1,720,997 research outputs found
Chromatin remodelling by polyamines and polyamine analogues
No full textNatural polyamines are involved in many
molecular processes, including maintenance of DNA
structure and RNA processing and translation. Our aim
here is to present an overview of the literature concerning
the significance of polyamines in the modulation of chromatin
arrangement and the transcriptional regulation of
gene expression. The pleiotropic picture emerging from the
published data highlights that these polycations take part in
apparently diverging effects, possibly depending on the
heterogeneous experimental settings described, and on a
methodological approach aimed at the evaluation of the
global levels of the histone chemical modifications. Since
the relevant changes observed appear to be rather local and
gene specific, investigating histone modifications at the
level of specific gene promoters of interest is thus to be
recommended for future studies. Furthermore, decoding the
multiple regulatory mechanisms by which polyamines
exert their influence on chromatin-modifier enzymes will
reasonably require focus on selected individual polyamine regulated
genes. The evaluation of the many known chromatin-
remodeling enzymes for their individual susceptibility to polyamines or polyamine derivatives will also be helpful: determining how they discriminate between the different enzyme isoforms is expected to be a
fruitful line of research for drug discovery, e.g., in cancer prevention and therapy. Indeed, polyamine derivatives acting as epigenetic modulators appear to be molecules with great potential as antitumor drugs. All these novel polyamine-based pharmacologically active molecules are
thus promising tools, both as a stand-alone strategy and in
combination with other anticancer compounds
A pro-survival effect of polyamine depletion on norepinephrine-mediated apoptosis in cardiac cells. Role of signalling enzymes.
No full textRecent studies report that the primary transmitter of sympathetic nervous system norepinephrine (NE), which is actively produced in failing human heart, is able to induce apoptosis of rat cardiomyocytes. Apoptotic cell death of cardiomyocytes is involved in several cardiovascular diseases including ischemia, hypertrophy and heart failure, therefore representing a potential therapeutic target. The natural occurring polyamines, putrescine, spermidine and spermine, are biogenic amines involved in many cellular processes, including apoptosis. Thus, we have studied the involvement of polyamines in the apoptosis of cardiac cells induced by the treatment with NE. The results indicate that NE caused an early induction of the activity of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, followed by a later increase of apoptotic cell death. This effect was prevented in the presence of α-difluoromethylornithine, an irreversible inhibitor of ODC. Moreover, the study of some key signal transduction pathways revealed an involvement of AMP-activated protein kinase, AKT and p38 mitogen- activated protein kinases, in the modulation by polyamines of the response of cardiomyocytes to NE. In fact, polyamine-depleted cells showed an altered activation pattern of these kinases that may contrast apoptosis and appeared to result from a differential effect on the specific phosphatases that dephosphorylate and switch off these signaling proteins. In conclusion, these results indicate that in cardiac cells polyamines are involved in the execution of the death program activated by NE, and suggest that their apoptosis facilitating action is mediated by a network of specific phosphatases and kinases
Impact of CpG methylation in addressing adipose-derived stem cell differentiation towards the cardiac phenotype
No full textCardiovascular diseases are a major cause of mortality in industrialized countries. Patients who survive after an acute myocardial infarction (AMI) are prone to ventricular remodelling, resulting from loss of myocardial tissue, and to progressive chronic heart failure (CHF). Heart has just a minimal potential of repair and regeneration, thus the use of new strategies of treatment involving stem-cell transplantation and/or endogenous stem cell mobilization is expected as a promising alternative to standard therapy.
