Gestational hypoxia and epigenetic programming of brain development disorders

Adverse environmental conditions faced by an individual early during its life, such as gestational hypoxia, can have a profound influence on the risk of diseases, such as neurological disorders, in later life. Clinical and preclinical studies suggest that epigenetic programming of gene expression patterns in response to maternal stress have a crucial role in the fetal origins of neurological diseases. Herein, we summarize recent studies regarding the role of epigenetic mechanisms in the developmental programming of neurological diseases in offspring, primarily focusing on DNA methylation/demethylation and miRNAs. Such information could increase our understanding of the fetal origins of adult diseases and help develop effective prevention and intervention against neurological diseases

Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner

LAPTM4B allele *2 is a marker of poor prognosis following hepatic tumor resection for hepatocellular carcinoma.

BACKGROUND: Lysosomal protein transmembrane 4 beta (LAPTM4B) is a gene related to hepatocellular carcinoma that has two alleles designated LAPTM4B*1 and LAPTM4B*2. This study aimed to investigate the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who have undergone resection for hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: The LAPTM4B genotype was analyzed by PCR in 68 patients who had undergone curative hepatic resection for hepatocellular carcinoma. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan-Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both P<0.001). CONCLUSIONS/SIGNIFICANCE: Allele *2 of LAPTM4B is a risk factor associated with poor prognosis in patients with resected HCC. LAPTM4B status may be useful preoperatively as an adjunct in evaluation of the operability of HCC

5-AZA abrogates dexamethasone (DEX)-mediated effects on cardiomyocyte number in neonatal rats.

<p>Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Cardiomyocytes isolated from day 4 (P4), day 7 (P7) and day 14 (P14) neonatal hearts were counted and normalized to per gram of heart weight. Data are mean ± SEM, n = 5–20. * p<0.05, DEX <i>vs</i>. Saline; # p<0.05, +5-AZA <i>vs</i>. -5-AZA; † p<0.05, P7 <i>vs</i>. P4.</p

5-AZA blocks dexamethasone (DEX)-induced effects on cardiomyocyte proliferation and binucleation in neonatal rats.

<p>Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Panel <b>A</b>: Cardiomyocytes isolated from day 4 (P4) and day 7 (P7) neonatal hearts were double stained with α-actinin and Ki67, nuclei were stained with Hoechst. Panel <b>B</b>: Cardiomyocytes isolated from P7 neonatal hearts were examined for BrdU incorporation. Panel <b>C</b>: Cardiomyocytes isolated from P4 and P7 neonatal hearts were stained with α-actinin and Hoechst, and mononucleated and binucleated cells were determined. Data are mean ± SEM, n = 4–14. * p<0.05, DEX <i>vs</i>. Saline; # p<0.05, +5-AZA <i>vs</i>. -5-AZA; † p<0.05, P7 <i>vs</i>. P4.</p

Effect of dexamethasone (DEX) on cardiomyocyte proliferation in neonatal rats.

<p>Newborn rats were treated with tapered dose of DEX in the absence or presence of Ru486 during the first three days of postnatal life. Ru486 was administered 30 minutes prior to the DEX treatment. Panel <b>A</b>: Cardiomyocytes isolated from day 4 (P4) and day 7 (P7) neonatal hearts were double stained with α-actinin and Ki67, and nuclei were stained with Hoechst. Representative staining of α-actinin and Ki67 co-localization was shown in the upper panel. Panel <b>B</b>: Cardiomyocytes isolated from P7 neonatal hearts were examined for BrdU incorporation. Data are mean ± SEM, n = 4–14. * p<0.05, DEX <i>vs</i>. Saline.</p