Targeting bromodomain-containing proteins to prevent spontaneous preterm birth

2019 ◽  
Vol 133 (23) ◽  
pp. 2379-2400 ◽  
Author(s):  
Ratana Lim ◽  
Caitlyn Nguyen-Ngo ◽  
Martha Lappas
Keyword(s):  
Preterm Birth ◽  
Preterm Labor ◽  
Selective Inhibition ◽  
Clinical Samples ◽  
Fetal Membranes ◽  
Spontaneous Preterm Birth ◽  
Protein Inhibition ◽  
Decidual Cells ◽  
Gestational Tissues ◽  
Human And Mouse

Abstract Preterm birth is a global healthcare challenge. Spontaneous preterm birth (sPTB) is commonly caused by inflammation, yet there are currently no effective therapies available. The Bromodomain and Extra-Terminal motif (BET) proteins, Bromodomain-containing protein (Brd) 2 (Brd2), Brd3 and Brd4 regulate inflammation in non-gestational tissues. The roles of Brd2–4 in human pregnancy are unknown. Using human and mouse models, the present study has identified the Brd proteins part of the process by which inflammation induces parturition. Using human clinical samples, we demonstrate that labor and infection increase the expression of Brds in the uterus and fetal membranes. In primary human myometrial, amnion and decidual cells, we found that global Brd protein inhibition, as well as selective inhibition of Brds, suppressed inflammation-induced expression of mediators involved in myometrial contractions and rupture of fetal membranes. Importantly, studies in the mouse model demonstrate that the pan-Brd inhibitor JQ1 reduced intrauterine inflammation induced by bacterial endotoxin LPS as well as decreasing the effectiveness of LPS to induce parturition. These results implicate BET proteins as novel therapeutic targets for reducing inflammation associated with spontaneous preterm labor.

scholarly journals IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Lulu Wang ◽  
Zheng Liu ◽  
Dongni Huang ◽  
Yuxin Ran ◽  
Hanwen Zhang ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Signaling Pathway ◽  
Biological Effects ◽  
Clinical Samples ◽  
Fetal Membranes ◽  
Spontaneous Preterm Birth ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Anti Inflammatory

Spontaneous preterm birth (sPTB), defined as delivery before 37 weeks of gestation, is thought to be a multifactorial syndrome. However, the inflammatory imbalance at the maternal-fetal interface promotes excessive secretion of inflammatory factors and induces apoptosis and degradation of the extracellular matrix (ECM), which can subsequently lead to preterm birth. As an anti-inflammatory molecule in the IL-1 family, interleukin-37 (IL-37) mainly plays an inhibiting role in a variety of inflammatory diseases. However, as a typical inflammatory disease, no previous studies have been carried out to explore the role of IL-37 in sPTB. In this study, a series of molecular biological experiments were performed in clinical samples and human amniotic epithelial cell line (Wistar Institute Susan Hayflick (WISH)) to investigate the deficiency role of IL-37 and the potential mechanism. Firstly, the results indicated that the expression of IL-37 in human peripheral plasma and fetal membranes was significantly decreased in the sPTB group. Afterward, it is proved that IL-37 could significantly suppress the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in WISH cells. Simultaneously, once silence IL-37, LPS-induced apoptosis and activity of matrix metalloproteinases (MMPs) 2 and 9 were significantly increased. In addition, the western blot data showed that IL-37 performed its biological effects by inhibiting the NF-κB and IL-6/STAT3 pathway. In conclusion, our results suggest that IL-37 limits excessive inflammation and subsequently inhibits ECM remodeling and apoptosis through the NF-κB and IL-6/STAT3 signaling pathway in the fetal membranes.

scholarly journals Anti-inflammatory effects of gallic acid in human gestational tissues in vitro

Reproduction ◽  
2020 ◽  
Vol 160 (4) ◽  
pp. 561-578 ◽  
Author(s):  
Caitlyn Nguyen-Ngo ◽  
Carlos Salomon ◽  
Andrew Lai ◽  
Jane C Willcox ◽  
Martha Lappas
Keyword(s):  
Preterm Birth ◽  
Gallic Acid ◽  
Spontaneous Preterm Birth ◽  
Cell Contractility ◽  
Proteomic Approach ◽  
Decidual Cells ◽  
Foetal Membranes ◽  
Anti Inflammatory ◽  
Gestational Tissues

