Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies

Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents

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PREVALÊNCIA DA ANEMIA E FATORES ASSOCIADOS EM CRIANÇAS DE 6 A 24 MESES MATRICULADAS NA REDE PÚBLICA DE VENÂNCIO AIRES, RS, BRASIL

A anemia é uma síndrome clínica multifatorial considerada um grave problema de saúde pública. Segundo a Organização Mundial de Saúde (OMS), 25% da população mundial tem anemia, sendo maior a prevalência em gestantes (41,8%) e crianças menores de 60 meses (47,4%). O objetivo deste trabalho foi quantificar a prevalência da anemia em crianças com idades entre 6 e 24 meses matriculadas e frequentando a rede pública municipal de ensino de Venâncio Aires/RS no primeiro semestre de 2012 e verificar a possível associação com o número de irmãos e variáveis da alimentação. Foram avaliadas 113 crianças e os resultados deste estudo mostraram que a prevalência de anemia em crianças menores de 2 anos foi de 11,5%. Verificou-se correlação negativa entre a quantidade de hemoglobina e o número de irmãos. Concluímos que as crianças de 06 a 24 meses que frequentavam escolas municipais de educação infantil, no município de Venâncio Aires, tinham baixa prevalência de anemia comparada a outros resultados encontrados no país, sendo que os valores de hemoglobina foram associados inversamente ao número de irmãos. Foi encontrado um padrão inadequado de alimentação na maioria das crianças, com introdução precoce de alimentação complementar

PREVALÊNCIA DA ANEMIA E FATORES ASSOCIADOS EM CRIANÇAS DE 6 A 24 MESES MATRICULADAS NA REDE PÚBLICA DE VENÂNCIO AIRES, RS, BRASIL

A anemia é uma síndrome clínica multifatorial considerada um grave problema de saúde pública. Segundo a Organização Mundial de Saúde (OMS), 25% da população mundial tem anemia, sendo maior a prevalência em gestantes (41,8%) e crianças menores de 60 meses (47,4%). O objetivo deste trabalho foi quantificar a prevalência da anemia em crianças com idades entre 6 e 24 meses matriculadas e frequentando a rede pública municipal de ensino de Venâncio Aires/RS no primeiro semestre de 2012 e verificar a possível associação com o número de irmãos e variáveis da alimentação. Foram avaliadas 113 crianças e os resultados deste estudo mostraram que a prevalência de anemia em crianças menores de 2 anos foi de 11,5%. Verificou-se correlação negativa entre a quantidade de hemoglobina e o número de irmãos. Concluímos que as crianças de 06 a 24 meses que frequentavam escolas municipais de educação infantil, no município de Venâncio Aires, tinham baixa prevalência de anemia comparada a outros resultados encontrados no país, sendo que os valores de hemoglobina foram associados inversamente ao número de irmãos. Foi encontrado um padrão inadequado de alimentação na maioria das crianças, com introdução precoce de alimentação complementar

DNA damage in children and adolescents with cardiovascular disease risk factors

The risk of developing cardiovascular disease (CVD) is related to lifestyle (e.g. diet, physical activity and smoking) as well as to genetic factors. This study aimed at evaluating the association between CVD risk factors and DNA damage levels in children and adolescents. Anthropometry, diet and serum CVD risk factors were evaluated by standard procedures. DNA damage levels were accessed by the comet assay (Single cell gel electrophoresis; SCGE) and cytokinesis-blocked micronucleus (CBMN) assays in leukocytes. A total of 34 children and adolescents selected from a population sample were divided into three groups according to their level of CVD risk. Moderate and high CVD risk subjects showed significantly higher body fat and serum CVD risk markers than low risk subjects (P<0.05). High risk subjects also showed a significant increase in DNA damage, which was higher than that provided by low and moderate risk subjects according to SCGE, but not according to the CBMN assay. Vitamin C intake was inversely correlated with DNA damage by SCGE, and micronucleus (MN) was inversely correlated with folate intake. The present results indicate an increase in DNA damage that may be a consequence of oxidative stress in young individuals with risk factors for CVD, indicating that the DNA damage level can aid in evaluating the risk of CVD.O risco de desenvolver doença cardiovascular (DCV) está relacionado ao estilo de vida (por exemplo, dieta, atividade física e tabagismo), bem como a fatores genéticos. Este estudo teve como objetivo avaliar a associação entre fatores de risco cardiovascular e os níveis de danos ao DNA em crianças e adolescentes. Antropometria, dieta e fatores de risco para DCV foram avaliados através de procedimentos padrão. Níveis de danos no DNA foram avaliados através do ensaio cometa (eletroforese de célula única; EC) e do teste de micronúcleos em leucócitos. Um total de 34 crianças e adolescentes, selecionados a partir de uma amostra populacional, foram divididos em três grupos, de acordo com seu nível de risco de DCV. Indivíduos com níveis moderado e alto risco para DCV apresentaram de forma significativa maiores níveis de gordura corporal e de marcadores séricos de risco cardiovascular que indivíduos de baixo risco (P <0,05). Indivíduos de alto risco também mostraram um aumento significativo de danos ao DNA, de acordo com o EC, mas não de acordo com o teste de micronúcleos, do que indivíduos de risco baixo e moderado. A vitamina C consumida foi inversamente correlacionada com os danos ao DNA avaliados pelo EC, e o número de micronúcleos foi inversamente correlacionado com a ingestão de ácido fólico. Os resultados obtidos indicam um aumento de danos no DNA que pode ser consequente do estresse oxidativo em indivíduos jovens com fatores de risco para DCV, indicando que o nível de danos no DNA pode auxiliar na avaliação do risco de DCV

Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents

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Glucocorticoid Receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration

In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC–GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocytespecific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consumption in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/ or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target