Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays.

Sonic hedgehog (Shh) is a morphogen with important roles in embryonic development and in the development of a number of cancers. Its activity is modulated by interactions with binding partners and co-receptors including heparin and heparin sulfate proteoglycans (HSPG). To identify antagonists of Shh/heparin binding, a diverse collection of 34,560 chemicals was screened in single point 384-well format.

Sex-dependent effects of preconception exposure to arsenite on gene transcription in parental germ cells and on transcriptomic profiles and diabetic phenotype of offspring.

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetic phenotypes in both humans and mice. However, diabetogenic effects of iAs exposure during specific developmental windows have never been systematically studied. We have previously shown that in mice, combined preconception and in utero exposures to iAs resulted in impaired glucose homeostasis in male offspring.

Acetaminophen Modulates the Expression of Steroidogenesis-Associated Genes and Estradiol Levels in Human Placental JEG-3 Cells.

Acetaminophen is the only medication recommended for pain and fever management during pregnancy. However, studies have reported an association between in utero acetaminophen and neurocognitive disorders later in life. Additionally, acetaminophen has been shown to have endocrine disrupting properties altering hormones critical for normal fetal development.

Placental microRNAs: Responders to environmental chemicals and mediators of pathophysiology of the human placenta.

MicroRNAs (miRNAs) are epigenetic modifiers that play an important role in the regulation of the expression of genes across the genome. miRNAs are expressed in the placenta as well as other organs, and are involved in several biological processes including the regulation of trophoblast differentiation, migration, invasion, proliferation, apoptosis, angiogenesis and cellular metabolism. Related to their role in disease process, miRNAs have been shown to be differentially expressed between normal placentas and placentas obtained from women with pregnancy/health complications such as preeclampsia, gestational diabetes mellitus, and obesity.

Erratum: Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.

[This corrects the article DOI: 10.1093/eep/dvz010.][This corrects the article DOI: 10.

Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.

Acetaminophen is considered the safest antipyretic and analgesic medication for pregnant women. However, studies have reported that acetaminophen has endocrine disrupting properties and prenatal exposure has been associated with early life epigenetic changes and later life health outcomes. As the placenta is the central mediator of maternal and fetal interactions, exposure to acetaminophen during pregnancy could manifest as perturbations in the placenta epigenome.

Effects of Preconception and in Utero Inorganic Arsenic Exposure on the Metabolic Phenotype of Genetically Diverse Collaborative Cross Mice.

In humans and mice, in utero exposure to inorganic arsenic (iAs) is associated with adverse health outcomes later in life. The contribution of preconception exposure to the adverse outcomes in offspring has never been studied. Here combined in utero and postnatal exposures produce insulin resistance in two collaborative cross strains.

Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal socioeconomic status.

This study evaluated the hypothesis that prenatal maternal socioeconomic status (SES) adversity is associated with DNA methylation in the placenta. SES adversity was defined by the presence of, as well as a summative count of, four factors: less than college education, single marital status, food and nutritional service assistance, and public health insurance. Epigenome-wide DNA methylation was assessed using the Illumina EPIC array in 426 placentas from a sample of infants born < 28 weeks of gestation from the Extremely Low Gestational Age Newborn cohort.

Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells.

Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of GLI antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines.

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling.

Lipid raft membrane microdomains organize signaling by many prototypical receptors, including the Toll-like receptors (TLRs) of the innate immune system. Raft-localization of proteins is widely thought to be regulated by raft cholesterol levels, but this is largely on the basis of studies that have manipulated cell cholesterol using crude and poorly specific chemical tools, such as β-cyclodextrins. To date, there has been no proteome-scale investigation of whether endogenous regulators of intracellular cholesterol trafficking, such as the ATP binding cassette (ABC)A1 lipid efflux transporter, regulate targeting of proteins to rafts.

Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form.

We have generated a photoactivatable form of sonic hedgehog protein by modifying the N-terminal cysteine with the heterobifunctional photocrosslinker 4-maleimidobenzophenone (Bzm). The Bzm modification on ShhN imparted a significant increase in activity as assessed in the C3H10T1/2 functional assay with potency comparable to that of the endogenous dual-lipidated form of ShhN (ShhNp). Reversed-phase HPLC analysis indicated that the increase in activity compared to unmodified ShhN may be due in part to the hydrophobic nature of the benzophenone group.

TNF-α/IL-17 synergy inhibits IL-13 bioactivity via IL-13Rα2 induction.

IL-17 and TNF synergistically induce surface expression of IL-13R2 on primary lung fibroblasts, rendering them unresponsive to IL-13. Neutralizing antibodies to IL-13R2 restored IL-13-mediated signaling and transcriptome studies confirmed IL-13R2 is an IL-13 decoy receptor.