nweight (per gram of body weight) was significantly lower at 8 and 12 weeks in \nmice treated with 2 ng/g than in controls (p < 0.05) and was significantly lower \nat 12 weeks in mice treated with 20 ng/g than in controls (p < 0.01). The serum \ntestosterone concentration in treated mice was not significantly different from \nthat in controls. These results demonstrate that bisphenol A temporarily \nactivated aggressive behavior in mice at 8 weeks of age and that low doses of \nbisphenol A interfered with the normal development of reproductive organs. The \nmechanism activating this aggressive behavior was not elevated testosterone \nconcentration.",
"Since an emerging body of evidence is accumulating that endocrine disruptors \nexert their effects on the central nervous system, their neuronal risk \nassessment is now required. A previous study showed that a single intracisternal \nadministration of bisphenol A, an endocrine disruptor, into neonatal rats caused \nhyperactivity. To evaluate the neural risk assessment of bisphenol A, it is very \nimportant to test the potential of the chemical via an environmental exposure \nroute. In this study, we tested the hypothesis that oral exposure to bisphenol A \nwould exhibit effects observed previously with direct instillation. Oral \nadministration of 600mug/pup/day bisphenol A into male Wistar rats aged 5 days-3 \nweeks caused significant hyperactivity at 4-5 weeks of age. Treated rats were \nabout 1.3 times as active in the nocturnal phase as were vehicle-treated control \nrats (p<0.005). The long-term effects of the chemical resulted in a large \nreduction of immunoreactivity for tyrosine hydroxylase in the midbrain at 7 \nweeks of age, where terminal deoxynucleotidyl transferase-mediated dUTP nick \nend-labeling (TUNEL)-positive cells were detected. Furthermore, bisphenol A \ndecreased gene expression levels of dopamine transporter in adult rats.",
"Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals \n(EDC) used as the base compound in the manufacture of polycarbonate plastics. \nAlthough evidence points to consider exposure to BPA as a risk factor for \ninsulin resistance, its actions on whole body metabolism and on \ninsulin-sensitive tissues are still unclear. The aim of the present work was to \nstudy the effects of low doses of BPA in insulin-sensitive peripheral tissues \nand whole body metabolism in adult mice. Adult mice were treated with \nsubcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy \nhomeostasis was assessed with in vivo indirect calorimetry. Insulin signaling \nassays were conducted by western blot analysis. Mice treated with BPA were \ninsulin resistant and had increased glucose-stimulated insulin release. \nBPA-treated mice had decreased food intake, lower body temperature and locomotor \nactivity compared to control. In skeletal muscle, insulin-stimulated tyrosine \nphosphorylation of the insulin receptor β subunit was impaired in BPA-treated \nmice. This impairment was associated with a reduced insulin-stimulated Akt \nphosphorylation in the Thr(308) residue. Both skeletal muscle and liver \ndisplayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein \nkinase (MAPK) signaling pathway was also impaired in the skeletal muscle from \nBPA-treated mice. In the liver, BPA effects were of lesser intensity with \ndecreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β \nsubunit.In conclusion, short-term treatment with low doses of BPA slows down \nwhole body energy metabolism and disrupts insulin signaling in peripheral \ntissues. Thus, our findings support the notion that BPA can be considered a risk \nfactor for the development of type 2 diabetes.",
"The \"tolerable daily intake\" of bisphenol A, established by the European and US \nregulatory agencies, is based on a small number of reproductive toxicity studies \nin animals, mostly funded by industry, using protocols that adhere to regulatory \nguidelines. Many scientists consider these regulatory toxicology tests \nunsuitable for the evaluation of endocrine disrupters, because they cannot be \nused to demonstrate the effects of low doses of bisphenol A, observed in dozens \nof independent studies. Results obtained in studies of high doses of bisphenol A \nhave been extrapolated to predict the effects of low-dose exposure, according to \nthe principle that \"the dose makes the poison\". The validity of this \nextrapolation is disputed. Some human studies suggest that bisphenol A causes \ncoronary heart disease, increases the risk of type 2 diabetes, and has harmful \neffects on reproduction and development. Considerable data from rodent studies \nsuggest that low doses of bisphenol A affect reproduction, lipid metabolism and \nneurological development, usually following intrauterine or postnatal exposure. \nIn France, the use of bisphenol A in infant feeding bottles has been banned \nsince 30 June 2010, and in food packaging intended for children aged 0 to 3 \nyears since 1 January 2013. The ban is due to be extended to all food packaging \nas of 1 January 2015. Bisphenol A is not the only substance present in food \npackaging that could interfere with endocrine function. Too little is known yet \nabout the toxicology of bisphenol A substitutes. Several studies have shown that \nexposure to bisphenol A in adults and children can be greatly reduced by \nchoosing a varied diet based on fresh foods, and by avoiding the use of plastic \ntableware. To reduce exposure to bisphenol A and other chemicals with hormonal \nactivity that are present in food packaging, it seems reasonable to encourage \nthe consumption of fresh foods, avoiding canned food and plastic packaging for \nstoring and reheating food and beverages. These precautionary measures are most \nimportant for food and beverages intended for pregnant women and young children.",
"All of us now carry in our bodily tissues a virtual stew of heavy metals and \nhundreds of synthetic chemicals: persistent ones, which can have a \"half-life\" \nin the body of several years; and nonpersistent compounds, which may pass \nthrough the body in a matter of hours. Bisphenol A (BPA) is a nonpersistent \ncompound that can alter the reproductive system of laboratory animals even at \nextremely low exposure levels. This is relevant because BPA is chronically \npresent in our environment with the potential for constant exposure, making it \nfunctionally equivalent to a persistent compound. In this review the authors \nemphasize particular outcomes that occur in response to the relevant dose of BPA \nexposure that causes developmental effects on reproductive systems, brain and \nmetabolic processes, and the male germ line. At a specific dose level, BPA \nexposure also shows oxidative toxicity and carcinogenic effects.",
"Bisphenol A is widely used in food contact materials and other products and is \ndetected in human urine and blood. Bisphenol A may affect reproductive and \nneurological development; however, opinion of the European Food Safety Authority \n(EFSA) on bisphenol A (EFSA J, 13, 2015 and 3978) concluded that none of the \navailable studies were robust enough to provide a point of departure for setting \na tolerable daily intake for bisphenol A. In the present study, pregnant Wistar \nrats (n = 17-21) were gavaged from gestation day 7 to pup day 22 with bisphenol \nA doses of 0, 25 μg, 250 μg, 5 mg or 50 mg/kg bw/day. In the offspring, growth, \nsexual maturation, weights and histopathology of reproductive organs, oestrus \ncyclicity and sperm counts were assessed. Neurobehavioural development was \ninvestigated using a behavioural testing battery including tests for motor \nactivity, sweet preference, anxiety and spatial learning. Decreased sperm count \nwas found at the lowest bisphenol A dose, that is 25 μg/kg/day, but not at the \nhigher doses. Reproductive organ weight and histology were not affected and no \nbehavioural effects were seen in male offspring. In the female offspring, \nexposure to 25 μg/kg bw/day bisphenol A dose resulted in increased body weight \nlate in life and altered spatial learning in a Morris water maze, indicating \nmasculinization of the brain. Decreased intake of sweetened water was seen in \nfemales from the highest bisphenol A dose group, also a possible sign of \nmasculinization. The other investigated endpoints were not significantly \naffected. In conclusion, the present study using a robust experimental study \ndesign, has shown that developmental exposure to 25 μg/kg bw/day bisphenol A can \ncause adverse effects on fertility (decreased sperm count), neurodevelopment \n(masculinization of spatial learning in females) and lead to increased female \nbody weight late in life. These results suggest that the new EFSA temporary \ntolerable daily intake of 4 μg/kg bw/day is not sufficiently protective with \nregard to endocrine disrupting effects of bisphenol A in humans.",
"Bisphenol S (BPS) is the major substitute for the production of bisphenol A \n(BPA)-free products and detected in both food and environment. Although the \nrelationship between BPA exposure and increased risk of obesity and diabetes has \nbeen noted, the potential influence of BPS is not fully understood. Herein, a \nnon-targeted lipidomic study was performed to explore BPA/BPS exposure actions \nusing the 3T3-L1 preadipocyte differentiation model, and revealed the \ncomprehensive lipidome disturbance induced by either BPA or BPS exposure at \ndifferent doses of 0.01, 1 and 100 μM. BPA was more potent than BPS in \ndisturbance of lipid metabolism. A considerable similarity of BPS exposure to \nBPA was discovered. The key lipid remodeling in response to exposure was found \nto involve the cardiolipins, phosphatidylglycerols and fatty acids metabolic \npathways, providing novel clues of potential mechanism in which both BPA and BPS \nexposure could be associated with increased risk of insulin resistance. Our \nstudy supplies the perspective into the lipidome response to environmental \nstress induced by BPA/BPS, and shows that BPA-free products are not necessarily \nsafer. Substitution of BPA by its structural analog BPS should be therefore \nperformed with caution.",
"Bisphenol A has been shown to affect the reproduction of male rats and mice. \nHowever, the mechanism of action of bisphenol A on the epididymal sperm is not \nelucidated. The present study was undertaken to evaluate the effect of bisphenol \nA on the antioxidant system of rat epididymal sperm. Bisphenol A was \nadministered orally to male rats at the dose levels of 0.2, 2 and 20 microg/Kg \nbody weight per day for 45 days. After 24 h of the last treatment, rats were \nweighed and killed using anesthetic ether. The body weight of treated rats did \nnot show significant change as compared with the corresponding control groups. \nIn bisphenol A-treated rats there was a significant decrease in the weight of \nthe testis and epididymis; the weight of ventral prostate increased \nsignificantly whereas there was no significant change in the weight of seminal \nvesicles as compared with the corresponding group of control animals. Sperm \ncollected from the epididymis were used for sperm count and biochemical \nestimations. Administration of bisphenol A caused a reduction in the epididymal \nsperm motility and sperm count in a dose-dependent manner. The activities of \nsuperoxide dismutase, catalase, glutathione reductase and glutathione peroxidase \nwere decreased while the levels of H(2)O(2) and lipid peroxidation increased \nsignificantly in the treated rats as compared with the corresponding group of \ncontrol animals. The results suggested that graded doses of bisphenol A elicit \ndepletion of antioxidant defence system and induce oxidative stress in \nepididymal sperm of rats. In conclusion, the adverse effect of bisphenol A on \nmale reproduction may be due to induction of oxidative stress in sperm.",
"Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet \nfunction; however, the mechanisms behind these effects are poorly understood. \nMale mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. \nWhole-body glucose homeostasis, pancreatic islet morphology and function, and \nmiR-338-mediated molecular signal transduction analyses were examined. We showed \nthat BPA treatment led to a disruption of glucose tolerance and a compensatory \nincrease of pancreatic islets insulin secretion and pancreatic and duodenal \nhomeobox 1 (Pdx1) expression in mice. Inhibition of Pdx1 reduced \nglucose-stimulated insulin secretion and ATP production in the islets of \nBPA-exposed mice. Based on primary pancreatic islets, we also confirmed that \nmiR-338 regulated Pdx1 and thus contributed to BPA-induced insulin secretory \ndysfunction from compensation to decompensation. Short-term BPA exposure \ndownregulated miR-338 through activation of G-protein-coupled estrogen receptor \n1 (Gpr30), whereas long-term BPA exposure upregulated miR-338 through \nsuppression of glucagon-like peptide 1 receptor (Glp1r). Taken together, our \nresults reveal a molecular mechanism, whereby BPA regulates Gpr30/Glp1r to \nmediate the expression of miR-338, which acts to control Pdx1-dependent insulin \nsecretion. The Gpr30/Glp1r-miR-338-Pdx1 axis should be represented as a novel \nmechanism by which BPA induces insulin secretory dysfunction in pancreatic \nislets.-Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. MiR-338 controls \nBPA-triggered pancreatic islet insulin secretory dysfunction from compensation \nto decompensation by targeting Pdx-1.",
"Bisphenol A (BPA), a synthetic chemical used in the production of plastics since \nthe 1950s and a known endocrine disruptor, is a ubiquitous component of the \nmaterial environment and human body. New research on very-low-dose exposure to \nBPA suggests an association with adverse health effects, including breast and \nprostate cancer, obesity, neurobehavioral problems, and reproductive \nabnormalities. These findings challenge the long-standing scientific and legal \npresumption of BPA's safety. The history of how BPA's safety was defined and \ndefended provides critical insight into the questions now facing lawmakers and \nregulators: is BPA safe, and if not, what steps must be taken to protect the \npublic's health? Answers to both questions involve reforms in chemical policy, \nwith implications beyond BPA.",
"By virtue of its binding to steroid hormone receptors, bisphenol A (BPA, the \nunconjugated bioactive monomer) is hypothesized to be estrogenic when present in \nsufficient quantities in the body, raising concerns that widespread exposure to \nBPA may impact human health. To better understand the internal exposure of adult \nhumans to BPA and the relationship between the serum and urinary \npharmacokinetics of BPA, a clinical exposure study was conducted. Blood and \nurine samples were collected approximately hourly over a 24-h period from 20 \nadult volunteers who ingested 100% of one of three specified meals comprising \nstandard grocery store food items for breakfast, lunch, and dinner. The \nvolunteers' average consumption of BPA, estimated from the urinary excretion of \ntotal BPA ((TOT)BPA = conjugated BPA + BPA), was 0.27 μg/kg body weight (range, \n0.03-0.86), 21% greater than the 95th percentile of aggregate exposure in the \nadult U.S. population. A serum time course of (TOT)BPA was observable only in \nindividuals with exposures 1.3-3.9 times higher than the 95th percentile of \naggregate U.S. exposure. The (TOT)BPA urine concentration T(max) was 2.75 h \n(range, 0.75-5.75 h) post-meal, lagging the serum concentration T(max) by ∼1 h. \nSerum (TOT)BPA area under the curve per unit BPA exposure was between 21.5 and \n79.0 nM•h•kg/μg BPA. Serum (TOT)BPA concentrations ranged from less than or \nequal to limit of detection (LOD, 1.3 nM) to 5.7 nM and were, on average, 42 \ntimes lower than urine concentrations. During these high dietary exposures, \n(TOT)BPA concentrations in serum were undetectable in 83% of the 320 samples \ncollected and BPA concentrations were determined to be less than or equal to LOD \nin all samples.",
"Nowadays, endocrine disrupting chemical pollution has become one of the major \nconcerns due to the potential role of these chemicals in provoking endocrine \ndisorders especially type 2 diabetes. As a widespread endocrine disrupting \nchemical, Bisphenol A, with modest estrogenic activity can exert its detrimental \neffects in the different organs involved in type 2 diabetes such as pancreas, \nliver, adipocyte and skeletal muscles. Obesity, hepatic steatosis, impaired \ninsulin signaling and pancreatic islet function could be the main results of \nBisphenol A exposure. Epigenetic dysregulations can be suggested as an important \nunderlying mechanism for Bisphenol A toxicity in the endocrine system. The most \nstudied genes in this respect, which are responsible for glucose homeostasis \ninclude Pdx1, Gck, Igf2, Srebf1 and Srebf2. Aberrant DNA methylation, histone \ndemethylation and deacetylation and impaired miRNAs result in epigenetically \ndysfunctional genes that finally distract the normal glucose regulation. The \npresent study aimed to summarize the general effects of prenatal and postnatal \nBisphenol A exposure on glucose metabolism focusing on animal studies and review \nthe recent investigations on Bisphenol A -induced epigenetic perturbations that \naffect the normal glucose and lipid homeostasis and lead to type 2 diabetes.",
"Bisphenol A (BPA) is a small molecular weight endocrine disrupting chemical \n(EDC) that is used in the production of plastics with deleterious effects on \nvarious body systems while gallic acid (GA) is a known antioxidant capable of \nameliorating EDC-induced perturbations. In this study, adult male rats \n(180 ± 5 g) were divided into four groups of eight rats each: Group A (Control \nrats): 0.2 ml of corn oil; Group B (GA-treated rats): 20 mg/kg/day GA (dissolved \nin distilled water); Group C (BPA-treated rats): 10 mg/kg/day BPA suspended in \n0.2 ml corn oil; Group D (BPA + GA-treated rats): BPA (10 mg/kg/day) with a \nconcomitant GA (20 mg/kg/day). All treatments were orally administered for 14 \ndays. BPA induced significant decrease in systolic, diastolic and mean arterial \nblood pressure while causing a significant (p < 0.05) increase in heart rate in \nthe rats. It significantly (p < 0.05) raised both renal and cardiac reactive \noxygen species and depleted the antioxidant system. There were also significant \n(p < 0.05) increases in serum myeloperoxidase, nitric oxide, urea and creatinine \nin the BPA-treated rats. Lesions of the heart and kidney including inflammation, \nvascular congestion and erosion of epithelial cells were also observed in the \nBPA-treated rats. However, the concomitant treatment with GA ameliorated all the \nBPA-induced alterations of the cardio-renal system. Hence, low dose of GA serves \na protective function against BPA-induced toxicity of the heart and kidney.",
"Bisphenols are increasingly recognized as environmental pollutants with \nendocrine-disrupting potential. Nonetheless, the study of environmental \noccurrence and some endocrine-disrupting activities of some bisphenols came \nwidely into focus of research only recently. The aims of the present study were \nto: 1) determine the predominant bisphenols in Norwegian sewage sludge and \nsediment and in Czech surface waters, and 2) characterize the binding of \nbisphenols to a transport protein transthyretin (TTR) and their (anti-)thyroid, \n(anti-)progestagenic, and (anti-)androgenic activities. High-performance liquid \nchromatography with atmospheric pressure chemical ionization or photoionization \ncoupled with high resolution mass spectrometry (HPLC-APCI/APPI-HRMS) and \nChemically Activated LUciferase gene eXpression (CALUX) in vitro reporter gene \nbioassays were used to detect the target compounds and to determine \nendocrine-disrupting activities, respectively. Bisphenol A (BPA), 4,4'-bisphenol \nF (BPF), bisphenol S (BPS), and bisphenol E (BPE) were the most frequently found \ncompounds in municipal sewage sludge. Furthermore, bisphenol TMC (BPTMC) and \nbisphenol AF (BPAF) frequently occurred in sediment and surface waters, \nrespectively. BPA was the major contributor to Ʃ of bisphenols in Norwegian \nsewage sludge with exception of one sample where BPF predominated. We also \nmonitored a few bisphenols in sediment but only BPTMC was found. BPA, BPAF and \nBPF were the dominant bisphenols in Czech surface waters. Some bisphenols have \nshown TTR binding potency (BPAF = BPF > BPA = BPE) and some have displayed the \nfollowing endocrine-disrupting activities: anti-thyroid (BPAF), \nanti-progestagenic (BPTMC > BPA = BPAF), and anti-androgenic (BPAF > \nBPE > BPA > BPTMC > BPF > BPS). It is noteworthy that BPAF exhibited stronger or \nsimilarly potent endocrine-disrupting activities compared to BPA. Our results \nprovide new insights into these less-studied endocrine-disrupting activities of \nenvironmentally relevant bisphenols and may be useful in prioritizing those \ncompounds that deserve further attention in environmental monitoring and \neco-toxicological research.",
"Bisphenol A (BPA) is a monomer found in plastic products used daily for the \nstorage and consumption of food and beverages, such as plastic bottles, \ncontainers, and even toys. The molecule leaches out into the food, increasingly \nif exposed to warm temperatures and high acidity. BPA is known for many negative \neffects on the human body; for instance it acts as an xenoestrogen and \ninfluences fertility and gestation and might also have carcinogenic effects, \ncausing breast and prostate cancer. Although it has not yet been proven as a \ndirect cause of autoimmunity, many of the effects of BPA can be related to the \npathogenesis of autoimmune disease (AID). Its estrogenic behavior modulates the \nimmune system, it encourages the secretion of Prolactin that is known to be \nassociated to AID, it creates oxidative stress that triggers the immune system \nand so on. Therefore there is room to advise individuals at risk for AID to \navoid the consumption of BPA, similar to guidelines for pregnant women."
