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The precise mechanisms of tissue fibrosis have not yet been elucidated in systemic sclerosis (SSc). However, studies of the regulation of DNA methylation, the most widely studied epigenetic mechanism, have confirmed the involvement of the TET family proteins, recently identified DNA demethylases, in the pathogenesis of SSc. The mRNA levels of TET family members were compared in normal and SSc fibroblasts. The effects of hypoxia and siRNA specific to HIF-1α on TET expression were also examined. Global methylation status was analysed by LUMA. The presence of 5-hydroxymethylcytosine (5hmC) in SSc was examined by immunohistochemistry. The level of TET1 mRNA in SSc fibroblasts was elevated by 1.68 fold compared with that of normal fibroblasts, but the expression levels of TET2 and TET3 were comparable between both cell types. The expression levels of DNMT1 and DNMT3B mRNA have a tendency to elevate in SSc fibroblasts. Among TET family members, the expression of TET1 was exclusively induced by hypoxia via HIF-1α-independent pathways in SSc fibroblasts, but not in normal fibroblasts. The methylation level was decreased in SSc fibroblasts relative to normal fibroblasts, and 5hmC was present in dermal fibroblasts of skin sections from patients with SSc. TET1 expression in SSc fibroblasts was abnormally regulated in the hypoxic environment and accompanied by global DNA hypomethylation, suggesting the involvement of aberrant DNA methylation in the pathogenesis of SSc.

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We examined DNA demethylase (dMTase) expression, a common feature of ovarian cancer, to establish if there is any relationship between gene expression and disease stage, histopathology and survival. We also sought evidence of concurrent dMTase and lung resistance protein (LRP) expression. In 43 epithelial ovarian cancers studied we found that the relative strength of gene expression correlated with disease stage, histology and survival. dMTase expression was positive in 38/43 cases studied (88.4%). We also identified a significant correlation between dMTase and LRP expression. In 80% of cases where dMTase was not expressed, LRP was not found. Conversely, 70% of cases where dMTase expression was positive were also LRP-positive. We also identified a weak trend indicating that dMTase expression may occur more frequently in cases of endometrioid and serous adenocarcinoma. The expression of dMTase is a common feature of ovarian cancer and there is a correlation between dMTase and LRP expression, suggesting that there may be an epigenetic upregulation of the gene.

PurposeTransient receptor potential vanilloid 1 (TRPV1) not only is activated by multiple stimuli but also is involved with histamine-induced itch. The effects of TRPV1 on morphine-induced itch are unknown. We examined the effects of intrathecal administration of TRPV1 antagonist on morphine-induced itch, body temperature, and antinociception for mice.MethodsEach C57/BL6j mouse was intrathecally administered with one of the following solutions: morphine, SB366791 (as the TRPV1 antagonist), morphine + SB366791, saline, or vehicle. For each mouse, each instance of observed scratching behavior was counted, the body temperature was measured, and the nociceptive threshold was determined using the tail-immersion test.ResultsSB366791 dose-dependently reduced the scratching behavior induced by the administration of morphine. SB366791 and the morphine + SB366791 groups did not manifest an increase in body temperature. Antinociceptive effects were observed to occur dose-dependently for morphine but not for SB366791. Compared with morphine alone, the administration of morphine + SB366791 did not reduce significant antinociceptive effects.ConclusionWe propose that an intrathecal TRPV1 antagonist, SB366791, reduced morphine-induced itch without causing hyperthermia and did not suppress morphine-induced antinociception for mice.