The nitrogen-bearing heterocycle pyridine in its several analogous forms occupies an important position as a precious source of clinically useful agents in the field of medicinal chemistry research.

Maternally imprinted PEG10 and SGCE, separated by approximately 2.15 Mb from Syncytin (HERV-W) gene at 7q21.3, are implicated in choriocarcinoma and Silver-Russell syndrome. Here we have analyzed the temporal regulation of mRNA expression of these genes in placenta and demonstrate that Syncytin gene activation is highest in term placenta, PEG10, downregulated at early hypoxic phase, and highly activated at 11-12 wk of gestation. In contrast, transcription from SGCE remained unchanged throughout pregnancy, suggesting two neighboring imprinted genes are differentially regulated at very early pregnancy. Additionally, accumulation of two major species of mRNA (8 kb and 3.1 kb) encoded by HERV-W in placenta is regulated: 3.1 kb mRNA level remained unchanged throughout pregnancy, whereas the production of 8 kb species was highest in term placenta. Western blot and immunohistochemical staining of placental tissues with monoclonal antibodies revealed a marked reduction of syncytin glycoprotein synthesis in late pregnancy. Therefore, the relative levels of 3.1 kb and 8 kb mRNAs in trophoblasts could regulate syncytin protein synthesis, possibly by competition of the two mRNA species for translational apparatus.

The inability of the mother to switch from T helper cell type 1 (Th1) to Th2 cytokine profiles at the fetal-maternal interface has been proposed as one of the primary causes of miscarriage, intrauterine growth restriction (IUGR), and preeclampsia (PE). The Th1 [interferon-gamma (IFN-gamma), TNF-alpha, and IL-12] and Th2 (IL-4 and IL-10) cytokines have opposite effects on human pregnancy. Leukemia inhibitory factor (LIF) promotes embryo implantation and sustains pregnancy, whereas IFN-gamma and TNF-alpha are detrimental to pregnancy. Both IFN-gamma and LIF are produced by maternal cells and tissues at the fetal-maternal interface, whereas the IFN-gamma receptors (IFN-gamma R1 and IFN-gamma R2) and LIF receptor are abundantly expressed on the surface of placental trophoblasts. The effect of IFN-gamma on T lymphocyte activation is influenced by the relative membrane density of its two receptors, particularly IFN-gamma R2. In this study we report that in PE (25-40 wk gestation) and PE complicated by IUGR, IFN-gamma R2 protein expression is severely down-regulated and is similar to that observed in early placenta (7-10 wk gestation) developing under low O(2) tension. IFN-gamma production was found to be inversely related to the IFN-gamma R2 protein expression, and LIF receptor protein expression in PE mimicked that in early placental development. These results show that in PE, placental trophoblasts fail to establish an early to late switch with respect to IFN-gamma and IFN-gamma R2 expression. This supports the hypothesis that trophoblasts control the polarization of maternal immune effectors and cytokine profiles at the fetal-maternal interface that could be subject to oxidative stress in PE.

p53 function is modulated by several covalent and non-covalent modifiers. The architectural DNA- binding protein, High Mobility Group protein B-1 is a unique activator of p53. HMGB-1 protein is structured into two HMG-box domains, namely A-box and B-box, connected to a long highly acidic C-terminal domain. Here we report that both the C-terminal domain and A-box of HMGB-1 are critical for stimulation of p53-mediated DNA binding to its cognate site. Though deletion of these domains showed minimal effect in activation of p53-mediated transcription from the DNA template as compared to full-length HMGB-1, truncation of both the domains indeed showed significant reduction of transcriptional activation from the chromatin template as observed in DNA binding. Using transient transfection assays we showed that the C-terminal acidic domain and A-box of HMGB-1 are critical for the enhancement of the p53-mediated transactivation in vivo. Furthermore, the C-terminal domain and A-box deleted HMGB-1 could not activate p53-dependent apoptosis above the basal level. In conclusion, these results elucidate the role of acidic C-terminal domain and A-box of HMGB-1 in p53-mediated transcriptional activation and its further downstream effect.