] |
nan
|
52f3a9ef2059c6d71c000012
|
[
12091808,
21422919,
22146760,
12580776,
17693930,
16581974
] |
train
|
what is the role of FGF-2 in cardiac regeneration after myocardial infarction?
|
summary
|
Exogenous FGF-2 was shown to increase angiogenesis and myocardial perfusion, promote myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improve the cardiac function after myocardial infarction. Furthermore, prevascularization with basic FGF-incorporated microspheres enhances the benefits of cardiomyocyte transplantation. In another study, transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) was shown to promote Cardiac Progenitor Cells proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following myocardial infarction and improving cardiac function.
|
Exogenous FGF-2 was shown to increase angiogenesis and myocardial perfusion, promote myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improve the cardiac function after myocardial infarction. Furthermore, prevascularization with basic FGF-incorporated microspheres enhances the benefits of cardiomyocyte transplantation. In another study, transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) was shown to promote Cardiac Progenitor Cells proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following myocardial infarction and improving cardiac function.
|
[
"OBJECTIVE: The effects of cell transplantation on the ischemic failing heart \nhave already been documented. However, the area in and around infarct regions is \nnot a good environment for cells to survive in because they are exposed to poor \nconditions in which certain requirements cannot be adequately supplied. We \ntherefore designed a study to investigate the efficacy of prevascularization in \nischemic regions before cell transplantation.\nMETHODS: Rats with myocardial infarction were randomized into 4 groups: 11 rats \nreceived a culture medium injection to the left ventricular wall (control \ngroup), 11 received fetal cardiomyocyte transplantation (TX group), 11 received \ngelatin hydrogel microspheres incorporating basic fibroblast growth factor (FGF \ngroup), and 11 received basic fibroblast growth factor pretreatment \nsequentially, followed by cardiomyocyte transplantation (FGF-TX group). Four \nweeks later, left ventricular function was assessed by means of echocardiography \nand cardiac catheterization.\nRESULTS: In the FGF and FGF-TX groups neovascularization was found in the scar \ntissue 1 week later. The TX, FGF, and FGF-TX groups showed better fractional \nshortening than the control group (TX, FGF, FGF-TX, and control: 28% +/- 4.4%, \n24% +/- 8.6%, 27% +/- 7.3%, and 17% +/- 4.6%, respectively; P <.01). Left \nventricular maximum time-varying elastance was higher in the FGF-TX group than \nin the TX and FGF groups (FGF-TX, TX, and FGF: 0.52 +/- 0.23, 0.30 +/- 0.08, and \n0.27 +/- 0.20 mm Hg/microL, respectively; P <.01). Histologically, more \ntransplanted cells survived in the FGF-TX group than in the TX group.\nCONCLUSIONS: Prevascularization with basic fibroblast growth factor-incorporated \nmicrospheres enhances the benefits of cardiomyocyte transplantation. We expect \nthat this system will contribute to regeneration medicine through its extensive \napplication to other growth factors.",
"OBJECTIVE: To investigate the effects of exogenous basic fibroblast growth \nfactor (bFGF) on myocardial regeneration after acute myocardial infarction \n(AMI).\nMETHODS: AMI models were established by ligating the mid-third of left anterior \ndescending artery, thereafter, miniswines were randomly divided into control \n(none treatment, n = 6) and bFGF groups (n = 6). For the bFGF group, bFGF (100 \nμg) was injected with a sterile microinjection at five sites within the ischemic \nregion. 5-Bromo-2-deoxyuridine (250 mg) was administrated intravenously twice a \nweek after the operation, to label cells undergoing DNA replication. The \nexpression of stromal cell-derived factor-1α (SDF-1α) and CXC chemokine receptor \n4 (CXCR4), cardiac stem cell-mediated myocardial regeneration, myocardial \napoptosis, histological and immunohistochemical analyses, and cardiac function \nwere evaluated at different time points.\nRESULTS: Four weeks after bFGF therapy, it showed an increased vessel density \nand myocardial perfusion (P < 0.001), upregulative expression of SDF-1α and \nCXCR4 (P < 0.001), increased c-kit and 5-bromo-2-deoxyuridine-positive cells (P \n< 0.001), enhanced myocardial viability (P < 0.001), and improved left \nventricular ejection fraction (P = 0.007), compared with the control.\nCONCLUSION: Exogenous bFGF was shown to have increased angiogenesis and \nmyocardial perfusion, promoted myocardial regeneration by activating the \nSDF-1α/CXCR4 axis, and thereby improved the cardiac function, which may provide \na new therapeutic strategy for AMI.",
"OBJECTIVE: To investigate whether transmyocardial drilling revascularization \ncombined with heparinized basic fibroblast growth factor (bFGF)-incorporating \ndegradable stent implantation (TMDRSI) can promote myocardial regeneration after \nacute myocardial infarction (AMI).\nMETHODS: A model of AMI was generated by ligating the mid-third of left anterior \ndescending artery (LAD) of miniswine. After 6 h, the animals were divided into \nnone-treatment (control) group (n=6) and TMDRSI group (n=6). For TMDRSI group, \ntwo channels with 3.5 mm in diameter were established by a self-made drill in \nthe AMI region, into which a stent was implanted. Expression of stromal \ncell-derived factor-1(α) (SDF-1(α)) and CXC chemokine receptor 4 (CXCR4), \ncardiac stem cell (CSC)-mediated myocardial regeneration, myocardial apoptosis, \nmyocardial viability, and cardiac function were assessed at various time-points.\nRESULTS: Six weeks after the operation, CSCs were found to have differentiated \ninto cardiomyocytes to repair the infarcted myocardium, and all above indices \nshowed much improvement in the TMDRSI group compared with the control group \n(P<0.001).\nCONCLUSIONS: The new method has shown to be capable of promoting CSCs \nproliferation and differentiation into cardiomyocytes through activating the \nSDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing \nmyocardial regeneration following AMI and improving cardiac function. This may \nprovide a new strategy for myocardial regeneration following AMI.",
"Several studies have demonstrated that cell transplantation was effective for \nthe therapy of myocardial infarction. However, little care has been taken for \nthe blood supply indispensable to cell transplantation. This study is an \ninvestigation to evaluate the feasibility of in advance angiogenesis by gelatin \nmicrospheres incorporating basic fibroblast growth factor (bFGF) for the \ntransplantation therapy of cardiomyocytes with an ischemic cardiomyopathy model. \nRats with myocardial infarction received the intramuscular injection of culture \nmedium (Control), or that containing fetal cardiomyocytes (TX) or gelatin \nmicrospheres incorporating bFGF (FGF), and gelatin microspheres incorporating \nbFGF plus fetal cardiomyocytes 1 week later (FGF-TX). The left ventricle (LV) \nfunction of rat hearts was assessed by echocardiography and cardiac \ncatheterization 4 weeks later. The LV maximum time-varying elastance was \nsignificantly higher in the FGF-TX group than in other groups. The combination \nof bFGF-induced angiogenesis and cardiomyocyte transplantation is a promising \nprocedure to improve the LV function in rats with myocardial infarction.",
"Fibroblast growth factor 2 (FGF-2) plays an integral role in therapeutic \nangiogenesis associated with myocardial infarct healing. Calcium (Ca(2+)) is one \nof the most universal important signaling molecules that affect cell \nproliferation and angiogenesis. Calreticulin (CRT), a 46-kd (Ca(2+)) -binding \nchaperone found mainly in the endoplasmic reticulum, plays an important role in \nregulating calcium homeostasis. The role of CRT in FGF-2-induced angiogenesis \nand its signaling pathways in ischemic myocardium are not clear. For this study, \ntwo-dimensional gel electrophoresis and matrix-assisted laser desorption \nionization mass spectrometry were used to analyze CRT's differential expression \nin myocardial microvascular endothelial cells treated with or without FGF-2. \nWestern blotting analysis was used to detect the expression of CRT and \ncalcineurin (CaN) in sham-operated, FGF-2-, or saline intramyocardially injected \nmyocardium. It is found that FGF-2 induced angiogenesis after sustained ischemia \nwith downregulation of CRT expression and upregulation of CaN expression in \nmyocardium. The CRT expression was negatively correlated to angiogenesis. \nFurthermore, overexpression of CRT or inhibition of CaN with cyclosporine A \nabolishes FGF-2-induced microvascular endothelial cells proliferation and CaN \nexpression. The results indicate that intramyocardial administration of FGF-2 \ndecreases myocardial CRT expression in parallel with myocardial angiogenesis in \nischemic myocardium. The study further indicates that Ca(2+)/CaN signaling \npathway may be involved in CRT-related angiogenesis.",
"We previously reported that intramyocardial injection of bone marrow-derived \nmesenchymal stem cells overexpressing Akt (Akt-MSCs) inhibits ventricular \nremodeling and restores cardiac function measured 2 wk after myocardial \ninfarction. Here, we report that the functional improvement occurs in < 72 h. \nThis early remarkable effect cannot be readily attributed to myocardial \nregeneration from the donor cells. Thus, we hypothesized that paracrine actions \nexerted by the cells through the release of soluble factors might be important \nmechanisms of tissue repair and functional improvement after injection of the \nAkt-MSCs. Indeed, in the current study we demonstrate that conditioned medium \nfrom hypoxic Akt-MSCs markedly inhibits hypoxia-induced apoptosis and triggers \nvigorous spontaneous contraction of adult rat cardiomyocytes in vitro. When \ninjected into infarcted hearts, the Akt-MSC conditioned medium significantly \nlimits infarct size and improves ventricular function relative to controls. \nSupport to the paracrine hypothesis is provided by data showing that several \ngenes, coding for factors (VEGF, FGF-2, HGF, IGF-I, and TB4) that are potential \nmediators of the effects exerted by the Akt-MSC conditioned medium, are \nsignificantly up-regulated in the Akt-MSCs, particularly in response to hypoxia. \nTaken together, our data support Akt-MSC-mediated paracrine mechanisms of \nmyocardial protection and functional improvement."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009203', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016222', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012038']
|
532f03e6d6d3ac6a34000022
|
[
16304579,
21344679,
20200331,
18290252,
22748493,
15883211,
19591228,
20870802,
20971132,
22898045
] |
train
|
what is the role of GATA-4 in regeneration of the heart after myocardial infarction?
|
summary
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GATA-4 is implicated in cardiogenic differentiation of cardiac c-kit+AT2+ cells that represent approximately 0.19% of total cardiac cells in infarcted heart. GATA-4 overexpression in mesenchymal stem cells increases both survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct regenaration. In addition, interventions, such as hypergravity and 5-Aza treatment, induce expression of early muscle and cardiac markers like GATA-4 in BMSCs. A subpopulation of primitive cells from rat heart, expressing c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, exhibit a high in vitro proliferative potential. Progeny of these implanted cells have been shown to migrate along the infarcted scar, reconstitute regenerated cardiomyocytes with incorporation into host myocardium, and inhibit cardiac remodeling with decreased scar formation. In another study, TGF-beta has been shown to conduct the myogenic differentiation of stem cells by upregulating GATA-4 and NKx-2.5 expression and the intramyocardial implantation of TGF-beta-preprogrammed stem cells effectively assisted the myocardial regeneration. Furthermore, G-CSF treatment in postinfarcted murine hearts appears to be an effective approach for treating heart failure and also leads to induction of GATA-4 resulting in expression of various sarcomeric proteins.
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GATA-4 is implicated in cardiogenic differentiation of cardiac c-kit+AT2+ cells that represent approximately 0.19% of total cardiac cells in infarcted heart. GATA-4 overexpression in mesenchymal stem cells increases both survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct regenaration. In addition, interventions, such as hypergravity and 5-Aza treatment, induce expression of early muscle and cardiac markers like GATA-4 in BMSCs. A subpopulation of primitive cells from rat heart, expressing c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, exhibit a high in vitro proliferative potential. Progeny of these implanted cells have been shown to migrate along the infarcted scar, reconstitute regenerated cardiomyocytes with incorporation into host myocardium, and inhibit cardiac remodeling with decreased scar formation. In another study, TGF-beta has been shown to conduct the myogenic differentiation of stem cells by upregulating GATA-4 and NKx-2.5 expression and the intramyocardial implantation of TGF-beta-preprogrammed stem cells effectively assisted the myocardial regeneration. Furthermore, G-CSF treatment in postinfarcted murine hearts appears to be an effective approach for treating heart failure and also leads to induction of GATA-4 resulting in expression of various sarcomeric proteins.
