Increasing levels of tissue hypoxia have been reported as a natural feature of the aging prostate gland and may be a risk factor for the development of prostate cancer. In this study, we have used PwR-1E benign prostate epithelial cells and an equivalently aged hypoxia-adapted PwR-1E sub-line to identify phenotypic and epigenetic consequences of chronic hypoxia in prostate cells. We have identified a significantly altered cellular phenotype in response to chronic hypoxia as characterized by increased receptor-mediated apoptotic resistance, the induction of cellular senescence, increased invasion and the increased secretion of IL-1 beta, IL6, IL8 and TNFalpha cytokines. In association with these phenotypic changes and the absence of HIF-1 alpha protein expression, we have demonstrated significant increases in global levels of DNA methylation and H3K9 histone acetylation in these cells, concomitant with the increased expression of DNA methyltransferase DMNT3b and gene-specific changes in DNA methylation at key imprinting loci. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic hypoxic conditions in the prostate. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular phenotype with a potential role in tumour development.
Background
Immune system dysfunction is implicated in the pathophysiology of major depression, and is hypothesized to normalize with successful treatment. We aimed to investigate immune dysfunction in melancholic depression and its response to ECT.
Methods
55 melancholic depressed patients and 26 controls participated. 33 patients (60%) were referred for ECT. Blood samples were taken at baseline, one hour after the first ECT session, and 48 hours after ECT series completion.
Results
At baseline, melancholic depressed patients had significantly higher levels of the pro-inflammatory cytokine IL-6, and lower levels of the regulatory cytokine TGF-β than controls. A significant surge in IL-6 levels was observed one hour after the first ECT session, but neither IL-6 nor TGF-β levels normalized after completion of ECT series. Seventy per cent (n=23) of ECT recipients showed clinical response and 42% (n=10) reached remission. Neither IL-6 nor TGF-β changes correlated with clinical improvement following ECT. No significant changes in IL-10, TNF-α and CRP levels were found in relation to melancholia or response to ECT.
Limitations
As a naturalistic study, some potential confounders could not be eliminated or controlled, including medication use.
Conclusions
Melancholic depressed patients demonstrated a peripheral increase in IL-6 and reduction in TGF-β, which did not normalize despite clinical response to ECT. These findings may be consistent with emerging hypotheses of the role of inflammation in mediating neurotropin expression. The implications of chronic inflammation in the melancholic depressed population for future medical health, particularly cardiovascular risk, are largely unknown and warrant further investigation.
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