Stem cells are undifferentiated cells with self-renewal and differentiation potential. Among stem cells, embryonic (ESCs) are considered as the best for cardiac regeneration (Nir et al., 2003); on the other hand several issues, including ethical questions, immunorejection and teratoma formation, limit their practical use. To overcome these restrictions, research interest is focusing on adult stem cells, indentified in different tissues and resulted able to differentiate towards the cardiac phenotype. Stem cells obtained from bone marrow, contain a subpopulation of hematopoietic stem cells (HSCs) (Goodell et al., 1997), a component of mesenchymal stem cells (MSCs) (Pittenger and Martin, 2004) and multipotent progenitor cells (MAPCs) (Jiang et al., 2002). MSCs derived from bone-marrow show some potential of differentiation into beating cardiomyocytes in vitro (Makino et al., 1999; Hakuno et al., 2002; Fukuda, 2001; Toma et al., 2002). Somatic stem cells also include endothelial progenitor cells (EPCs), obtained from peripheral circulation (Badorff et al., 2003), and cells arisen from umbilical cord (USSCs). USSCs showed capacity of differentiation towards the cardiac phenotype and to promote angiogenesis (Badorff et al., 2003; Kogler et al., 2004). Resident stem cells, located in cardiac niches, showed a differentiation potential towards cardiomyocites (Bollini et al., 2010]. In the last decade another group of somatic stem cells, derived from adipose tissue (ADSCs) was studied, most of all for their easy way of extraction, relative abundance and differentiative capacity towards different lineages.
This chapter will focus on this last family of somatic stem cells. We will describe the features of ADSCs, how to isolate them from lipoaspirates, their cell surface markers and their differentiative potential. We will also report of ADSCs ability to differentiate into cardiomyocytes. Finally we will outline the epigenetic signature of ADSCs, to define if epigenetic modifications could influence their commitment towards a specific phenotype
Epigenetic signature of early cardiac regulatory genes in human adipose-derived stem cells
No full textAdipose-derived stem cells (ADSCs) are stromal
mesenchymal stem cells isolated from lipoaspirates,
and they display a broad potential to differentiate toward
different lineages. The role of epigenetics in regulating the
expression of their lineage-specific genes is under evaluation,
however till date virtually nothing is known about the
relative significance of cardiac-specific transcription factor
genes in human ADSCs. The aim of this study was
to investigate DNA promoter methylation and relevant
histone modifications involving MEF-2C, GATA-4, and
Nkx2.5 in native human ADSCs. CpG sites at the transcription
start in their promoters were found unmethylated
using methylation-specific PCR. Chromatin immunoprecipitation
assay showed low levels of total acetylated H3 histone (acH3) and high levels of trimethylated lysine 27 in
H3 histone (H3K27me3) which were associated with both
GATA-4 and Nkx2.5 promoters, indicating their transcriptional
repressive chromatin arrangement. On the other
hand, the opposite was apparent for MEF-2C promoter.
Accordingly, MEF-2C—but not GATA-4 and Nkx2.5—
transcripts were evidenced in native human ADSCs. These
results suggest that the chromatin arrangement of these
early cardiac regulatory genes could be explored as a level
of intervention to address the differentiation of human
ADSCs toward the cardiac lineage
Modificazioni post-traduzionali dei filamenti intermedi: chiave di volta nell’insufficienza cardiaca?
No full textSharing pathogenetic mechanisms between acute myocardial infarction and Alzheimer's disease as shown by partially overlapping of gene variant profiles.
No full textGene variants that promote inflammation and cholesterol metabolism have been associated with acute myocardial infarction (AMI) and Alzheimer's disease (AD). We investigated a panel of relevant polymorphisms to distinguish genetic backgrounds for AMI and AD: IL10 -1082G/A, IL6 -174G/C, TNF -308G/A, IFNG +874T/A, SERPINA3 -51G/T, HMGCR -911C/A, APOE ε2/3/4 (280 AMI cases, 257 AD cases, and 1307 population controls, all Italian (presumed risk alleles are shown in bold). Six genetic risk sets I to VI were identified by fuzzy latent classification: I had low risk; II and III had low risk before age 65 (II, III); low risk sets lacked pro-inflammatory alleles for HMGCR-TNF-APOE. Pro-inflammatory alleles for SERPINA3-IL10-IFNG were found for high risk sets IV to VI. Set IV 'AMI < age 40, AD < age 65' included risk alleles for HMGCR. Set V 'AMI over a broad range of age' included risk alleles for TNF+IL6. Set VI 'AMI at ages 40 to 55, AD ages 65+' included APOE ε4. Close resemblance to the high risk sets, as indicated by membership scores close to one, defined high relative risks. We conclude that AMI and AD share genetic backgrounds involving cholesterol metabolism and the upregulation of inflammation and that gene-gene interactions in relevant sets of genes may be useful in defining inherited risk for common disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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