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[
"Chronic heart failure remains a leading cause of mortality. Although granulocyte \ncolony-stimulating factor (G-CSF) is reported to have a beneficial affect on \npostinfarction cardiac remodeling and dysfunction when administered before the \nonset of or at the acute stage of myocardial infarction (MI), its effect on \nestablished heart failure is unknown. We show here that subcutaneous \nadministration of G-CSF greatly improves the function of murine hearts failing \ndue to a large, healed MI. G-CSF changed the geometry of the infarct scar from \nelongated and thin to short and thick, induced hypertrophy among surviving \ncardiomyocytes, and reduced myocardial fibrosis. Expression of G-CSF receptor \nwas confirmed in failing hearts and was upregulated by G-CSF treatment. G-CSF \ntreatment also led to activation of signal transducer and activator of \ntranscription-3 and induction of GATA-4 and various sarcomeric proteins such as \nmyosin heavy chain, troponin I and desmin. Expression of metalloproteinase-2 and \n-9 was also increased in G-CSF-treated hearts, while that of tumor necrosis \nfactor-alpha, angiotensin II type 1 receptor (AT1) and transforming growth \nfactor-beta1 was reduced. Although activation of Akt was noted in G-CSF-treated \nhearts, vessel density was unchanged, and apoptosis was too rare to exert a \nmeaningful effect. No bone marrow-derived cardiomyocytes or vascular cells were \ndetected in the failing hearts of green fluorescent protein chimeric mice. \nFinally, beneficial effects of G-CSF on cardiac function were found persisting \nlong after discontinuing the treatment (2 weeks). Collectively, these findings \nsuggest G-CSF administration could be an effective approach to treating chronic \nheart failure following a large MI.",
"BACKGROUND AND PURPOSE: The in vivo cardiac differentiation and functional \neffects of unmodified adult bone marrow mesenchymal stem cells (BMSCs) after \nmyocardial infarction (MI) is controversial. Our previous results suggested that \nhypergravity promoted the cardiomyogenic differentiation of BMSCs, and thus we \npostulated that ex vivo pretreatment of BMSCs using hypergravity and \n5-azacytidine (5-Aza) would lead to cardiomyogenic differentiation and result in \nsuperior biological and functional effects on cardiac regeneration of infarcted \nmyocardium.\nMETHODS: We used a rat MI model generated by ligation of the coronary artery. \nHomogeneous rat BMSCs were isolated, culture expanded, and differentiated into a \ncardiac lineage by adding hypergravity (2G) for 3 days and 5-Aza (50 lmol/L, 24 \nh). Rats underwent BMSCs (labeled with DAPI) injection after the infarction and \nwere randomized into five groups. Group A rats received the control medium, \nGroup B rats received unmodified BMSCs, Group C rats received BMSCs treated with \nhypergravity, Group D rats received BMSCs treated with 5-Aza, and Group E rats \nreceived BMSCs treated with 5-Aza and hypergravity (n = 6).\nRESULTS: After hypergravity and 5-Aza treatment, BMSCs showed positive for the \nearly muscle and cardiac markers GATA-4, MEF-2, and Nkx2-5 with RT-PCR. We also \nfound that hypergravity could enhance the activities of MEF-2 via promoting the \nnuclear export of HDAC5. The frozen section showed that the implanted BMSCs \nlabeled with DAPI survived and angiogenesis was identified at the implantation \nsite. In Groups B, C, D, and E rats, pre-treated BMSCs colocalized with \nα-actinin, and Group E rats showed a significantly larger increase in left \nventricular function.\nCONCLUSIONS: The biological ex vivo cardiomyogenic differentiation of adult \nBMSCs with hypergravity and 5-Aza prior to their transplantation is feasible and \nappears to improve their in vivo cardiac differentiation as well as the \nfunctional recovery in a rat model of the infarcted myocardium.",
"BACKGROUND: Recent data suggest that GATA-4 is an antiapoptotic factor required \nfor adaptive responses and a key regulator of hypertrophy and \nhypertrophy-associated genes in the heart. As a leading cause of chronic heart \nfailure, reversal of postinfarction left ventricular remodeling represents an \nimportant target for therapeutic interventions. Here, we studied the role of \nGATA-4 as a mediator of postinfarction remodeling in rats.\nMETHODS AND RESULTS: Myocardial infarction, caused by ligating the left anterior \ndescending coronary artery, significantly decreased the DNA binding activity of \nGATA-4 at day 1, whereas at 2 weeks the GATA-4 DNA binding was significantly \nupregulated. To determine the functional role of GATA-4, peri-infarct \nintramyocardial delivery of adenoviral vector expressing GATA-4 was done before \nleft anterior descending coronary artery ligation. Hearts treated with GATA-4 \ngene transfer exhibited significantly increased ejection fraction and fractional \nshortening. Accordingly, infarct size was significantly reduced. To determine \nthe cardioprotective mechanisms of GATA-4, myocardial angiogenesis, rate of \napoptosis, c-kit+ cardiac stemlike cells, and genes regulated by GATA-4 were \nstudied. The number of capillaries and stemlike cells was significantly \nincreased, and decreased apoptosis was observed.\nCONCLUSION: These results indicate that the reversal of reduced GATA-4 activity \nprevents adverse postinfarction remodeling through myocardial angiogenesis, \nantiapoptosis, and stem cell recruitment. GATA-4-based gene transfer may \nrepresent a novel, efficient therapeutic approach for heart failure.",
"BACKGROUND: The heart is a highly vascular organ and prolonged interruption of \nmyocardial blood flow initiates events that culminate in cardiac myocyte death. \nProposed experimental reparative strategies include harvesting potent cells \nfollowed by direct injection into ischemic myocardium to achieve myogenesis and \nangiogenesis.\nMETHODS: Accordingly, we set out to isolate and expand a purified population of \nadult rat putative cardiomyocyte precursors, and to identify their \ncharacteristics in vitro. By using an acute myocardial infarction model and \ndirect cell implantation, we further tested the hypothesis that these cells are \nan ideal cell source for myocardial regeneration and can enhance cardiac repair \nafter implantation into the ischemic rat heart.\nRESULTS: We describe here the identification of a subpopulation of primitive \ncells from rat heart, processing stem cell marker, c-kit and myogenic \ntranscriptional factors, GATA-4 and MEF 2C, and cardiac specific proteins, \ntroponin-I, alpha-sarcomeric actinin and connexin-43. They exhibited a high in \nvitro proliferative potential. These findings strongly suggest that these cells \nare putative cardiomyocyte precursors. After transplantation, they were able to \nbe retained and proliferate (13.63 +/- 5.97% after 2 weeks) within the ischemic \nheart. Progeny of implanted cells migrated along the infarcted scar, \nreconstituted regenerated cardiomyocytes with incorporation into host \nmyocardium, and inhibited cardiac remodeling with decreased scar formation.\nCONCLUSION: Our findings suggest that putative cardiomyocyte precursors isolated \nfrom adult heart could potentially be an autologous cell source for myocardial \nregeneration cell therapy.",
"BACKGROUND: Placement of an elastic biodegradable patch onto a subacute \nmyocardial infarct (MI) provides temporary elastic support that may act to \neffectively alter adverse left ventricular (LV) remodeling processes.\nMETHODS: Two weeks after permanent left coronary ligation in Lewis rats, the \ninfarcted anterior wall was covered with polyester urethane urea (MI + PEUU; n = \n15) or expanded polytetrafluoroethylene (MI + ePTFE; n = 15) patches, or had no \nimplantation (MI + sham; n = 12). Eight weeks after surgery, cardiac function \nand histology were assessed.\nRESULTS: The ventricular wall in the MI + ePTFE and MI + sham groups was \ncomposed of fibrous tissue, whereas PEUU implantation induced α-smooth muscle \nactin-positive muscle bundles coexpressing sarcomeric α-actinin and \ncardiac-specific troponin-T. This pattern of colocalization was also found in \ndeveloping embryonic myocardium. Cardiac transcription factors Nkx-2.5 and \nGATA-4 were strongly expressed in the muscle bundles. In the MI + sham group, \nend-diastolic LV cavity area (EDA) increased and the percentage of fractional \narea change (%FAC) decreased. For ePTFE patched animals, both EDA and %FAC \ndecreased. In contrast, with MI + PEUU patching, %FAC increased and EDA was \nmaintained. With dobutamine-stress echocardiography, MI + PEUU patched LVs \npossessed contractile reserve significantly larger than the MI + sham group.\nCONCLUSIONS: MI + PEUU patch implantation onto subacute infarcted myocardium \ninduced muscle cellularization with characteristics of early developmental \ncardiomyocytes as well as providing a functional reserve.",
"BACKGROUND: Recent studies have shown that bone marrow-derived stem cells \ndifferentiate into the phenotype of cardiomyocytes in vivo and in vitro. We \ntried to regenerate infarcted myocardium by implanting ex vivo transforming \ngrowth factor (TGF)-beta-preprogrammed CD117 (c-kit)-positive (CD117+) stem \ncells intramyocardially.\nMETHODS AND RESULTS: CD117+ cells were isolated from the bone marrow mononuclear \ncells of GFP-transgenic or normal C57/BL6 mice. The myogenic differentiation of \nCD117+ cells was achieved by cultivation with TGF-beta. Using an acute \nmyocardial infarction model, we also tried to regenerate infarcted myocardium by \nimplanting untreated (newly isolated) or preprogrammed (24 hours of cultivation \nwith 5 ng/mL TGF-beta1) CD117+ cells intramyocardially. TGF-beta increased the \ncellular expression of myosin, troponins, connexin-43, GATA-4, and NKx-2.5, \nwhich suggested that it induced the myogenic differentiation of CD117+ cells. \nCompared with the effects of PBS injection only, the microvessel density in the \ninfarcted myocardium was increased significantly 3 months after the implantation \nof either TGF-beta-preprogrammed or untreated CD117+ cells. Moreover, many of \nthe TGF-beta-preprogrammed CD117+ cells were stained positively for myosin, \nwhereas few of the untreated CD117+ cells were. Histological analysis revealed \nnewly regenerated myocardium in the left ventricular anterior wall after the \nimplantation of TGF-beta-preprogrammed cells but not untreated cells. \nFurthermore, the left ventricular percent fraction shortening was significantly \nhigher after the implantation of TGF-beta-preprogrammed cells than after the \nimplantation of untreated CD117+ cells.\nCONCLUSIONS: TGF-beta conducted the myogenic differentiation of CD117+ stem \ncells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the \nintramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively \nassisted the myocardial regeneration and induced therapeutic angiogenesis, \ncontributing to functional cardiac regeneration.",
"The expression pattern of angiotensin AT2 receptors with predominance during \nfetal life and upregulation under pathological conditions during tissue \ninjury/repair process suggests that AT2 receptors may exert an important action \nin injury/repair adaptive mechanisms. Less is known about AT2 receptors in acute \nischemia-induced cardiac injury. We aimed here to elucidate the role of AT2 \nreceptors after acute myocardial infarction. Double immunofluorescence staining \nshowed that cardiac AT2 receptors were mainly detected in clusters of small \nc-kit+ cells accumulating in peri-infarct zone and c-kit+AT2+ cells increased in \nresponse to acute cardiac injury. Further, we isolated cardiac c-kit+AT2+ cell \npopulation by modified magnetic activated cell sorting and fluorescence \nactivated cell sorting. These cardiac c-kit+AT2+ cells, represented \napproximately 0.19% of total cardiac cells in infarcted heart, were \ncharacterized by upregulated transcription factors implicated in cardiogenic \ndifferentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal \n(Tbx-3, c-Myc, Akt). When adult cardiomyocytes and cardiac c-kit+AT2+ cells \nisolated from infarcted rat hearts were cocultured, AT2 receptor stimulation in \nvitro inhibited apoptosis of these cocultured cardiomyocytes. Moreover, in vivo \nAT2 receptor stimulation led to an increased c-kit+AT2+ cell population in the \ninfarcted myocardium and reduced apoptosis of cardiomyocytes in rats with acute \nmyocardial infarction. These data suggest that cardiac c-kit+AT2+ cell \npopulation exists and increases after acute ischemic injury. AT2 receptor \nactivation supports performance of cardiomyocytes, thus contributing to \ncardioprotection via cardiac c-kit+AT2+ cell population.",
"Transplanted mesenchymal stem cells (MSC) release soluble factors that \ncontribute to cardiac repair and vascular regeneration. We hypothesized that \noverexpression of GATA-4 enhances the MSC secretome, thereby increasing cell \nsurvival and promoting postinfarction cardiac angiogenesis. MSCs harvested from \nmale rat bone marrow were transduced with GATA-4 (MSC(GATA-4)) using the murine \nstem cell virus retroviral expression system; control cells were either \nnontransduced (MSC(bas)) or transduced with empty vector (MSC(Null)). Compared \nwith these control cells, MSC(GATA-4) were shown by immunofluorescence, \nreal-time PCR, and Western blotting to have higher expression of GATA-4. An \nincreased expression of angiogenic factors in MSC(GATA-4) and higher MSC \nresistance against hypoxia were observed. Human umbilical vein endothelial cells \n(HUVEC) treated with MSC(GATA-4) conditioned medium exhibited increased \nformation of capillary-like structures and promoted migration, compared with \nHUVECs treated with MSC(Null) conditioned medium. MSC(GATA-4) were injected into \nthe peri-infarct region in an acute myocardial infarction model in \nSprague-Dawley rats developed by ligation of the left anterior descending \ncoronary artery. Survival of MSC(GATA-4), determined by Sry expression, was \nincreased at 4 days postengraftment. MSC(GATA-4)-treated animals showed \nsignificantly improved cardiac function as assessed by echocardiography. \nFurthermore, fluorescent microsphere and histological studies revealed increased \nblood flow and blood vessel density and reduced infarction size in \nMSC(GATA-4)-treated animals. We conclude that GATA-4 overexpression in MSCs \nincreased both MSC survival and angiogenic potential in ischemic myocardium and \nmay therefore represent a novel and efficient therapeutic approach for \npostinfarct remodeling.",
"Adult bone marrow (BM) harbors several small populations of cells which may \ncontribute to cardiac and endothelial repair, such as endothelial progenitor \ncells (EPCs), mesenchymal stromal cells (MSCs) and very small embryonic-like \ncells (VSELs) expressing several markers of pluripotent stem cells (PSCs), such \nas Oct-4, Nanog and SSEA-1. Such cells were identified in mice bone marrow, \nperipheral blood and solid organs as well as in umbilical cord blood (UCB) and \nperipheral blood (PB) in humans. The adult BM-derived VSELs may undergo \ndifferentiation into cells derived for all three germ layers, including \ncardiomyocytes and vascular endothelial cells. VSELs can be isolated using a \nmultiparameter live cell sorting technique with special gating strategy based on \ntheir small size, expression of stem cell markers (Sca-1 in mice, CXCR4 and \nCD133 in humans) and absence of hematopoietic lineage markers (CD45(-) Lin(-)). \nExperiments in murine models of myocardial infarction (MI) demonstrated \npopulation of VSELs expressed also early markers of cardiac and endothelial \nlineages (GATA-4, Nkx2.5/Csx, VE-cadherin, von Willebrand factor) which migrated \nto stromal-derived factor-1 (SDF-1) and other chemoattractant gradient and \nunderwent rapid mobilization into peripheral blood in experimental MI mice \nmodels. Recently, we demonstrated the mobilization of VSELs expressing PSC, \nearly cardiac and endothelial markers in patients with acute MI. In addition to \nBM, VSELs were also identified in several murine solid organs including the \nheart and brain, as well as in umbilical cord blood and peripheral blood in \nadult humans. We hypothesized that VSELs are quiescent progeny of \nepiblast-derived PSCs that are deposited during organogenesis in developing \norgans. In experimental MI intramyocardial injection of VSELs was more efficient \nthan that of HSCs at improving left ventricular ejection fraction and \nattenuation of myocardial hypertrophy. VSELs can be useful in translational \nstudies of cardiovascular repair.",
"Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose \ntissue-derived multi-lineage progenitor cells improved left ventricular function \nand survival of rats with myocardial infarction. Here we examined the effect of \nintracoronary artery transplantation of human CLCs in a swine model of chronic \nheart failure. Twenty-four pigs underwent balloon-occlusion of the first \ndiagonal branch followed by reperfusion, with a second balloon-occlusion of the \nleft ascending coronary artery 1 week later followed by reperfusion. Four weeks \nafter the second occlusion/reperfusion, 17 of the 18 surviving animals with \nsevere chronic MI (ejection fraction <35% by echocardiography) were \nimmunosuppressed then randomly assigned to receive either intracoronary artery \ntransplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with \nheparin. Intracoronary artery transplantation was followed by the distribution \nof DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at \npost-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac \nfunction in the hCLCs transplanted group, but not in the control animals, \nindicating myocardial functional recovery by hCLCs intracoronary \ntransplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted \nanimals were still alive compared with only 1 of the 5 control (p=0.0147). \nHistological studies at week 12 post-transplantation demonstrated engraftment of \nthe pre DiI-stained hCLCs into the scarred myocardium and their expression of \nhuman specific alpha-cardiac actin. Human alpha cardiac actin-positive cells \nalso expressed cardiac nuclear factors; nkx2.5 and GATA-4. Our results suggest \nthat intracoronary artery transplantation of hCLCs is a potentially effective \ntherapeutic strategy for future cardiac tissue regeneration."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006321', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D050980', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009203', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012038']
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train
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what is the role of IGF-1 in cardiac regeneration after myocardial infarction?
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summary
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Ischemia-reperfusion injury is a strong stimulus for both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of IGF-1. Furthermore, in an animal model of myocardial infarction, intracoronary administration of IGF-1 is shown to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function. IGF-1 is a potent modulator of stem cell replication, commitment to the myocyte lineage, and myocyte differentiation. In another study, the dual delivery of IGF-1 and HGF from affinity-binding alginate biomaterial prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry and increased the incidence of GATA-4-positive cell clusters. The addition of nanofiber-mediated IGF-1 delivery to Cardiac Progenitor Cells therapy improved in part the recovery of myocardial structure and function after infarction. IGF-1 promotes proliferation and survival of CPCs. The strategy of IGF-1 transgene expression has shown to induce massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.
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Ischemia-reperfusion injury is a strong stimulus for both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of IGF-1. Furthermore, in an animal model of myocardial infarction, intracoronary administration of IGF-1 is shown to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function. IGF-1 is a potent modulator of stem cell replication, commitment to the myocyte lineage, and myocyte differentiation. In another study, the dual delivery of IGF-1 and HGF from affinity-binding alginate biomaterial prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry and increased the incidence of GATA-4-positive cell clusters. The addition of nanofiber-mediated IGF-1 delivery to Cardiac Progenitor Cells therapy improved in part the recovery of myocardial structure and function after infarction. IGF-1 promotes proliferation and survival of CPCs. The strategy of IGF-1 transgene expression has shown to induce massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.
