Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia

Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses. Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFN alpha) protein expression by immunohistochemistry. Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas. Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials. (C) 2020 The Authors. Published by Elsevier B.V.Peer reviewe

Insights into the post-transcriptional regulation of the mitochondrial electron transport chain

The regulation of the mitochondrial electron transport chain is central to the control of cellular homeostasis. There are significant gaps in our understanding of how the expression of the mitochondrial and nuclear genome-encoded components of the electron transport chain are co-ordinated, and how the assembly of the protein complexes that constitute the electron transport chain are regulated. Furthermore, the role post-transcriptional gene regulation may play in modulating these processes needs to be clarified. This review summarizes the current knowledge regarding the post-transcriptional gene regulation of the electron transport chain and highlights how noncoding RNAs may contribute significantly both to complex electron transport chain regulatory networks and to mitochondrial dysfunction

Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

<p>The incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene <i>Atg7</i> in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.</p

2-methoxyestradiol Prevents LNCaP Tumor Development in Nude Mice: Potential Role of G/M Regulatory proteins

Nontoxic naturally occurring metabolite of estrogen namely 2-methoxyestradial (2ME 2 ) found in serum and urine has been shown to be antitumorigenic in various tumor models including the prostate. A recent study conducted in breast cancer cells showed growth stimulatory effect of 2ME 2 when used at low concentrations (10-750 nM). Studies from our laboratory has demonstrated prostate tumor preventive ability of 50 mg/kg 2-ME 2 . In this study we show that concentrations of 2-ME 2 as low as 1 μM is sufficient to inhibit proliferation and induce apoptosis in androgen responsive LNCaP cells. In addition oral administration of doses lower than 50 mg/kg prevented prostate tumor development in LNCaP xenograft model. The observed tumor growth inhibition was associated with induction of apoptosis, increased expression of Wee1 kinase and p34cdc2. In addition administration of 25 mg/kg 2-ME 2 prevented tumor development significantly that is associated with reduction in serum PSA levels