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[
"Ischemic heart disease is characterized chronically by a healed infarct, foci of \nmyocardial scarring, cavitary dilation, and impaired ventricular performance. \nThese alterations can only be reversed by replacement of scarred tissue with \nfunctionally competent myocardium. We tested whether cardiac progenitor cells \n(CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated \nlocally by hepatocyte growth factor and insulin-like growth factor-1 invade the \nscarred myocardium and generate myocytes and coronary vessels improving the \nhemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful \nchemoattractant of CPCs, and insulin-like growth factor-1 promotes their \nproliferation and survival. Injection of CPCs or growth factors led to the \nreplacement of approximately 42% of the scar with newly formed myocardium, \nattenuated ventricular dilation and prevented the chronic decline in function of \nthe infarcted heart. Cardiac repair was mediated by the ability of CPCs to \nsynthesize matrix metalloproteinases that degraded collagen proteins, forming \ntunnels within the fibrotic tissue during their migration across the scarred \nmyocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, \nexcluding cell fusion. Clinically, CPCs represent an ideal candidate cell for \ncardiac repair in patients with chronic heart failure. CPCs may be isolated from \nmyocardial biopsies and, following their expansion in vitro, administered back \nto the same patients avoiding the adverse effects associated with the use of \nnonautologous cells. Alternatively, growth factors may be delivered locally to \nstimulate resident CPCs and promote myocardial regeneration. These forms of \ntreatments could be repeated over time to reduce progressively tissue scarring \nand expand the working myocardium.",
"Strategies for cardiac repair include injection of cells, but these approaches \nhave been hampered by poor cell engraftment, survival, and differentiation. To \naddress these shortcomings for the purpose of improving cardiac function after \ninjury, we designed self-assembling peptide nanofibers for prolonged delivery of \ninsulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation \nfactor, to the myocardium, using a \"biotin sandwich\" approach. Biotinylated \nIGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated \nself-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 \nbut did not prevent self-assembly of the peptides into nanofibers within the \nmyocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased \nactivation of caspase-3, and increased expression of cardiac troponin I in \ncardiomyocytes. After injection into rat myocardium, biotinylated nanofibers \nprovided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in \nvivo increased activation of Akt in the myocardium. When combined with \ntransplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased \ncaspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% \ncompared with cells embedded within nanofibers alone or with untethered IGF-1. \nFinally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved \nsystolic function after experimental myocardial infarction, demonstrating how \nengineering the local cellular microenvironment can improve cell therapy.",
"BACKGROUND: Previous study demonstrated the improvement of cardiac function was \nproportional to the number of cells implanted. Therefore, increasing cell \nsurvival in the infarcted myocardium might contribute to the improvement of the \nfunctional benefit of cell transplantation.\nMETHODS AND RESULTS: MSCs were treated with IGF-1 in vitro and infused into the \nacute myocardial infarction rats via the tail vein. After treatment of MSCs with \nIGF-1 for 48 h, flow cytometric analysis showed marked enhancement of expression \nof CXCR4 in the cell surface. After 4 weeks of transplantation, we found 1) a \ngreater number of engrafted MSCs arrived and survived in the peri-infarct \nregion; 2) TnT protein expression and capillary density were enhanced; 3) LV \ncavitary dilation, transmural infarct thinning, deposition of total collagen in \nthe peri-infarct region and cardiac dysfunction were attenuated.\nCONCLUSION: 1) IGF-1 treatment has time-dependent and dose-dependent effects on \nCXCR4 expression in MSCs in vitro. 2) IGF-1 improves the efficacy of MSCs \ntransplantation in a rat model of myocardial infarction mainly via enhancement \nof the number of cells attracted into the infarcted heart. These findings \nprovide a novel stem cell therapeutic avenue against ischemic heart disease.",
"Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and \ninsulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the \ncorresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes \nCSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF \nand IGF-1 were injected in the hearts of infarcted mice to favor, respectively, \nthe translocation of CSCs-ECCs from the surrounding myocardium to the dead \ntissue and the viability and growth of these cells within the damaged area. To \nfacilitate migration and homing of CSCs-ECCs to the infarct, a growth factor \ngradient was introduced between the site of storage of primitive cells in the \natria and the region bordering the infarct. The newly-formed myocardium \ncontained arterioles, capillaries, and functionally competent myocytes that with \ntime increased in size, improving ventricular performance at healing and long \nthereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after \ntreatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of \nmyocytes reached the adult phenotype, varying in size from 10,000 to 20,000 \nmicrom3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 \nmyocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 \nmonths. Myocardial regeneration induced increased survival and rescued animals \nwith infarcts that were up to 86% of the ventricle, which are commonly fatal. In \nconclusion, the heart has an endogenous reserve of CSCs-ECCs that can be \nactivated to reconstitute dead myocardium and recover cardiac function.",
"We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like \ngrowth factor (IGF)-1 showed improved survival and engraftment in the infarcted \nheart and promoted stem cell recruitment through paracrine release of stromal \ncell-derived factor (SDF)-1alpha. Rat bone marrow-derived MSCs were used as \nnontransduced ((Norm)MSCs) or transduced with adenoviral-null vector \n((Null)MSCs) or vector encoding for IGF-1 ((IGF-1)MSCs). (IGF-1)MSCs secreted \nhigher IGF-1 until 12 days of observation (P<0.001 versus (Null)MSCs). Molecular \nstudies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and \ninhibition of glycogen synthase kinase 3beta besides release of SDF-1alpha in \nparallel with IGF-1 expression in (IGF-1)MSCs. For in vivo studies, 70 muL of \nDMEM without cells (group 1) or containing 1.5x10(6) (Null)MSCs (group 2) or \n(IGF-1)MSCs (group 3) were implanted intramyocardially in a female rat model of \npermanent coronary artery occlusion. One week later, immunoblot on rat heart \ntissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group \n3 and higher survival of (IGF-1)MSCs (P<0.06 versus (Null)MSCs) (n=6 per group). \nSDF-1alpha was increased in group 3 animal hearts (20-fold versus group 2), with \nmassive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells \ninto the infarcted heart. Infarction size was significantly reduced in cell \ntransplanted groups compared with the control. Confocal imaging after \nimmunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand \nfactor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of \nleft ventricular function, including ejection fraction and fractional \nshortening, were improved in group 3 as compared with group 1 (P<0.05). In \nconclusion, the strategy of IGF-1 transgene expression induced massive stem cell \nmobilization via SDF-1alpha signaling and culminated in extensive \nangiomyogenesis in the infarcted heart.",
"To determine whether IGF-1 opposes the stimulation of myocyte death in the \nsurviving myocardium after infarction, transgenic mice overexpressing human \nIGF-1B in myocytes (FVB.Igf+/-) and wild-type littermates at 1.5 and 2.5 mo of \nage were subjected to coronary ligation and killed 7 d later. Myocardial \ninfarction involved an average 50% of the left ventricle, and produced cardiac \nfailure. In the region proximate to infarction, myocyte apoptosis increased 4. \n2-fold and 2.1-fold in nontransgenics at 1.5 and 2.5 mo, respectively. \nCorresponding increases in myocyte necrosis were 1. 8-fold and 1.6-fold. In \ncontrast, apoptotic and necrotic myocyte death did not increase in FVB.Igf+/- \nmice at either age after infarction. In 2.5-mo-old infarcted nontransgenics, \nfunctional impairment was associated with a 29% decrease in wall thickness, 43% \nincrease in chamber diameter, and a 131% expansion in chamber volume. \nConversely, the changes in wall thickness, chamber diameter, and cavitary volume \nwere 41, 58, and 48% smaller in infarcted FVB.Igf+/- than in nontransgenics. The \ndifferential response to infarction of FVB.Igf+/- mice resulted in an attenuated \nincrease in diastolic wall stress, cardiac weight, and left and right \nventricular weight-to-body wt ratios. In conclusion, constitutive overexpression \nof IGF-1 prevented activation of cell death in the viable myocardium after \ninfarction, limiting ventricular dilation, myocardial loading, and cardiac \nhypertrophy.",
"BACKGROUND: Cell therapy with bone marrow-derived mononuclear cells (BMCs) can \nimprove recovery of cardiac function after ischemia; however, the molecular \nmechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators \nof gene expression and modulate the pathophysiology of cardiovascular diseases.\nMETHODS AND RESULTS: We demonstrated that intramyocardial delivery of BMCs in \ninfarcted mice regulates the expression of cardiac miRNAs and significantly \ndownregulates the proapoptotic miR-34a. In vitro studies confirmed that the \nsupernatant of BMC inhibited the expression of H(2)O(2)-induced miR-34a and \ncardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies \ndirected against insulin-like growth factor-1 (IGF-1). Indeed, IGF-1 \nsignificantly inhibited H(2)O(2)-induced miR-34a expression, and miR-34a \noverexpression abolished the antiapoptotic effect of IGF-1. Likewise, inhibition \nof IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 \nexpression and the protective effect on cardiac function and increased apoptosis \nand cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor \nand the mature miR-34a, but did not interfere with the transcription of the \nprimary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a.\nCONCLUSIONS: Together, our data demonstrate that the paracrine regulation of \ncardiac miRNAs by transplanted BMCs contributes to the protective effects of \ncell therapy. BMCs release IGF-1, which inhibits the processing of miR-34a, \nthereby blocking cardiomyocyte apoptosis.",
"Although most medicines have historically been small molecules, many newly \napproved drugs are derived from proteins. Protein therapies have been developed \nfor treatment of diseases in almost every organ system, including the heart. \nGreat excitement has now arisen in the field of regenerative medicine, \nparticularly for cardiac regeneration after myocardial infarction. Every year, \nmillions of people suffer from acute myocardial infarction, but the adult \nmammalian myocardium has limited regeneration potential. Regeneration of the \nheart after myocardium infarction is therefore an exciting target for protein \ntherapeutics. In this review, we discuss different classes of proteins that have \ntherapeutic potential to regenerate the heart after myocardial infarction. \nProtein candidates have been described that induce angiogenesis, including \nfibroblast growth factors and vascular endothelial growth factors, although thus \nfar clinical development has been disappointing. Chemotactic factors that \nattract stem cells, e.g., hepatocyte growth factor and stromal cell-derived \nfactor-1, may also be useful. Finally, neuregulins and periostin are proteins \nthat induce cell-cycle reentry of cardiomyocytes, and growth factors like IGF-1 \ncan induce growth and differentiation of stem cells. As our knowledge of the \nbiology of regenerative processes and the role of specific proteins in these \nprocesses increases, the use of proteins as regenerative drugs could develop as \na cardiac therapy.",
"The aim of this study was to investigate whether supplemental IGF-1Ea transgene \nexpression induces activation of local cardiac and bone marrow stem cell \npopulation to mediate mammalian heart repair. In physiologic conditions, cardiac \noverexpression of the IGF-1Ea propeptide is associated with an enrichment of \nc-Kit/Sca-1 positive side population cells in the bone marrow and the occurrence \nof an endothelial-primed CD34 positive side population in the heart. This \ncellular profile is shown here to correlate with the expression of cytokines \ninvolved in stem cell mobilization and vessel formation. This molecular and \ncellular interplay favored IGF-1Ea-mediated vessel formation in injured hearts. \nThe physiologic and pathologic connection between cytokines and stem cells in \nresponse to IGF-1Ea may represent an important model to understand how to elicit \nendogenous reparative signaling.",
"RATIONALE: Age and coronary artery disease may negatively affect the function of \nhuman cardiac stem cells (hCSCs) and their potential therapeutic efficacy for \nautologous cell transplantation in the failing heart.\nOBJECTIVE: Insulin-like growth factor (IGF)-1, IGF-2, and angiotensin II (Ang \nII), as well as their receptors, IGF-1R, IGF-2R, and AT1R, were characterized in \nc-kit(+) hCSCs to establish whether these systems would allow us to separate \nhCSC classes with different growth reserve in the aging and diseased myocardium.\nMETHODS AND RESULTS: C-kit(+) hCSCs were collected from myocardial samples \nobtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac \nsurgery for coronary artery disease. The expression of IGF-1R in hCSCs \nrecognized a young cell phenotype defined by long telomeres, high telomerase \nactivity, enhanced cell proliferation, and attenuated apoptosis. In addition to \nIGF-1, IGF-1R(+) hCSCs secreted IGF-2 that promoted myocyte differentiation. \nConversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, \nidentified senescent hCSCs with impaired growth reserve and increased \nsusceptibility to apoptosis. The ability of IGF-1R(+) hCSCs to regenerate \ninfarcted myocardium was then compared with that of unselected c-kit(+) hCSCs. \nIGF-1R(+) hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of \nIGF-1R(+) hCSCs with IGF-2 resulted in the formation of more mature myocytes and \nsuperior recovery of ventricular structure.\nCONCLUSIONS: hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which \nare potent modulators of stem cell replication, commitment to the myocyte \nlineage, and myocyte differentiation, which points to this hCSC subset as the \nideal candidate cell for the management of human heart failure.",
"The purpose of this study was to determine whether the heart in large mammals \ncontains cardiac progenitor cells that regulate organ homeostasis and regenerate \ndead myocardium after infarction. We report that the dog heart possesses a \ncardiac stem cell pool characterized by undifferentiated cells that are \nself-renewing, clonogenic, and multipotent. These clonogenic cells and early \ncommitted progeny possess a hepatocyte growth factor (HGF)-c-Met and an \ninsulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated \nto induce their migration, proliferation, and survival. Therefore, myocardial \ninfarction was induced in chronically instrumented dogs implanted with \nsonomicrometric crystals in the region of the left ventricular wall supplied by \nthe occluded left anterior descending coronary artery. After infarction, HGF and \nIGF-1 were injected intramyocardially to stimulate resident cardiac progenitor \ncells. This intervention led to the formation of myocytes and coronary vessels \nwithin the infarct. Newly generated myocytes expressed nuclear and cytoplasmic \nproteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas \nalpha-sarcomeric actin, cardiac myosin heavy chain, troponin I, and \nalpha-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were \nalso present. Myocardial reconstitution resulted in a marked recovery of \ncontractile performance of the infarcted heart. In conclusion, the activation of \nresident primitive cells in the damaged dog heart can promote a significant \nrestoration of dead tissue, which is paralleled by a progressive improvement in \ncardiac function. These results suggest that strategies capable of activating \nthe growth reserve of the myocardium may be important in cardiac repair after \nischemic injury.",
"Proper spatio-temporal delivery of multiple therapeutic proteins represents a \nmajor challenge in therapy strategies aimed at inducing myocardial regeneration \nafter myocardial infarction (MI). We hypothesized that the dual delivery of \ninsulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) by \ninjectable affinity-binding alginate biomaterial would maximize their \ntherapeutic effects, leading to a more favorable course of tissue restoration \nafter acute MI. A sequential release of IGF-1 followed by HGF was attained from \naffinity-binding alginate biomaterial, which also protected the proteins from \nproteolysis (shown by mass spectroscopy). The released factors retained \nbioactivity, as judged by their capability to activate their respective \nsignaling pathways and to prevent cardiomyocyte apoptosis in vitro. In a rat \nmodel of acute MI, an intramyocardial injection of the dual IGF-1/HGF \naffinity-bound alginate biomaterial preserved scar thickness, attenuated infarct \nexpansion and reduced scar fibrosis after 4 weeks, concomitantly with increased \nangiogenesis and mature blood vessel formation at the infarct. Furthermore, this \ntreatment prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry \nand increased the incidence of GATA-4-positive cell clusters. The dual delivery \nof IGF-1 and HGF from affinity-binding alginate biomaterial represents a useful \nstrategy to treat MI. It showed a marked therapeutic efficacy at various tissue \nlevels, as well as potential to induce endogenous regeneration of cardiac \nmuscle.",
"BACKGROUND: Myoblast transplantation (Tx) is promising for the improvement of \ncardiac function in ischemic cardiomyopathy. Insulin-like growth factor-1 \n(IGF-1) has anti-apoptotic and angiogenic effects, and induces myocyte \nhypertrophy. Our hypothesis is that topical and slow-release IGF-1 enhances the \nefficacy of Tx through its multiple functions.\nMETHODS: Four weeks after coronary artery ligation, Lewis rats were divided into \nfour groups: (1) IGF-1+Tx, injection of 6 x 10(6) myoblasts into the infarcted \narea with placement of an IGF-1-impregnated sheet on the left ventricular (LV) \nfree wall; (2) Tx, Tx alone; (3) IGF-1, IGF-1 sheet alone; and (4) control. We \nmeasured cardiac function and performed immunohistochemical examinations.\nRESULTS: At 4 weeks after treatment, LV diastolic dimension was the smallest, \nend-systolic elastance was the highest, and tau was the smallest in the IGF-1+Tx \ngroup. The graft volume in the IGF-1+Tx group was 3-fold larger than in the Tx \ngroup. One day after transplantation, TUNEL-positive donor cells were fewer in \nthe IGF-1+Tx than in the Tx group. Western blot analysis demonstrated that the \nphosphorylation of Akt increased and the expression of Bax decreased in the \ntransplanted area of IGF-1+Tx rats compared with Tx rats. The vascular density \nin the peri-infarcted area was larger in IGF-1+Tx than in Tx rats. The mean \ndiameter of graft-derived myotubes was larger in IGF-1+Tx than in Tx animals.\nCONCLUSIONS: IGF-1 increases the graft volume and enhances the efficacy of Tx in \nthe chronic myocardial infarction model due to its multiple effects of \npreventing apoptosis, inducing angiogenesis, and promoting myoblast growth.",
"To explore how cardiac regeneration and cell turnover adapts to disease, \ndifferent forms of stress were studied for their effects on the cardiac \nprogenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, \nand mast cells. Adult female rats were examined during pregnancy, after \nmyocardial infarction and ischemia-reperfusion injury with/out insulin like \ngrowth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac \nsub-domains were analyzed at one and two weeks post-intervention, both at the \nmRNA and protein levels. While pregnancy and myocardial infarction up-regulated \nNkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion \ninjury induced the strongest up-regulation which occurred globally throughout \nthe entire heart and not just around the site of injury. This response seems to \nbe partly mediated by increased endogenous production of IGF-1 and HGF. Contrary \nto c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while \nischemia-reperfusion injury induced not a global but a focal up-regulation in \nthe outflow tract and also in the peri-ischemic region, correlating with the \nup-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the \nendogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. \nc-Kit expression was not further influenced by the exogenous growth factors. \nThis indicates that there is a spatial mismatch between on one hand c-Kit and \nNkx2.5 expression and on the other hand Isl1 expression. In conclusion, \nischemia-reperfusion injury was the strongest stimulus with both global and \nfocal cardiomyocyte progenitor cell marker up-regulations, correlating to the \nendogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy \ninduced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes \nthroughout the heart. Utilization of these pathways could provide new strategies \nfor the treatment of cardiac disease.",
"OBJECTIVES: The purpose of this study was to test the ability of insulin-like \ngrowth factor (IGF)-1/hepatocyte growth factor (HGF) to activate resident \nendogenous porcine cardiac stem/progenitor cells (epCSCs) and to promote \nmyocardial repair through a clinically applicable intracoronary injection \nprotocol in a pig model of myocardial infarction (MI) relevant to human disease.\nBACKGROUND: In rodents, cardiac stem/progenitor cell (CSC) transplantation as \nwell as in situ activation through intramyocardial injection of specific growth \nfactors has been shown to result in myocardial regeneration after acute \nmyocardial infarction (AMI).\nMETHODS: Acute MI was induced in pigs by a 60-min percutaneous transluminal \ncoronary angiography left anterior descending artery occlusion. The IGF-1 and \nHGF were co-administered through the infarct-related artery in a single dose \n(ranging from 0.5 to 2 μg HGF and 2 to 8 μg IGF-1) 30 min after coronary \nreperfusion. Pigs were sacrificed 21 days later for dose-response relationship \nevaluation by immunohistopathology or 2 months later for cardiac function \nevaluation by cardiac magnetic resonance imaging.\nRESULTS: The IGF-1/HGF activated c-kit positive-CD45 negative epCSCs and \nincreased their myogenic differentiation in vitro. The IGF-1/HGF, in a \ndose-dependent manner, improved cardiomyocyte survival, and reduced fibrosis and \ncardiomyocyte reactive hypertrophy. It significantly increased c-kit \npositive-CD45 negative epCSC number and fostered the generation of new \nmyocardium (myocytes and microvasculature) in infarcted and peri-infarct/border \nregions at 21 and 60 days after AMI. The IGF-1/HGF reduced infarct size and \nimproved left ventricular function at 2 months after AMI.\nCONCLUSIONS: In an animal model of AMI relevant to the human disease, \nintracoronary administration of IGF-1/HGF is a practical and effective strategy \nto reduce pathological cardiac remodeling, induce myocardial regeneration, and \nimprove ventricular function.",
"The injured mammalian heart is particularly susceptible to tissue deterioration, \nscarring, and loss of contractile function in response to trauma or sustained \ndisease. We tested the ability of a locally acting insulin-like growth factor-1 \nisoform (mIGF-1) to recover heart functionality, expressing the transgene in the \nmouse myocardium to exclude endocrine effects on other tissues. supplemental \nmIGF-1 expression did not perturb normal cardiac growth and physiology. \nRestoration of cardiac function in post-infarct mIGF-1 transgenic mice was \nfacilitated by modulation of the inflammatory response and increased \nantiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased \nproliferative activity several weeks after injury. The canonical signaling \npathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, \nwhich instead activated alternate PDK1 and SGK1 signaling intermediates. The \nrobust response achieved with the mIGF-1 isoform provides a mechanistic basis \nfor clinically feasible therapeutic strategies for improving the outcome of \nheart disease.",
"BACKGROUND: Cardiac progenitor cells (CPCs) possess the insulin-like growth \nfactor-1 (IGF-1)-IGF-1 receptor system, and IGF-1 can be tethered to \nself-assembling peptide nanofibers (NF-IGF-1), leading to prolonged release of \nthis growth factor to the myocardium. Therefore, we tested whether local \ninjection of clonogenic CPCs and NF-IGF-1 potentiates the activation and \ndifferentiation of delivered and resident CPCs enhancing cardiac repair after \ninfarction.\nMETHODS AND RESULTS: Myocardial infarction was induced in rats, and untreated \ninfarcts and infarcts treated with CPCs or NF-IGF-1 only and CPCs and NF-IGF-1 \ntogether were analyzed. With respect to infarcts exposed to CPCs or NF-IGF-1 \nalone, combination therapy resulted in a greater increase in the ratio of left \nventricular mass to chamber volume and a better preservation of +dP/dt, -dP/dt, \nejection fraction, and diastolic wall stress. Myocardial regeneration was \ndetected in all treated infarcts, but the number of newly formed myocytes with \ncombination therapy was 32% and 230% higher than with CPCs and NF-IGF-1, \nrespectively. Corresponding differences in the volume of regenerated myocytes \nwere 48% and 115%. Similarly, the length density of newly formed coronary \narterioles with both CPCs and NF-IGF-1 was 73% and 83% greater than with CPCs \nand NF-IGF-1 alone, respectively. Importantly, activation of resident CPCs by \nparacrine effects contributed to cardiomyogenesis and vasculogenesis. \nCollectively, CPCs and NF-IGF-1 therapy reduced infarct size more than CPCs and \nNF-IGF-1 alone.\nCONCLUSIONS: The addition of nanofiber-mediated IGF-1 delivery to CPC therapy \nimproved in part the recovery of myocardial structure and function after \ninfarction."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009203', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012038', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D007334']
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train
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what is the role of MEF-2 in cardiomyocyte differentiation?
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summary
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The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors that are essential for differentiation of all muscle lineages but their mechanisms of action remain largely undefined. MEF2C expression initiates cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression. Inactivation of the MEF2C gene causes cardiac developmental arrest and severe downregulation of a number of cardiac markers including atrial natriuretic factor (ANF). BMP-2, a regulator of cardiac development during embryogenesis, was shown to increase PI 3-kinase activity in cardiac precursor cells, resulting in increased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A. Furthermore, expression of MEF-2A increased MHC expression in a PI 3-kinase-dependent manner. Other studies showed that Gli2 and MEF2C proteins form a complex, capable of synergizing on cardiomyogenesis-related promoters. Dominant interference of calcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity seen during myoblast differentiation, as well as the expression of endogenous MEF2-target genes. These findings show that MEF-2 can direct early stages of cell differentiation into a cardiomyogenic pathway.
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The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors that are essential for differentiation of all muscle lineages but their mechanisms of action remain largely undefined. MEF2C expression initiates cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression. Inactivation of the MEF2C gene causes cardiac developmental arrest and severe downregulation of a number of cardiac markers including atrial natriuretic factor (ANF). BMP-2, a regulator of cardiac development during embryogenesis, was shown to increase PI 3-kinase activity in cardiac precursor cells, resulting in increased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A. Furthermore, expression of MEF-2A increased MHC expression in a PI 3-kinase-dependent manner. Other studies showed that Gli2 and MEF2C proteins form a complex, capable of synergizing on cardiomyogenesis-related promoters. Dominant interference of calcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity seen during myoblast differentiation, as well as the expression of endogenous MEF2-target genes. These findings show that MEF-2 can direct early stages of cell differentiation into a cardiomyogenic pathway.
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[
"Histone deacetylase (HDAC) inhibitors are promising new epi-drugs, but the \npresence of both class I and class II enzymes in HDAC complexes precludes a \ndetailed elucidation of the individual HDAC functions. By using the class \nII-specific HDAC inhibitor MC1568, we separated class I- and class II-dependent \neffects and defined the roles of class II enzymes in muscle differentiation in \ncultured cells and in vivo. MC1568 arrests myogenesis by (i) decreasing myocyte \nenhancer factor 2D (MEF2D) expression, (ii) by stabilizing the HDAC4-HDAC3-MEF2D \ncomplex, and (iii) paradoxically, by inhibiting differentiation-induced MEF2D \nacetylation. In vivo MC1568 shows an apparent tissue-selective HDAC inhibition. \nIn skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 \nwithout affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a \nrepressed state. Our results suggest that HDAC class II-selective inhibitors \nmight have a therapeutic potential for the treatment of muscle and heart \ndiseases.",
"The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors \nthat are essential for differentiation of all muscle lineages but their \nmechanisms of action remain largely undefined. In mammals, the earliest site of \nMEF2 expression is the heart where the MEF2C isoform is detectable as early as \nembryonic day 7.5. Inactivation of the MEF2C gene causes cardiac developmental \narrest and severe downregulation of a number of cardiac markers including atrial \nnatriuretic factor (ANF). However, most of these promoters contain no or low \naffinity MEF2 binding sites and they are not significantly activated by any MEF2 \nproteins in heterologous cells suggesting a dependence on a cardiac-enriched \ncofactor for MEF2 action. We provide evidence that MEF2 proteins are recruited \nto target promoters by the cell-specific GATA transcription factors, and that \nMEF2 potentiates the transcriptional activity of this family of \ntissue-restricted zinc finger proteins. Functional MEF2/GATA-4 synergy involves \nphysical interaction between the MEF2 DNA-binding domain and the carboxy zinc \nfinger of GATA-4 and requires the activation domains of both proteins. However, \nneither MEF2 binding sites nor MEF2 DNA binding capacity are required for \ntranscriptional synergy. The results unravel a novel pathway for transcriptional \nregulation by MEF2 and provide a molecular paradigm for elucidating the \nmechanisms of action of MEF2 in muscle and non-muscle cells.",
"The calcium/calmodulin-dependent protein phosphatase calcineurin is required for \nthe induction of transcriptional events that initiate and promote myogenic \ndifferentiation. An important effector for calcineurin in striated muscle is the \ntranscription factor myocyte enhancer factor 2 (MEF2). The targeting of the \nenzyme and substrate to specific intracellular compartments by scaffold proteins \noften confers specificity in phosphatase activity. We now show that the \nscaffolding protein mAKAP organizes a calcineurin/MEF2 signaling complex in \nmyocytes, regulating gene transcription. A calcineurin/mAKAP/MEF2 complex can be \nisolated from C2C12 cells and cardiac myocytes, and the calcineurin/MEF2 \nassociation is dependent on mAKAP expression. We have identified a peptide \ncomprising the calcineurin binding domain in mAKAP that can disrupt the binding \nof the phosphatase to the scaffold in vivo. Dominant interference of \ncalcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity \nseen during myoblast differentiation, as well as the expression of endogenous \nMEF2-target genes. Furthermore, disruption of calcineurin binding to mAKAP in \ncardiac myocytes inhibits adrenergic-induced cellular hypertrophy. Together \nthese data illustrate the importance of calcineurin anchoring by the mAKAP \nscaffold for MEF2 regulation.",
"The growth and differentiation factor bone morphogenetic protein-2 (BMP-2) \nregulates cardiac development during vertebrate embryogenesis. In cardiac \nprecursor cells, BMP-2 has recently been shown to induce expression of cardiac \ntranscription factors, including myocyte enhancer factor 2A (MEF-2A). The \nspecific signal transduction mechanism by which BMP-2 regulates these actions is \nnot known. We investigated the role of phosphatidylinositol (PI) 3-kinase in \nregulating these processes in cardiomyocyte precursor CL6 cells. BMP-2 increased \nPI 3-kinase activity in these cells in a time-dependent manner, resulting in \nincreased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A. \nInhibition of PI 3-kinase abolished these actions of BMP-2, indicating the \ninvolvement of PI 3-kinase in these processes. Furthermore, BMP-2 stimulated \nspecific protein.DNA complex formation when an MEF-2 DNA recognition element was \nused as probe. Antibody supershift assay confirmed the presence of MEF-2A in \nthis protein.DNA complex. Inhibition of PI 3-kinase activity completely \nprevented the MEF-2A.DNA complex formation. BMP-2 also increased transcription \nof a reporter gene driven by an MEF-2-specific DNA element in a PI \n3-kinase-dependent manner. Ectopic expression of MEF-2A increased BMP-2 \ntranscription to the same extent induced by BMP-2, indicating that MEF-2A may \nparticipate in BMP-2 autoregulation in CL6 cells. Expression of dominant \nnegative PI 3-kinase completely abolished BMP-2-induced as well as \nMEF-2A-mediated BMP-2 transcription. Furthermore expression of MEF-2A increased \nMHC expression in a PI 3-kinase-dependent manner. Together these data provide \nthe first evidence that BMP-2-induced PI 3-kinase signaling regulates MEF-2A \nexpression and define a mechanism of MEF-2A-dependent BMP-2 transcription.",
"The Myocyte Enhancer Factor-2 (MEF2) family of transcription factors regulates \ngene expression during cardiomyocyte differentiation and adaptation of the \nmyocardium to stress. MEF2 activity is enhanced by increasing its transcription \nand by MAPK-dependent phosphorylation, and is reduced by binding to class-II \nHistone Deacetylases and by miR-1-mediated degradation of its transcript. Here \nwe show that MEF2 protein abundance is regulated at the translational level, \ndetermining myocyte size, during hypertrophy. In order to reduce MEF2 protein \nexpression, its silencing through RNA interference required serum deprivation \nand, even in this condition, MEF2 protein abundance recovered to basal levels in \npresence of phenylephrine. Hypertrophic agonist stimulation of neonatal \nventricular cardiomyocytes increased Mef2 expression by enhancing its \ntranslation, without changing its transcription or blocking degradation of the \nprotein. MEF2 abundance was increased by Calcineurin overexpression in vivo and \nwas reduced by Calcineurin inhibition in vitro, without affecting Mef2 mRNA \nlevels. Calcineurin activity influenced expression of Polypyrimidine Tract \nProtein (PTB), contributing to MEF2 translation. Thus, our results show a \npreviously unrecognized but relevant level of MEF2 activity regulation through \nthe control of its translation that involves Calcineurin and PTB.",
"The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only \nimportant for controlling gene expression in normal cellular programs, like \nmuscle differentiation, T-cell apoptosis, neuronal survival, and synaptic \ndifferentiation, but has also been linked to cardiac hypertrophy and other \npathological conditions. Lysine acetylation has been shown to modulate MEF2 \nfunction, but it is not so clear which deacetylase(s) is involved. We report \nhere that treatment of HEK293 cells with trichostatin A or nicotinamide \nupregulated MEF2D acetylation, suggesting that different deacetylases catalyze \nthe deacetylation. Related to the trichostatin A sensitivity, histone \ndeacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little \ndeacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated \nMEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 \nfailed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize \nprimarily the MEF2-specific domain, we found that HDAC3 interacts directly with \nthe MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and \np300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the \nnuclear receptor corepressor SMRT (silencing mediator of retinoid acid and \nthyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards \nMEF2 and PCAF. Supporting the physical interaction and deacetylase activity, \nHDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These \nresults reveal an unexpected role for HDAC3 and suggest a novel pathway through \nwhich MEF2 activity is controlled in vivo.",
"A myocyte-specific enhancer-binding factor (MEF-2) DNA binding site was \nidentified in the rat alpha-myosin heavy chain (MHC) gene adjacent to the E-box \nbinding site for alpha-MHC binding factor-2 (BF-2). Mutation of the MEF-2 site, \nwithin the context of the full-length promoter, reduced activity by 85 and 80% \nin neonatal cardiomyocytes and the adult heart, respectively. Mutation of the \nBF-2 site reduced activity approximately 70% in both models. A MEF-2/BF-2 double \nmutant gave significantly less activity than the BF-2 mutant but not the MEF-2 \nmutant, suggesting the possibility that BF-2 and MEF-2 interact. Mutations in \nMEF-2, which decreased functional activity, also abolished MEF-2 DNA binding \nactivity. MEF-2 DNA binding activity was present in the developing heart, \nreached a peak in the late fetal and early neonatal stages, and then declined to \nlow levels in the adult heart. The adult levels were sufficient to support \nalpha-MHC gene expression. MEF-2 activity was increased 2-3-fold in the adult \nheart subjected to a pressure or volume overload. Two working models are \nproposed as possible explanations of the antithetic relationship between MEF-2 \nlevels and alpha-MHC gene expression.",
"Mitochondrial morphology is crucial for tissue homeostasis, but its role in cell \ndifferentiation is unclear. We found that mitochondrial fusion was required for \nproper cardiomyocyte development. Ablation of mitochondrial fusion proteins \nMitofusin 1 and 2 in the embryonic mouse heart, or gene-trapping of Mitofusin 2 \nor Optic atrophy 1 in mouse embryonic stem cells (ESCs), arrested mouse heart \ndevelopment and impaired differentiation of ESCs into cardiomyocytes. Gene \nexpression profiling revealed decreased levels of transcription factors \ntransforming growth factor-β/bone morphogenetic protein, serum response factor, \nGATA4, and myocyte enhancer factor 2, linked to increased Ca(2+)-dependent \ncalcineurin activity and Notch1 signaling that impaired ESC differentiation. \nOrchestration of cardiomyocyte differentiation by mitochondrial morphology \nreveals how mitochondria, Ca(2+), and calcineurin interact to regulate Notch1 \nsignaling.",
"The transcription factors Gli2 (glioma-associated factor 2), which is a \ntransactivator of Sonic Hedgehog (Shh) signalling, and myocyte enhancer factor \n2C (MEF2C) play important roles in the development of embryonic heart muscle and \nenhance cardiomyogenesis in stem cells. Although the physiological importance of \nShh signalling and MEF2 factors in heart development is well known, the \nmechanistic understanding of their roles is unclear. Here, we demonstrate that \nGli2 and MEF2C activated each other's expression while enhancing \ncardiomyogenesis in differentiating P19 EC cells. Furthermore, dominant-negative \nmutant proteins of either Gli2 or MEF2C repressed each other's expression, while \nimpairing cardiomyogenesis in P19 EC cells. In addition, chromatin \nimmunoprecipitation (ChIP) revealed association of Gli2 to the Mef2c gene, and \nof MEF2C to the Gli2 gene in differentiating P19 cells. Finally, \nco-immunoprecipitation studies showed that Gli2 and MEF2C proteins formed a \ncomplex, capable of synergizing on cardiomyogenesis-related promoters containing \nboth Gli- and MEF2-binding elements. We propose a model whereby Gli2 and MEF2C \nbind each other's regulatory elements, activate each other's expression and form \na protein complex that synergistically activates transcription, enhancing \ncardiac muscle development. This model links Shh signalling to MEF2C function \nduring cardiomyogenesis and offers mechanistic insight into their in vivo \nfunctions.",
"The Nkx2-5 homeodomain protein plays a key role in cardiomyogenesis. Ectopic \nexpression in frog and zebrafish embryos results in an enlarged myocardium; \nhowever, expression of Nkx2-5 in fibroblasts was not able to trigger the \ndevelopment of beating cardiac muscle. In order to examine the ability of Nkx2-5 \nto modulate endogenous cardiac specific gene expression in cells undergoing \nearly stages of differentiation, P19 cell lines overexpressing Nkx2-5 were \ndifferentiated in the absence of Me2SO. Nkx2-5 expression induced \ncardiomyogenesis in these cultures aggregated without Me2SO. During \ndifferentiation into cardiac muscle, Nkx2-5 expression resulted in the \nactivation of myocyte enhancer factor 2C (MEF2C), but not MEF2A, -B, or -D. In \norder to compare the abilities of Nkx2-5 and MEF2C to induce cellular \ndifferentiation, P19 cells overexpressing MEF2C were aggregated in the absence \nof Me2SO. Similar to Nkx2-5, MEF2C expression initiated cardiomyogenesis, \nresulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, \nNkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression. These \nfindings indicate the presence of a positive regulatory network between Nkx2-5 \nand MEF2C and show that both factors can direct early stages of cell \ndifferentiation into a cardiomyogenic pathway."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D032383', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0035051', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D064326']
|
530b7ae4970c65fa6b00000b
|
[
18832581,
21611174,
22982064,
23293297,
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23270300,
23166366
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train
|
what is the role of TGFbeta in cardiac regeneration after myocardial injury?
|
summary
|
TGFβ is activated in the myocardium in response to injury and plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. In fact, upregulation of TGF-beta signaling promotes the formation of a myofibroblast-like phenotype. TGF-beta interacts with bone morphogenic protein and Wnt pathways to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells, determining whether functional regeneration or the formation of scar tissue follows an injury. In addition, TGF-beta enhances the formation of cardiospheres and could potentially enhance the regenerative potential of adult cardiac progenitor cells.
|
TGFβ is activated in the myocardium in response to injury and plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. In fact, upregulation of TGF-beta signaling promotes the formation of a myofibroblast-like phenotype. TGF-beta interacts with bone morphogenic protein and Wnt pathways to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells, determining whether functional regeneration or the formation of scar tissue follows an injury. In addition, TGF-beta enhances the formation of cardiospheres and could potentially enhance the regenerative potential of adult cardiac progenitor cells.
|
[
"The regulation of valve interstitial cell (VIC) function in response to tissue \ninjury and valve disease is not well understood. Because transforming growth \nfactor-beta (TGF-beta) has been implicated in tissue repair, we tested the \nhypothesis that TGF-beta is a regulator of VIC activation and associated cell \nresponses that occur during early repair processes. We used a well-characterized \nwound model that was created by mechanical denudation of a confluent VIC \nmonolayer to study activation and repair 24 hours after wounding. VIC activation \nwas demonstrated by immunofluorescent localization of alpha-smooth muscle actin \n(alpha-SMA), and alpha-SMA mRNA levels were quantified by real-time polymerase \nchain reaction. Proliferation and apoptosis were quantified by bromodeoxyuridine \nstaining and terminal deoxynucleotidyl transferase dUTP nick end labeling, \nrespectively. Repair was quantified by measuring VIC extension into the wound, \nand TGF-beta expression was shown by immunofluorescent localization of \nintracellular TGF-beta. Compared with nonwounded monolayers, VICs at the wound \nedge showed alpha-SMA staining, increased alpha-SMA mRNA content, elongation \ninto the wound with stress fibers, proliferation, and apoptosis. VICs at the \nwound edge also showed increased TGF-beta and pSmad2/3 staining with \nco-expression of alpha-SMA. Addition of TGF-beta neutralizing antibody to the \nwound decreased VIC activation, alpha-SMA mRNA content, proliferation, \napoptosis, wound closure rate, and stress fibers. Conversely, exogenous addition \nof TGF-beta to the wound increased VIC activation, proliferation, wound closure \nrate, and stress fibers. Thus, wounding activates VICs, and TGF-beta signaling \nmodulates VIC response to injury.",
"Growing evidence suggests the Wnt family of secreted glycoproteins and their \nassociated signaling pathways, linked to development, are recapitulated during \nwound repair and regeneration events. However, the role of the Wnt pathway in \nsuch settings remains unclear. In the current study, we treated mouse \nfibroblasts with 250 ng/mL of recombinant Wnt3a for 72 hours and examined its \naffect on cell morphology and function. Wnt3a induced a spindle-like morphology \nin fibroblasts characterized by the increased formation of stress fibres. Wnt3a \ndecreased the proliferation of fibroblasts, but significantly increased cell \nmigration as well as fibroblast-mediated contraction of a collagen lattice. \nWnt3a significantly increased the expression of TGF-β and its associated \nsignaling through SMAD2. Consistent with this, we observed significantly \nincreased smooth muscle α-actin expression and incorporation of this contractile \nprotein into stress fibres following Wnt3a treatment. Knockdown of β-catenin \nusing siRNA reversed the Wnt3a-induced smooth muscle α-actin expression, \nsuggesting these changes were dependent on canonical Wnt signaling through \nβ-catenin. Neutralization of TGF-β with a blocking antibody significantly \ninhibited the Wnt3a-induced smooth muscle α-actin expression, indicating these \nchanges were dependent on the increased TGF-β signaling. Collectively, this data \nstrongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype \nin cultured fibroblasts, in part, by upregulating TGF-β signaling through SMAD2 \nin a β-catenin-dependent mechanism. As myofibroblasts are critical regulators of \nwound healing responses, these findings may have important implications for our \nunderstanding of normal and aberrant injury and repair events.",
"Fibroblasts are the predominant cell type in the cardiac interstitium. As the \nmain matrix-producing cells in the adult mammalian heart, fibroblasts maintain \nthe integrity of the extracellular matrix network, thus preserving geometry and \nfunction. Following myocardial infarction fibroblasts undergo dynamic phenotypic \nalterations and direct the reparative response. Due to their strategic location, \ncardiac fibroblasts serve as sentinel cells that sense injury and activate the \ninflammasome secreting cytokines and chemokines. During the proliferative phase \nof healing, infarct fibroblasts undergo myofibroblast transdifferentiation \nforming stress fibers and expressing contractile proteins (such as α-smooth \nmuscle actin). Mechanical stress, transforming growth factor (TGF)-β/Smad3 \nsignaling and alterations in the composition of the extracellular matrix induce \nacquisition of the myofibroblast phenotype. In the highly cellular and growth \nfactor-rich environment of the infarct, activated myofibroblasts produce matrix \nproteins, proteases and their inhibitors regulating matrix metabolism. As the \ninfarct matures, \"stress-shielding\" of myofibroblasts by the cross-linked matrix \nand growth factor withdrawal may induce quiescence and ultimately cause \napoptotic death. Because of their critical role in post-infarction cardiac \nremodeling, fibroblasts are promising therapeutic targets following myocardial \ninfarction. However, the complexity of fibroblast functions and the \npathophysiologic heterogeneity of post-infarction remodeling in the clinical \ncontext discourage oversimplified approaches in clinical translation. This \narticle is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac \nPathways of Differentiation, Metabolism and Contraction.",
"Adult mammalian cardiomyocytes have little capacity to proliferate in response \nto injury, a deficiency that underlies the poor regenerative ability of human \nhearts after myocardial infarction. By contrast, zebrafish regenerate heart \nmuscle after trauma by inducing proliferation of spared cardiomyocytes, \nproviding a model for identifying manipulations that block or enhance these \nevents. Although direct genetic or chemical screens of heart regeneration in \nadult zebrafish present several challenges, zebrafish embryos are ideal for \nhigh-throughput screening. Here, to visualize cardiomyocyte proliferation events \nin live zebrafish embryos, we generated transgenic zebrafish lines that employ \nfluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. We \nthen performed a chemical screen and identified several small molecules that \nincrease or reduce cardiomyocyte proliferation during heart development. These \ncompounds act via Hedgehog, Insulin-like growth factor or Transforming growth \nfactor β signaling pathways. Direct examination of heart regeneration after \nmechanical or genetic ablation injuries indicated that these pathways are \nactivated in regenerating cardiomyocytes and that they can be pharmacologically \nmanipulated to inhibit or enhance cardiomyocyte proliferation during adult heart \nregeneration. Our findings describe a new screening system that identifies \nmolecules and pathways with the potential to modify heart regeneration.",
"Autologous cardiac progenitor cells (CPCs) isolated as cardiospheres (CSps) \nrepresent a promising candidate for cardiac regenerative therapy. A better \nunderstanding of the origin and mechanisms underlying human CSps formation and \nmaturation is undoubtedly required to enhance their cardiomyogenic potential. \nEpithelial-to-mesenchymal transition (EMT) is a key morphogenetic process that \nis implicated in the acquisition of stem cell-like properties in different adult \ntissues, and it is activated in the epicardium after ischemic injury to the \nheart. We investigated whether EMT is involved in the formation and \ndifferentiation of human CSps, revealing that an up-regulation of the expression \nof EMT-related genes accompanies CSps formation that is relative to primary \nexplant-derived cells and CSp-derived cells grown in a monolayer. EMT and CSps \nformation is enhanced in the presence of transforming growth factor β1 (TGFβ1) \nand drastically blocked by the type I TGFβ-receptor inhibitor SB431452, \nindicating that TGFβ-dependent EMT is essential for the formation of these \nniche-like 3D-multicellular clusters. Since TGFβ is activated in the myocardium \nin response to injury, our data suggest that CSps formation mimics an adaptive \nmechanism that could potentially be enhanced to increase in vivo or ex vivo \nregenerative potential of adult CPCs.",
"Myocardial infarction is the most common cause of cardiac injury and results in \nacute loss of a large number of myocardial cells. Because the heart has \nnegligible regenerative capacity, cardiomyocyte death triggers a reparative \nresponse that ultimately results in formation of a scar and is associated with \ndilative remodeling of the ventricle. Cardiac injury activates innate immune \nmechanisms initiating an inflammatory reaction. Toll-like receptor-mediated \npathways, the complement cascade and reactive oxygen generation induce nuclear \nfactor (NF)-kappaB activation and upregulate chemokine and cytokine synthesis in \nthe infarcted heart. Chemokines stimulate the chemotactic recruitment of \ninflammatory leukocytes into the infarct, while cytokines promote adhesive \ninteractions between leukocytes and endothelial cells, resulting in \ntransmigration of inflammatory cells into the site of injury. Monocyte subsets \nplay distinct roles in phagocytosis of dead cardiomyocytes and in granulation \ntissue formation through the release of growth factors. Clearance of dead cells \nand matrix debris may be essential for resolution of inflammation and transition \ninto the reparative phase. Transforming growth factor (TGF)-beta plays a crucial \nrole in cardiac repair by suppressing inflammation while promoting myofibroblast \nphenotypic modulation and extracellular matrix deposition. Myofibroblast \nproliferation and angiogenesis result in formation of highly vascularized \ngranulation tissue. As the healing infarct matures, fibroblasts become apoptotic \nand a collagen-based matrix is formed, while many infarct neovessels acquire a \nmuscular coat and uncoated vessels regress. Timely resolution of the \ninflammatory infiltrate and spatial containment of the inflammatory and \nreparative response into the infarcted area are essential for optimal infarct \nhealing. Targeting inflammatory pathways following infarction may reduce \ncardiomyocyte injury and attenuate adverse remodeling. In addition, \nunderstanding the role of the immune system in cardiac repair is necessary in \norder to design optimal strategies for cardiac regeneration.",
"Adult stem cells are activated to proliferate and differentiate during normal \ntissue homeostasis as well as in disease states and injury. This activation is a \nvital component in the restoration of function to damaged tissue via either \ncomplete or partial regeneration. When regeneration does not fully occur, \nreparative processes involving an overproduction of stromal components ensure \nthe continuity of tissue at the expense of its normal structure and function, \nresulting in a \"reparative disorder\". Adult stem cells from multiple organs have \nbeen identified as being involved in this process and their role in tissue \nrepair is being investigated. Evidence for the participation of mesenchymal \nstromal cells (MSCs) in the tissue repair process across multiple tissues is \noverwhelming and their role in reparative disorders is clearly demonstrated, as \nis the involvement of a number of specific signaling pathways. Transforming \ngrowth factor beta, bone morphogenic protein and Wnt pathways interact to form a \ncomplex signaling network that is critical in regulating the fate choices of \nboth stromal and tissue-specific resident stem cells (TSCs), determining whether \nfunctional regeneration or the formation of scar tissue follows an injury. A \ngrowing understanding of both TSCs, MSCs and the complex cascade of signals \nregulating both cell populations have, therefore, emerged as potential \ntherapeutic targets to treat reparative disorders. This review focuses on recent \nadvances on the role of these cells in skeletal muscle, heart and lung tissues.",
"AIMS: In the adult heart, Notch signalling regulates the response to injury. \nNotch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the \ndevelopment of cardiac hypertrophy and fibrosis. The role of Notch in the \nmesenchymal stromal cell fraction, which contains cardiac fibroblasts and \ncardiac precursor cells, is, however, largely unknown. In the present study, we \nevaluate, therefore, whether forced activation of the Notch pathway in \nmesenchymal stromal cells regulates pathological cardiac remodelling.\nMETHODS AND RESULTS: We generated transgenic mice overexpressing the Notch \nligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in \nadjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated \nNotch sustained cardiac precursor and myocyte proliferation after birth, and led \nto increased numbers of cardiac myocytes in adult mice. In the adult heart under \npressure overload, Notch inhibited the development of cardiomyocyte hypertrophy \nand transforming growth factor-β/connective tissue growth factor-mediated \ncardiac fibrosis. Most importantly, Notch activation in the stressed adult heart \nreduced the proliferation of myofibroblasts and stimulated the expansion of stem \ncell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac \nprecursor cells.\nCONCLUSIONS: We conclude that Notch is pivotal in the healing process of the \ninjured heart. Specifically, Notch regulates key cellular mechanisms in the \nmesenchymal stromal cell population, and thereby controls the balance between \nfibrotic and regenerative repair in the adult heart. Altogether, these findings \nindicate that Notch represents a unique therapeutic target for inducing \nregeneration in the adult heart via mobilization of cardiac precursor cells."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016212', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006321', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006335', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012038']
|
52f4f2082059c6d71c00001d
|
[
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] |
train
|
what is the role of erythropoietin in cardiac regeneration after myocardial infarction?
|
summary
|
In preclinical studies, erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction indicating that erythropoietin may play a role in the stimulation of cell regeneration under normal physiologic conditions and in patients with myocardial injury. Epo overexpression was found to enhance the cellular regenerative properties of MSCs by both autocrine and paracrine pathways. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with erythropoietin in patients with myocardial infarction.
|
In preclinical studies, erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction indicating that erythropoietin may play a role in the stimulation of cell regeneration under normal physiologic conditions and in patients with myocardial injury. Epo overexpression was found to enhance the cellular regenerative properties of MSCs by both autocrine and paracrine pathways. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with erythropoietin in patients with myocardial infarction.
|
[
"OBJECTIVES: We assessed the effects of erythropoietin (EPO) treatment in a rat \nmodel of post-myocardial infarction (MI) heart failure.\nBACKGROUND: Erythropoietin, traditionally known as a hematopoietic hormone, has \nbeen linked to neovascularization. Whereas administration of EPO acutely after \nMI reduces infarct size and improves cardiac function, its role in the failing \nheart is unknown.\nMETHODS: Rats underwent coronary ligation or sham surgery. Rats with MI were \nrandomly assigned to: untreated (MI), a single bolus of EPO immediately after MI \ninduction (MI-EPO-early), EPO treatment immediately after MI and once every \nthree weeks (MI-EPO-early+late), and EPO treatment starting three weeks after \ninduction of MI, once every three weeks (MI-EPO-late). After nine weeks, \nhemodynamics, infarct size, myosin heavy chain (MHC) isoforms, myocyte \nhypertrophy, and capillary density were measured.\nRESULTS: Erythropoietin treatment started immediately after MI (MI-EPO-early and \nMI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p < 0.01) \nand, accordingly, hemodynamic improvement. Erythropoietin treatment, started \nthree weeks after MI (MI-EPO-late), did not affect infarct size, but resulted in \nan improved cardiac performance, reflected by a 34% reduction in left \nventricular end-diastolic pressure (p < 0.01), and 46% decrease in atrial \nnatriuretic peptide levels (p < 0.05). The improved cardiac function was \naccompanied by an increased capillary density (p < 0.01), an increased \ncapillary-to-myocyte ratio (p < 0.05), and a partial reversal of beta-MHC (p < \n0.05) in all treated groups.\nCONCLUSIONS: In addition to its effect on infarct size reduction, EPO treatment \nimproves cardiac function in a rat model of post-MI heart failure. This \nobservation may be explained by neovascularization, associated with an increased \nalpha-MHC expression.",
"BACKGROUND: Expanded endothelial progenitor cells (eEPC) improve global left \nventricular function in experimental myocardial infarction (MI). Erythropoietin \nbeta (EPO) applied together with eEPC may improve regional myocardial function \neven further by anti-apoptotic and cardioprotective effects. Aim of this study \nwas to evaluate intramyocardial application of eEPCs and EPO as compared to \neEPCs or EPO alone in experimental MI.\nMETHODS AND RESULTS: In vitro experiments revealed that EPO dosed-dependently \ndecreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA \nexpression in eEPC of proangiogenic and proinflammatory mediators measured by \nTaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion \nof the left anterior descending coronary artery of nude rats (n = 8-9). After \nmyocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel \ndensity were enhanced in the border zone of the infarct area. Moreover, \napoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to \ntransplantation of eEPCs alone. Regional wall motion of the left ventricle was \nmeasured using Magnetic Resonance Imaging. After injection of eEPC in the \npresence of EPO regional wall motion significantly improved as compared to \ninjection of eEPCs or EPO alone.\nCONCLUSION: Intramyocardial transplantation of eEPC in the presence of EPO \nduring experimental MI improves regional wall motion. This was associated with \nan increased local inflammation, vasculogenesis and survival of the transplanted \ncells. Local application of EPO in addition to cell therapy may prove beneficial \nin myocardial remodeling.",
"Animal models that mimic cardiovascular diseases are indispensable tools for \nunderstanding the mechanisms underlying the diseases at the cellular and \nmolecular level. This review focuses on various methods in preclinical research \nto create small animal models of cardiac diseases, such as myocardial \ninfarction, dilated cardiomyopathy, heart failure, myocarditis and cardiac \nhypertrophy, and the related stem cell treatment for these diseases.",
"OBJECTIVES: We investigated the effects of erythropoietin (EPO) on \nneovascularization and cardiac function after myocardial infarction (MI).\nBACKGROUND: Erythropoietin exerts antiapoptotic effects and mobilizes \nendothelial progenitor cells (EPCs).\nMETHODS: We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) \ngroup], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent \nligation of the coronary artery in dogs. Control animals received saline \nimmediately after the ligation.\nRESULTS: The infarct size 6 h after MI was significantly smaller in the EPO(0) \ngroup than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week \nafter MI, the circulating CD34-positive mononuclear cell numbers in both the \nEPO(0) and the EPO(6h) groups were significantly higher than in the control \ngroup. In the ischemic region, the capillary density and myocardial blood flow 4 \nweeks after MI was significantly higher in both the EPO(0) and the EPO(6h) \ngroups than in the control group. Four weeks after MI, left ventricular (LV) \nejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher \nthan that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) \ngroup but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The \nLV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) \ngroups was significantly lower than either the control or the EPO(1wk) group. \nHematologic parameters did not differ among the groups.\nCONCLUSIONS: In addition to its acute infarct size-limiting effect, EPO enhances \nneovascularization, likely via EPC mobilization, and improves cardiac \ndysfunction in the chronic phase, although it has time-window limitations.",
"BACKGROUND: Revascularization of infarcted myocardium results in release of \ninflammatory cytokines mediating myocardial reperfusion injury and heart \nfailure. Blockage of inflammatory pathways dampens myocardial injury and reduces \ninfarct size. We compared the impact of the interleukin-1 receptor antagonist \nAnakinra and erythropoietin on myocardial ischemia/reperfusion injury. In \ncontrast to others, we hypothesized that drug administration prior to \nreperfusion reduces myocardial damage.\nMETHODS AND RESULTS: 12-15 week-old Lewis rats were subjected to myocardial \nischemia by a 1 hr occlusion of the left anterior descending coronary artery. \nAfter 15 min of ischemia, a single shot of Anakinra (2 mg/kg body weight (bw)) \nor erythropoietin (5000 IE/kg bw) was administered intravenously. In contrast to \nerythropoietin, Anakinra decreased infarct size (P < 0.05, N = 4/group) and \ntroponin T levels (P < 0.05, N = 4/group).\nCONCLUSION: One-time intravenous administration of Anakinra prior to myocardial \nreperfusion reduces infarct size in experimental ischemia/reperfusion injury. \nThus, Anakinra may represent a treatment option in myocardial infarction prior \nto revascularization.",
"BACKGROUND: Endothelial progenitor cells (EPCs) participate in vascular repair \nand angiogenesis. Thus, EPC transplantation into ischemic myocardium might \nimprove cardiac function; however, the vast majority of cells die within a short \nperiod. The present study was designed to investigate whether exogenous \nerythropoietin (EPO) delivery could improve the survival of transplanted EPCs \nand enhance the efficiency of EPC-based cell therapy.\nMETHODS: Myocardial infarction was induced in wild-type mice by ligating the \nleft anterior descending coronary artery. Enhanced green fluorescent \nprotein-EPCs with or without EPO were transplanted into peri-infarct myocardium. \nEnhanced green fluorescent protein-EPCs were detected 7 and 28 d after surgery. \nThe amount of circulating EPCs was analyzed 3 and 28 d after surgery. The \nstromal cell-derived factor-1α and vascular endothelial growth factor \nconcentrations, microvessel density, apoptosis, fibrosis in the peri-infarct \nmyocardium, and cardiac function were compared among the groups.\nRESULTS: More enhanced green fluorescent protein-EPCs were found in the hearts \ntreated with EPC + EPO than in those treated with EPC alone. The circulating EPC \nlevel was markedly elevated after EPC + EPO treatment compared with EPC \napplication alone. Stromal cell-derived factor-1α and vascular endothelial \ngrowth factor were increased accordingly, along with increased microvessel \ndensity, decreased apoptosis, and reduced fibrosis in the peri-infarct \nmyocardium. Left ventricular fractional shortening was greater and the \ninterventricular septum was thicker after EPC + EPO treatment compared with EPC \ntreatment alone.\nCONCLUSIONS: EPO improved the efficiency of EPC therapy in mice with myocardial \ninfarction. This effect was associated with enhanced transplanted EPC survival \nand autologous EPC mobilization.",
"The regenerative capacity of the myocardium and its blood vessels has now been \nwell demonstrated. The cytokines granulocyte colony-stimulating factor, \nerythropoietin, and stem cell factor may play a role in helping to stimulate \ncell regeneration under normal physiologic conditions and in patients with \nmyocardial injury. After an ischemic insult, cytokines are released into the \nperipheral circulation and signal for the mobilization of stem cells. In \nexperimental cardiac injury models, the addition of cytokines has been shown to \nimprove myocardial function with and without the concurrent use of stem cell \ntherapy. Preliminary studies in humans using cytokine therapy alone for treating \nmyocardial infarction have been disappointing. Future studies in patients with \nmyocardial injury need to examine the use of various combinations of cytokines, \nwith and without the addition of intravascular stem cell infusions or direct \nstem cell injections.",
"AIMS: Mesenchymal stromal cells (MSCs) possess intrinsic features that identify \nthem as useful for treating ischaemic syndromes. Poor in vivo \nsurvival/engraftment of MSCs, however, limits their overall effectiveness. In \nthis work, we tested whether genetically engineering MSCs to secrete \nerythropoietin (Epo) could represent a better therapeutic platform than MSCs in \ntheir native form.\nMETHODS AND RESULTS: MSCs from C57Bl/6 mice were retrovirally transduced with \neither an empty vector or one that causes the production of Epo and were then \nanalysed for the alterations in angiogenic and survival potential. Using a mouse \nmodel of myocardial infarction (MI), the regenerative potential of null MSCs and \nEpo-overexpressing MSCs (Epo+MSCs) was assessed using serial echocardiogram and \ninvasive haemodynamic measurements. Infarct size, capillary density and \nneutrophil influx were assessed using histologic techniques. Using in vitro \nassays coupled with an in vivo Matrigel plug assay, we demonstrate that \nengineering MSCs to express Epo does not alter their immunophenotype or \nplasticity. However, relative to mock-modified MSCs [wild-type (WT)-MSCs], \nEpo+MSCs are more resilient to apoptotic stimuli and initiate a more robust \nhost-derived angiogenic response. We also identify and characterize the \nautocrine loop established on MSCs by having them secrete Epo. Furthermore, in a \nmurine model of MI, animals receiving intracardiac injections of Epo+MSCs \nexhibited significantly enhanced cardiac function compared with WT-MSCs and \nsaline-injected control animals post-MI, owing to the increased myocardial \ncapillary density and the reduced neutrophilia.\nCONCLUSION: Epo overexpression enhances the cellular regenerative properties of \nMSCs by both autocrine and paracrine pathways.",
"Mobilization of bone marrow-derived stem cells (BMCs) was shown to have \nprotective effects after myocardial infarction (MI). However, the classical \nmobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after \nrevealing an impaired homing capacity. In the search for superior cytokines, \nerythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in \na murine model of surgically induced MI the influence of EPO treatment on \nsurvival and functional parameters as well as BMC mobilization, homing, and \neffect on resident cardiac stem cells (CSCs). Human EPO was injected \nintraperitoneally after ligation of the left anterior descendens (LAD) for 3 \ndays with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume \nrelationships were investigated in vivo. Cardiac tissues were analyzed by \nhistology. To show the effect on BMCs and CSCs, FACS analyses were performed. \nHoming factors were analyzed by quantitative reverse transcription-polymerase \nchain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant \nimprovement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic \nparameters associated with attenuated remodeling, enhanced neovascularization, \nand diminished apoptotic cells in the peri-infarct area were improved. BMC \nsubpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and \nhoming of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic \nmyocardium was enhanced. However, there was no beneficial effect on CSCs. We \nhave shown that EPO application after MI shows cardioprotective effects. This \nmay be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 \naxis. However, EPO has no beneficial effects on resident CSCs. Therefore, new \ntreatment regimes using EPO together with other agents may combine complementary \nbeneficial effects preventing ischemic cardiomyopathy.",
"We postulated that combining erythropoietin (EPO) infusion with bone marrow \nmesenchymal stem cells (MSC) delivery may give better prognosis in a rat \ninfarcted heart. Acute myocardial infarction (MI) model was developed by \ncoronary artery ligation. Animals were grouped (n=18) to receive intramyocardial \ninjection of 30 microl saline solution without cells (EPO and control groups) or \nwith 3x10(6) MSC from transgenic green fluorescent protein (GFP)+ male mice (MSC \nand MSC-EPO groups). The animals received either 5000 U/kg body weight EPO (EPO \nand MSC-EPO groups) or saline solution (MSC and control groups) for 7 days after \nMI. Cardiac functions were measured by echocardiography and cardiac tissue was \nharvested for immunohistological studies 3 weeks after surgery. We observed \nregeneration of MSC in and around the infarcted myocardium in MSC and MSC-EPO \ngroups. Capillary density was markedly enhanced with significantly smaller \ninfarct size and reduced fibrotic area in MSC-EPO group as compared with other \nthree groups. A smaller left ventricular (LV) diastolic dimension and a higher \nLV fractional shortening were observed in MSC-EPO group than in other three \ngroups. Transplantation of MSC combined with cytokine EPO is superior to either \nof the monotherapy approach for angiomyogenesis and cardiac function recovery.",
"Erythropoietin improves myocardial function and enhances re-endothelialisation. \nAim of this study was to analyse progenitor cell mobilisation and restenosis in \npatients from the Regeneration of Vital Myocardium in ST-Segment Elevation \nMyocardial Infarction by Erythropoietin (REVIVAL-3) study. Patients with STEMI \nundergoing percutaneous coronary intervention (PCI) were randomly assigned to \nEpoetin beta (EPO) (n=68) or placebo (n=70). Drug-eluting stents (DES) were \nutilised in 93% of patients receiving EPO and in 95% of patients receiving \nplacebo (p=0.83). Serial venous blood samples were drawn; CD133+ progenitor \ncells were quantified by four-colour flow cytometry and cytokines interleukin \n(IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor (TNF) alpha were \nanalysed by cytometric bead array. Forty-eight hours after PCI a significant \nincrease in CD133+ progenitor cells was observed in the EPO group. Yet, no \ndifferences in plasma cytokines were found. Quantitative coronary angiography \nafter six months revealed an increase in segment diameter stenosis in the EPO \ngroup (32 ± 19% vs. 26 ± 14%, p=0.046). However, this increase in neointima \ngeneration was not associated with progenitor cell mobilisation. EPO in patients \nwith STEMI treated with PCI is associated with an increase in diameter stenosis \nthat is not associated with circulating progenitor cells.",
"BACKGROUND: Transplantation of marrow stromal cells (MSC) has been shown to \nimprove heart perfusion and cardiac function after ischemia. Erythropoietin \n(EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim \nof this study was to investigate the effect of EPO on the therapeutic potency of \nMSC transplantation in a rat model of myocardial infarction.\nMETHODS: MSC viability was detected by MTT and flow cytometry following culture \nin serum-free medium for 24 h with or without EPO. Release of vascular \nendothelial growth factor (VEGF) by MSC incubated with different doses of EPO \nwas assayed using ELISA. Immediately after coronary ligation, autologous MSC (3 \nx 10(6) cells) were injected into the ischemic myocardium (MSC and MSC-EPO \ngroups). EPO (3,000 U/kg body weight) was injected daily for 3 consecutive days \nstarting 1 day prior to ligation. The same EPO dose was also injected for \nconsecutive 3 days starting 15 days after surgery (EPO and MSC-EPO groups). \nControl animals were injected saline solution for the same time period. Cardiac \nfunction was assessed by echocardiography 2 and 21 days after surgery, \nrespectively. Western blot and immunohistological assessments were performed to \nexamine the effects of treatments.\nRESULTS: In vitro, EPO inhibited MSC apoptosis induced by serum-free medium and \nincreased vascular endothelial growth factor (VEGF) release by MSC. In vivo, \ncardiac infarct size was significantly smaller, cardiac function significantly \nimproved, and capillary density obviously higher in the MSC and EPO groups than \nin the control group. Combined treatment with EPO infusion and MSC \ntransplantation demonstrated a further decrease in infarct size, a further \nimprovement in cardiac function, and a further increase in capillary density \ncompared with MSC or EPO alone. Furthermore, a higher ratio of phosphorylated \nAkt to total Akt was measured by Western blot; Bcl-2 was upregulated and Bax was \ndownregulated by immunohistochemistry in the MSC-EPO group compared to the other \nthree groups.\nCONCLUSION: Transplantation of MSC combined with EPO infusion is superior to MSC \nmonotherapy for angiogenesis and cardiac function recovery.",
"AIMS: Erythropoietin (EPO) improves cardiac function and induces \nneovascularization in chronic heart failure (CHF), although the exact mechanism \nhas not been elucidated. We studied the effects of EPO on homing and \nincorporation of endothelial progenitor cells (EPC) into the myocardial \nmicrovasculature and myocardial expression of angiogenic factors.\nMETHODS AND RESULTS: CHF was induced in rats by coronary artery ligation \nresulting in myocardial infarction (MI) after bone marrow had been replaced by \nhuman placental alkaline phosphatase (hPAP) transgenic cells. We studied the \neffects of darbepoetin alfa treatment (EPO, 40 microg/kg, every 3 weeks, \nstarting 3 weeks after MI) on longitudinal changes in left ventricular (LV) \nfunction, circulating EPC, myocardial histology, and expression of vascular \nendothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented \nLV-dilatation and improved cardiac function (all P < 0.05), which was associated \nwith 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC \nfrom the bone marrow (P < 0.01), which resulted in a three-fold increased homing \nof EPC into the cardiac microvasculature. The percentage of the endothelium that \nconsisted of bone marrow derived cells was significantly increased (3.9 +/- 0.5 \nvs. 11.4 +/- 1%, P < 0.001) comprising 30% of the newly formed capillaries. In \naddition, EPO treatment resulted in a 4.5-fold increased myocardial expression \nof VEGF, which correlated strongly with neovascularization (r = 0.67; P < \n0.001). VEGF was equally expressed by endothelial cells of myocardial and bone \nmarrow origin.\nCONCLUSION: EPO-induced neovascularization in post-MI heart failure is mediated \nthrough a combination of EPC recruitment from the bone marrow and increased \nmyocardial expression of VEGF.",
"Erythropoietin (EPO) has been suggested to have a cardioprotective effect \nagainst ischemia. The purpose of this study was to examine the effects of EPO on \ncardiac remodeling after myocardial infarction (MI). MI was induced by ligation \nof the coronary artery in Wistar rats. The rats with MI were randomly divided \ninto untreated MI and two EPO-treated MI groups. EPO was administered \nsubcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 \ntimes a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the \nincrease in activated caspase 3, matrix metalloproteinase-2, and transcriptional \nactivation of activator protein-1 in non-infarcted myocardium. Four weeks after \nMI, left ventricular weight, left ventricular end-diastolic pressure, and left \nventricular dimension were increased, and ejection fraction and E wave \ndeceleration time were decreased. EPO significantly attenuated this ventricular \nremodeling and systolic and diastolic dysfunction. In addition, EPO \nsignificantly attenuated the interstitial fibrosis and remodeling-related gene \nexpression in non-infarcted myocardium. Furthermore, EPO significantly enhanced \nangiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In \nconclusion, when administered after MI, EPO prevents cardiac remodeling and \nimproves ventricular function with enhanced angiogenesis and reduced apoptosis.",
"Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes \nbeneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO \ninjection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) \nmodel. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac \ninjection. Compared to myocardial infarction control group (MIC), EPO \nsignificantly improved left ventricular function (n =11-14, P < 0.05) and \ndecreased right ventricular wall stress (n = 8, P < 0.05) assessed by \npressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction \nsize (20.1 +/- 1.1% versus 27.8 +/- 1.2%; n = 6-8, P < 0.001) and greater \ncapillary density (338.5 +/- 14.7 versus 259.8 +/- 9.2 vessels per mm2; n = 6-8, \nP < 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial \napoptosis by approximately 41% (0.27 +/- 0.03% versus 0.42 +/- 0.03%; n = 6, P= \n0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by \nquantitative realtime PCR and immunohistology. c-Kit(+) and CD34(+) stem cells \nwere significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral \nblood (n = 7, P < 0.05) and 48 hrs in the infarcted hearts (n = 6, P < 0.001). \nFurther, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in \nMI-EPO hearts (n = 7, P < 0.05). Intracardiac EPO injection restores myocardial \nfunctions following MI, which may attribute to the improved early recruitment of \nc-Kit(+) and CD34(+) stem cells via the enhanced expression of chemoattractant \nSDF-1.",
"Granulocyte colony-stimulating factor (G-CSF) and erythropoietin are two \ncytokines that have been demonstrated to improve cardiac function and perfusion \nin myocardial infarction. G-CSF was initially evaluated as a stem cell mobilizer \nand erythropoietin as a cytoprotective agent. However, both cytokines have \ndirect cytoprotective effects and stem cell-mobilizing ability. Direct \ncytoprotective effects of both cytokines are commonly mediated by the Jak-STAT \npathway. In preclinical study, G-CSF and erythropoietin improved cardiac \nfunction and perfusion by angiomyogenesis and protection of cardiomyocytes in \nmyocardial infarction. However, results from recent clinical trials did not \nsupport beneficial effects of cytokine therapy with G-CSF or erythropoietin \nalone in patients with myocardial infarction. Further studies are required to \nelucidate the mechanism of action and to improve therapeutic efficacy by \nemploying novel strategies, such as combined cytokines.",
"BACKGROUND: In experimental models of acute myocardial infarction (AMI), \nerythropoietin (EPO) reduces infarct size and improves left ventricular (LV) \nfunction. However, in the clinical setting, the effect of EPO in AMI was \nunclear. We conducted a systematic review and meta-analysis of randomized \ncontrolled trials (RCTs) of EPO to explore the safety and therapeutic effects of \nEPO in patients with AMI.\nMETHODS: We identified reports of RCTs comparing EPO to placebo for AMI in adult \nhumans in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. \nOutcomes included all-cause mortality, major cardiovascular events, cardiac \nfunction by LV ejection fraction and infarct size.\nRESULTS: We included 13 articles of RCTs with data for 1,564 patients. \nErythropoietin therapy did not improve LV ejection fraction (weighted mean \ndifference [WMD] 0.33, 95% CI -1.90 to 1.24, P = .68) and had no effect on \ninfarct size, as measured by cardiac magnetic resonance imaging (WMD -0.12, \n-2.16 to 1.91, P = .90) or serum peak value of creatine kinase-MB (WMD -2.01, \n-25.70 to 21.68, P = .87). Erythropoietin treatment did not decrease the risk of \ntotal adverse cardiac events (relative risk [RR] 1.02, 0.65-1.61, P = .92). \nErythropoietin treatment also failed to decrease the risk of heart failure (RR, \n0.69, 0.27-1.72, P = .42) and all-cause mortality (RR 0.55, 0.22-1.33, P = .18). \nMoreover, EPO had no effect on the risk of stent thrombosis (RR, 0.69, \n0.29-1.64, P = .40).\nCONCLUSION: Erythropoietin in patients with AMI seems to have no clinical \nbenefit for heart function or reducing infarct size, cardiovascular events, and \nall-cause mortality. Erythropoietin may not be a choice for patients with AMI."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009203', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012038', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004921']
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train
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which mutations of troponin C gene have been found to cause hypertrophic cardiomyopathy?
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list
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The following mutations of troponin C gene have been found to cause hypertrophic cardiomyopathy: L29Q; A8V; A31S; E134D; c.363dupG; A23Q; D145E and C84Y
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['L29Q', 'A8V', 'A31S', 'E134D', 'c.363dupG', 'A23Q', 'D145E', 'C84Y']
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[
"The Ca(2+) binding properties of the FHC-associated cardiac troponin C (cTnC) \nmutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted \nthin filament preparations, and skinned cardiomyocytes. While higher Ca(2+) \nbinding affinity was apparent for the L29Q mutant in isolated cTnC, this \nphenomenon was not observed in the cTn complex. At the level of the thin \nfilament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the \nCa(2+) affinity by 27% in the steady-state measurement and increased the Ca(2+) \ndissociation rate by 20% in the kinetic studies. Molecular dynamics simulations \nsuggest that L29Q destabilizes the conformation of cNTnC in the presence of \nphosphomimetic cTnI and potentially modulates the Ca(2+) sensitivity due to the \nchanges of the opening/closing equilibrium of cNTnC. In the skinned \ncardiomyocyte preparation, L29Q cTnC increased Ca(2+) sensitivity in a highly \nsarcomere length (SL)-dependent manner. The well-established reduction of Ca(2+) \nsensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the \nmutation and it also depressed the SL-dependent increase in myofilament Ca(2+) \nsensitivity. This might result from its modified interaction with cTnI which \naltered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. \nThis study demonstrates that the L29Q mutation alters the contractility and the \nfunctional effects of the phosphomimetic cTnI in both thin filament and single \nskinned cardiomyocytes and importantly that this effect is highly sarcomere \nlength dependent.",
"The cardiac troponin C (cTnC) mutation, L29Q, has been found in a patient with \nfamilial hypertrophic cardiomyopathy. We previously showed that L29, together \nwith neighboring residues, Asp2, Val28, and Gly30, plays an important role in \ndetermining the Ca(2+) affinity of site II, the regulatory site of mammalian \ncardiac troponin C (McTnC). Here we report on the Ca(2+) binding characteristics \nof L29Q McTnC and D2N/V28I/L29Q/G30D McTnC (NIQD) utilizing the Phe(27) --> Trp \n(F27W) substitution, allowing one to monitor Ca(2+) binding and release. We also \nstudied the effect of these mutants on Ca(2+) activation of force generation in \nsingle mouse cardiac myocytes using cTnC replacement, together with sarcomere \nlength (SL) dependence. The Ca(2+)-binding affinity of site II of L29Q \nMcTnC(F27W) and NIQD McTnC(F27W) was approximately 1.3- and approximately \n1.9-fold higher, respectively, than that of McTnC(F27W). The Ca(2+) \ndisassociation rate from site II of L29Q McTnC(F27W) and NIQD McTnC(F27W) was \nnot significantly different than that of control (McTnC(F27W)). However, the \nrate of Ca(2+) binding to site II was higher in L29Q McTnC(F27W) and NIQD \nMcTnC(F27W) relative to control (approximately 1.5-fold and approximately \n2.0-fold respectively). The Ca(2+) sensitivity of force generation was \nsignificantly higher in myocytes reconstituted with L29Q McTnC (approximately \n1.4-fold) and NIQD McTnC (approximately 2-fold) compared with those \nreconstituted with McTnC. Interestingly, the change in Ca(2+) sensitivity of \nforce generation in response to an SL change (1.9, 2.1, and 2.3 mum) was \nsignificantly reduced in myocytes containing L29Q McTnC or NIQD McTnC. These \nresults demonstrate that the L29Q mutation enhances the Ca(2+)-binding \ncharacteristics of cTnC and that when incorporated into cardiac myocytes, this \nmutant alters myocyte contractility.",
"The present study investigates the effects of the first mutation of troponin C \n(hcTnC(L29Q)) found in a patient with hypertrophic cardiomyopathy (HCM) on \nforce-pCa relations and the interplay with phosphorylation of sarcomeric PKA \nsubstrates. In triton-skinned murine cardiac fibers, the endogenous mcTnC was \nextracted and the fibers were subsequently reconstituted with recombinant \nwild-type and mutant hcTnC. Force-pCa relations of preparations containing \nhcTnC(L29Q) or hcTnC(WT) were similar. Incubation of fibers reconstituted with \nthe recombinant proteins with phosphatase to dephosphorylate sarcomeric PKA \nsubstrates induced an increase in Ca2+ sensitivity, slightly more pronounced \n(0.04 pCa units) in hcTnC(L29Q)-containing fibers. Incubation of the \ndephosphorylated fibers with PKA induced significant rightward shifts of \nforce-pCa relations of similar magnitude with both, hcTnC(L29Q) and hcTnC(WT). \nNo significant effects of hcTnC(L29Q) on the velocity of unloaded shortening \nwere observed. In conclusion, no major differences in contractile parameters of \npreparations containing hcTnC(L29Q) compared to hcTnC(WT) were observed. \nTherefore, it appears unlikely that hcTnC(L29Q) induces the development of HCM \nby affecting the regulation of Ca2+-activated force and interference with \nPKA-mediated modulation of the Ca2+ sensitivity of contraction.",
"Recently four new hypertrophic cardiomyopathy mutations in cardiac troponin C \n(cTnC) (A8V, C84Y, E134D, and D145E) were reported, and their effects on the \nCa(2+) sensitivity of force development were evaluated (Landstrom, A. P., \nParvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., \nOmmen, S. R., Potter, J. D., and Ackerman, M. J. (2008) J. Mol. Cell. Cardiol. \n45, 281-288). We performed actomyosin ATPase and spectroscopic solution studies \nto investigate the molecular properties of these mutations. Actomyosin ATPase \nactivity was measured as a function of [Ca(2+)] utilizing reconstituted thin \nfilaments (TFs) with 50% mutant and 50% wild type (WT) and 100% mutant cardiac \ntroponin (cTn) complexes: A8V, C84Y, and D145E increased the Ca(2+) sensitivity \nwith only A8V demonstrating lowered Ca(2+) sensitization at the 50% ratio when \ncompared with 100%; E134D was the same as WT at both ratios. Of these four \nmutants, only D145E showed increased ATPase activation in the presence of \nCa(2+). None of the mutants affected ATPase inhibition or the binding of cTn to \nthe TF measured by co-sedimentation. Only D145E increased the Ca(2+) affinity of \nsite II measured by 2-(4'-(2''-iodoacetamido)phenyl)aminonaphthalene-6-sulfonic \nacid fluorescence in isolated cTnC or the cTn complex. In the presence of the \nTF, only A8V was further sensitized to Ca(2+). Circular dichroism measurements \nin different metal-bound states of the isolated cTnCs showed changes in the \nsecondary structure of A8V, C84Y, and D145E, whereas E134D was the same as WT. \nPyMol modeling of each cTnC mutant within the cTn complex revealed potential for \nlocal changes in the tertiary structure of A8V, C84Y, and D145E. Our results \nindicate that 1) three of the hypertrophic cardiomyopathy cTnC mutants increased \nthe Ca(2+) sensitivity of the myofilament; 2) the effects of the mutations on \nthe Ca(2+) affinity of isolated cTnC, cTn, and TF are not sufficient to explain \nthe large Ca(2+) sensitivity changes seen in reconstituted and fiber assays; and \n3) changes in the secondary structure of the cTnC mutants may contribute to \nmodified protein-protein interactions along the sarcomere lattice disrupting the \ncoupling between the cross-bridge and Ca(2+) binding to cTnC.",
"The objective of this work was to investigate the effect of hypertrophic \ncardiomyopathy-linked A8V and E134D mutations in cardiac troponin C (cTnC) on \nthe response of reconstituted thin filaments to calcium upon phosphorylation of \ncardiac troponin I (cTnI) by protein kinase A. The phosphorylation of cTnI at \nprotein kinase A sites was mimicked by the S22D/S23D double mutation in cTnI. \nOur results demonstrate that the A8V and E134D mutations had no effect on the \nextent of calcium desensitization of reconstituted thin filaments induced by \ncTnI pseudophosphorylation. However, the A8V mutation enhanced the effect of \ncTnI pseudophosphorylation on the rate of dissociation of calcium from \nreconstituted thin filaments and on the calcium dependence of actomyosin ATPase. \nConsequently, while the A8V mutation still led to a slower rate of dissociation \nof calcium from reconstituted thin filaments upon pseudophosphorylation of cTnI, \nthe ability of the A8V mutation to decrease the rate of calcium dissociation was \nweakened. In addition, the ability of the A8V mutation to sensitize actomyosin \nATPase to calcium was weakened after cTnI was replaced by the phosphorylation \nmimetic of cTnI. Consistent with the hypothesis that the E134D mutation is \nbenign, it exerted a minor to no effect on the rate of dissociation of calcium \nfrom reconstituted thin filaments or on the calcium sensitivity of actomyosin \nATPase, regardless of the cTnI phosphorylation status. In conclusion, our study \nenhances our understanding of how cardiomyopathy-linked cTnC mutations affect \nthe response of reconstituted thin filaments to calcium upon cTnI \nphosphorylation.",
"Defined as clinically unexplained hypertrophy of the left ventricle, \nhypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of \nthe cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are \na relatively rare cause of HCM. Here, we report clinical and functional \ncharacterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM \nproband with multiple episodes of ventricular fibrillation and aborted sudden \ncardiac death. Diagnosed at age 5, the proband is family history-negative for \nHCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted \ncardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which \nincreased Ca(2+) sensitivity with no effect on the maximal contractile force \ngeneration. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% \ncTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100% \ncTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the \nactomyosin ATPase without affecting the inhibitory qualities of the ATPase. The \nsecondary structure of the cTnC mutant was evaluated by circular dichroism, \nwhich did not indicate global changes in structure. Fluorescence studies \ndemonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, \nthin filament, and to a lesser degree, thin filament with myosin subfragment 1. \nThese results suggest that this mutation has a direct effect on the Ca(2+) \nsensitivity of the myofilament, which may alter Ca(2+) handling and contribute \nto the arrhythmogenesis observed in the proband. In summary, we report a novel \nmutation in the TNNC1 gene that is associated with HCM pathogenesis and may \npredispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM.",
"Cardiac diseases associated with mutations in troponin subunits include \nhypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive \ncardiomyopathy (RCM). Altered calcium handling in these diseases is evidenced by \nchanges in the Ca(2+) sensitivity of contraction. Mutations in the Ca(2+) \nsensor, troponin C (TnC), were generated to increase/decrease the Ca(2+) \nsensitivity of cardiac skinned fibers to create the characteristic effects of \nDCM, HCM, and RCM. We also used a reconstituted assay to determine the mutation \neffects on ATPase activation and inhibition. One mutant (A23Q) was found with \nHCM-like properties (increased Ca(2+) sensitivity of force and normal levels of \nATPase inhibition). Three mutants (S37G, V44Q, and L48Q) were identified with \nRCM-like properties (a large increase in Ca(2+) sensitivity, partial loss of \nATPase inhibition, and increased basal force). Two mutations were identified \n(E40A and I61Q) with DCM properties (decreased Ca(2+) sensitivity, maximal force \nrecovery, and activation of the ATPase at high [Ca(2+)]). Steady-state \nfluorescence was utilized to assess Ca(2+) affinity in isolated cardiac (c)TnCs \ncontaining F27W and did not necessarily mirror the fiber Ca(2+) sensitivity. \nCircular dichroism of mutant cTnCs revealed a trend where increased \nalpha-helical content correlated with increased Ca(2+) sensitivity in skinned \nfibers and vice versa. The main findings from this study were as follows: 1) \ncTnC mutants demonstrated distinct functional phenotypes reminiscent of bona \nfide HCM, RCM, and DCM mutations; 2) a region in cTnC associated with increased \nCa(2+) sensitivity in skinned fibers was identified; and 3) the F27W reporter \nmutation affected Ca(2+) sensitivity, maximal force, and ATPase activation of \nsome mutants.",
"PurposeHypertrophic cardiomyopathy is the most common cause of sudden death in \nyoung people, including trained athletes, and is caused by mutations in genes \nencoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene \n(TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. We describe a \nnovel type of mutation (c.363dupG) in Troponin C, a rare form of hypertrophic \ncardiomyopathy.\nMETHODS: A family in which a 19-year-old asymptomatic male died of sudden \ncardiac death due to hypertrophic cardiomyopathy was genetically studied by \nsequencing 17 genes associated with hypertrophic cardiomyopathy or its \nphenocopies.\nRESULTS: A c.363dupG mutation in Troponin C was identified, and tested across \nthe family.\nCONCLUSIONS: We report the first frameshift mutation (c.363dupG or \np.Gln122AlafsX30) in Troponin C causing hypertrophic cardiomyopathy (and sudden \ncardiac death) in a 19-year-old male, and have demonstrated that the mutation \nsegregates with hypertrophic cardiomyopathy within the family.",
"Troponin C (TnC) is the calcium-binding subunit of the troponin complex \nresponsible for initiating striated muscle contraction in response to calcium \ninflux. In the skeletal TnC isoform, calcium binding induces a structural change \nin the regulatory N-domain of TnC that involves a transition from a closed to \nopen structural state and accompanying exposure of a large hydrophobic patch for \ntroponin I (TnI) to subsequently bind. However, little is understood about how \ncalcium primes the N-domain of the cardiac isoform (cTnC) for interaction with \nthe TnI subunit as the open conformation of the regulatory domain of cTnC has \nbeen observed only in the presence of bound TnI. Here we use paramagnetic \nrelaxation enhancement (PRE) to characterize the closed to open transition of \nisolated cTnC in solution, a process that cannot be observed by traditional \nnuclear magnetic resonance methods. Our PRE data from four spin-labeled \nmonocysteine constructs of isolated cTnC reveal that calcium binding triggers \nmovement of the N-domain helices toward an open state. Fitting of the PRE data \nto a closed to open transition model reveals the presence of a small population \nof cTnC molecules in the absence of calcium that possess an open conformation, \nthe level of which increases substantially upon Ca(2+) binding. These data \nsupport a model in which calcium binding creates a dynamic equilibrium between \nthe closed and open structural states to prime cTnC for interaction with its \ntarget peptide. We also used PRE data to assess the structural effects of a \nfamilial hypertrophic cardiomyopathy point mutation located within the N-domain \nof cTnC (A8V). The PRE data show that the Ca(2+) switch mechanism is perturbed \nby the A8V mutation, resulting in a more open N-domain conformation in both the \napo and holo states.",
"We investigated structural and functional aspects of the first mutation in \nTNNC1, coding for the calcium-binding subunit (cTnC) of cardiac troponin, which \nwas detected in a patient with hypertrophic cardiomyopathy [ Hoffmann B, \nSchmidt-Traub H, Perrot A, Osterziel KJ & Gessner R (2001) Hum Mut17, 524]. This \nmutation leads to a leucine-glutamine exchange at position 29 in the \nnonfunctional calcium-binding site of cTnC. Interestingly, the mutation is \nlocated in a putative interaction site for the nonphosphorylated N-terminal arm \nof cardiac troponin I (cTnI) [ Finley NL, Abbott MB, Abusamhadneh E, Gaponenko \nV, Dong W, Seabrook G, Howarth JW, Rana M, Solaro RJ, Cheung HC et al. (1999) \nEJB Lett453, 107-112]. According to peptide array experiments, the \nnonphosphorylated cTnI arm interacts with cTnC around L29. This interaction is \nalmost abolished by L29Q, as observed upon protein kinase A-dependent \nphosphorylation of cTnI at serine 22 and serine 23 in wild-type troponin. With \nCD spectroscopy, minor changes are observed in the backbone of Ca2+-free and \nCa2+-saturated cTnC upon the L29Q replacement. A small, but significant, \nreduction in calcium sensitivity was detected upon measuring the Ca2+-dependent \nactomyosin subfragment 1 (actoS1)-ATPase activity and the sliding velocity of \nthin filaments. The maximum actoS1-ATPase activity, but not the maximum sliding \nvelocity, was significantly enhanced. In addition, we performed our \ninvestigations at different levels of protein kinase A-dependent phosphorylation \nof cTnI. The in vitro assays mainly showed that the Ca2+ sensitivity of the \nactoS1-ATPase activity, and the mean sliding velocity of thin filaments, were no \nlonger affected by protein kinase A-dependent phosphorylation of cTnI owing to \nthe L29Q exchange in cTnC. The findings imply a hindered transduction of the \nphosphorylation signal from cTnI to cTnC.",
"Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined \nby a hypertrophied left ventricle, is one of the main causes of sudden death in \nyoung athletes, and has been associated with mutations in most sarcomeric \nproteins (tropomyosin, troponin T and I, and actin, etc.). Many of these \nmutations appear to affect the functional properties of cardiac troponin C \n(cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of \nHCM, yet surprisingly, prior to this report, cTnC had not been classified as a \nHCM-susceptibility gene. In this study, we show that mutations occurring in the \nhuman cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well \nestablished HCM-susceptibility genes that encode other sarcomeric proteins. \nComprehensive open reading frame/splice site mutation analysis of TNNC1 \nperformed on 1025 unrelated HCM patients enrolled over the last 10 years \nrevealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. \nFunctional studies with these recombinant HcTnC HCM mutations showed increased \nCa(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery \n(A8V and D145E). These results are consistent with the HCM functional phenotypes \nseen with other sarcomeric-HCM mutations (E134D showed no changes in these \nparameters). This is the largest cohort analysis of TNNC1 in HCM that details \nthe discovery of at least three novel HCM-associated mutations and more strongly \nlinks TNNC1 to HCM along with functional evidence that supports a central role \nfor its involvement in the disease. This study may help to further define TNNC1 \nas an HCM-susceptibility gene, a classification that has already been \nestablished for the other members of the troponin complex.",
"The role of the C-domain sites of cardiac troponin C in the modulation of the \ncalcium signal remains unclear. In this study, we investigated the effects of \nhypertrophic cardiomyopathy-linked mutations A8V, E134D, and D145E in cardiac \ntroponin C on the properties of the C-domain sites. The A8V mutation had \nessentially no effect on the calcium or magnesium binding properties of the \nC-domain sites, while the mutation E134D moderately decreased calcium and \nmagnesium binding affinities. On the other hand, the D145E mutation affected \ncooperative interactions between sites III and IV, significantly reducing the \ncalcium binding affinity of both sites. Binding of the anchoring region of \ncardiac troponin I (corresponding to residues 34-71) to cardiac troponin C with \nthe D145E mutation was not able to recover normal calcium binding to the \nC-domain. Experiments utilizing the fluorescent hydrophobic probe bis-ANS \nsuggest that the D145E mutation dramatically reduced the extent of \ncalcium-induced hydrophobic exposure by the C-domain. At high nonphysiological \ncalcium concentration, A8V, E134D, and D145E mutations minimally affected the \naffinity of cardiac troponin C for the regulatory region of cardiac troponin I \n(corresponding to residues 128-180). In contrast, at lower physiological calcium \nconcentration, the D145E mutation led to an approximately 8-fold decrease in the \naffinity of cardiac troponin C for the regulatory region of cardiac troponin I. \nOur results suggest that calcium binding properties of the C-domain sites might \nbe important for the proper regulatory function of cardiac troponin C."
] |
['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002312', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D019209', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009154']
|
60292dc61cb411341a000110
|
[
1501489,
15302523,
23172095,
2179633
] |
train
|
Αre plants from the genus Strychnos the original source of curare?
|
yesno
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Species of plants from the genus Strychnos are the source of curare.
|
yes
|
[
"The history to about 1850 of the muscle-relaxant poison curare is discussed, \nespecially the developments leading to the botanical identification of the \nplants that yield the alkaloidal active principles: Loganiaceae (Strychnos \nspecies) and Menispermaceae (Abuta, Chondrodendron, and Curarea species). One of \nthe earliest encounters with the poison appears to have been during the \nexploration of the Lake Maracaibo region in Colombia by Alonso Pérez de Tolosa \nin 1548. It is pointed out (yet again) that Sir Walter Ralegh did not bring back \nthe poison to Europe in 1595 and that it was Keymis who first came across the \nword ourari when exploring the lower reaches of the Orinoco in 1596. Gumilla, La \nCondamine, Ulloa, Veigl, and others gave much additional information about the \npoison during the 18th century. Scientific studies began in the latter part of \nthe century when Schreber listed the botanical identities of four of the plant \ncomponents entering into the curare prepared by the Akawai Indians of Surinam. \nAs far as is known, none of these people actually saw curare being made. \nThereafter, progress was rapid. Humboldt and Bonpland were the first trained \nscientists to witness the preparation of the poison, at the very beginning of \nthe 19th century. Subsequent exploration by Martius and Spix, Poeppig, Youd, the \nSchomburgk brothers, De Castelnau and Deville, Spruce, and others, up to the \nmiddle of the century, extended and deepened botanical and ethnological \nknowledge of curare. Study of its physiology started at about that time with the \nclassical experiments of Rudolf von Koelliker and Claude Bernard.",
"Poisons are widespread in plants and animals and humankind has often tried to \nturn them to its own advantage. Owing to their poisonous properties, some \nspecies of Strychnos genus have been employed mainly in hunting and fishing, as \nan adjunct to weapons used not only in the search of food and clothes, but also \nfor preventing depredation by wild animals. They have been employed for martial \nand criminal purposes and also as a means of determining guilt or innocence. By \ntheir nature, poisons such as strychnine and curare affect the functioning of \nthe victim's body; this also means that they have been, and are, an important \nsource of pharmacological tools and medicines all over the world. With such \npotentially dangerous substances, care in medication is essential to avoid \ncomplications by overdose. All these points are approached in the present \nreview.",
"INTRODUCTION: The natives that dwell along the banks of the Orinoco and Amazon \nrivers have used different poisons from plants for centuries. The study reviews \nthe historical and ethnographic aspects of the use of curares and timbós in the \nAmazonian region.\nDEVELOPMENT: Curare is prepared by boiling the roots, bark and stalks of \ndifferent plants belonging to the Loganiaceae (Strychnos) and Menispermaceae \nfamilies (Chondrodendron, Curarea and Abuta). The curares of the eastern Amazon \nare extracted from different species of Strychnos that contain quaternary \nalkaloids, which act by blocking the neuromuscular junction. They are used to \nhunt wild animals and death comes about due to paralysis of the skeletal \nmuscles. The first muscles to be paralysed are those of the eyes, nose and neck, \nand then those in the limbs; the diaphragm is the muscle that takes the longest \nto become paralysed. The earliest chronicles reporting their use were written by \nFernandez de Oviedo, Cristoval de Acuna, Antonio de Ulloa and Jose Gumilla. La \nCondamine, Humbolt, Waterton and Schomburgk, among others, carried out a number \nof different ethnobotanical studies on curare. The ichthyotoxic poisons from \nplants, which are known as timbós or barbascos, are characterised by their high \nlevel of solubility, their fast diffusion and their high rate of activity. At \nleast 70 plant species are used to poison the fish in the tributaries of the \nAmazon with the aim of make fishing easier. Sapindaceae, Papilionaceae, \nEuphorbiaceae and Theophrastaceae contain ichthyotoxic substances, such as \nrotenone or saponins.\nCONCLUSIONS: Ethnohistorical and ethnographic accounts show that the Amazonian \ncultures have a deep understanding of the toxic properties of curares and \ntimbós.",
"The ethnobotanical uses of South American species of Strychnos L. (Loganiaceae) \nare reviewed, with the exception of their major rôle in the preparation of \ncurare, which will be dealt with in detail elsewhere. Medicinal uses are less \ncommon than is the case with the African and Asian species of the genus. About \n140 samples, mostly of leaves, belonging to 53 species, have been screened for \nalkaloids. As with species from other parts of the world, the stem bark and root \nbark tend to be a richer source than leaves. Nor-harman is present in extracts \nfrom S. barnhartiana leaves. Pyridino-indolo-quinolizidinone (angustine-type) \nbases are also found in several species. The occurrence and pharmacology of the \n(non-curarizing) alkaloids known to be present in South American Strychnos \nspecies is reviewed."
] |
nan
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