Spontaneous preterm birth is the leading cause of neonatal mortality and morbidity globally. Activation of the maternal immune system leads to a downstream cascade of proinflammatory events that culminate in the activation of spontaneous uterine contractions and the rupture of the foetal membranes. Anti-inflammatory agents may be a novel therapeutic approach to prevent inflammation-induced myometrial contractions and premature rupture of foetal membranes. The polyphenol gallic acid has been previously shown to exert potent anti-inflammatory effects. Thus, this study aimed to determine the effect of gallic acid on proinflammatory and pro-labour mediators in cytokine-stimulated gestational tissues in vitro. In primary human cells isolated from myometrium and foetal membranes (decidua, and amnion mesenchymal and epithelial cells), gallic acid treatment suppressed inflammation-induced expression of proinflammatory cytokines and chemokines and extracellular matrix-degrading and matrix-remodelling enzymes. Gallic acid also significantly inhibited inflammation-induced myometrial activation as evidenced by decreased expression of contraction-associated proteins, the uterotonic PGF2α and collagen cell contractility. Using a global proteomic approach, gallic acid may differentially regulate proteins associated with collagen synthesis, cell contractility and protein synthesis in primary myometrial and decidual cells. In summary, gallic acid inhibited inflammation-induced mediators involved in active labour in primary cells isolated from myometrium and foetal membranes. These in vitro studies suggest that the polyphenol gallic acid may be able to suppress the production of proinflammatory and pro-labour mediators involved in myometrial contractions and rupture of foetal membranes. Future preclinical studies may elucidate the efficacy of gallic acid in preventing inflammation-driven preterm birth.

scholarly journals Impact of preconception vaginal microbiota on women’s risk of spontaneous preterm birth: protocol for a prospective case-cohort study

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e035186 ◽  
Author(s):  
Erica M Lokken ◽  
Kishorchandra Mandaliya ◽  
Sujatha Srinivasan ◽  
Barbra A Richardson ◽  
John Kinuthia ◽  
...  
Keyword(s):  
Cohort Study ◽  
Preterm Birth ◽  
Umbilical Cord ◽  
Bacterial Species ◽  
Vaginal Microbiota ◽  
Fetal Membrane ◽  
Fetal Membranes ◽  
Rrna Gene ◽  
Spontaneous Preterm Birth ◽  
Increased Risk

IntroductionBacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis.Methods and analysisHIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord.Ethics and disseminationThis study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

Optineurin suppression activates the mediators involved in the terminal effector pathways of human labour and delivery

2017 ◽  
Vol 29 (6) ◽  
pp. 1074
Author(s):  
Ratana Lim ◽  
Gillian Barker ◽  
Martha Lappas
Keyword(s):  
Preterm Birth ◽  
Mrna Expression ◽  
Prostaglandin F2α ◽  
Binding Activity ◽  
Negative Regulator ◽  
Fetal Membranes ◽  
Spontaneous Preterm Birth ◽  
Monocyte Chemoattractant Protein 1 ◽  
Myometrial Cells ◽  
Dna Binding Activity

Spontaneous preterm birth remains the major cause of neonatal death and morbidity. Studies in non-gestational tissues report that optineurin (OPTN) is critical in the termination of NFKB1 activity and control of inflammation, central features of spontaneous preterm birth. The aims of the present study were to determine: (1) OPTN expression in fetal membranes and the myometrium during labour; (2) the effects of IL1B on OPTN expression in primary myometrial cells; and (3) the effects of OPTN short interference (si) RNA on IL1B-stimulated proinflammatory and prolabour mediators. OPTN mRNA and protein expression was significantly decreased with spontaneous term labour in fetal membranes and the myometrium. Although there was no effect of spontaneous preterm labour on OPTN expression in fetal membranes, there was decreased OPTN expression in membranes with chorioamnionitis and myometrial cells treated with 1ng mL–1 IL1B for 1 or 6 h. In cells transfected with OPTN siRNA, significant increases were seen in IL1B-stimulated IL6, tumour necrosis factor, CXCL8 and monocyte chemoattractant protein-1 mRNA expression and release, cyclo-oxygenase-2 and prostanoid PTGFR receptor mRNA expression and the release of prostaglandin F2α. There was no change in IL1B-stimulated NFKBIA expression; however, there was increased NFKB1 p65 DNA-binding activity. The results of the present study suggest that OPTN is a negative regulator of inflammation-induced prolabour mediators.

731: Prediction of spontaneous preterm birth in women with preterm labor - analysis of 27 proteins by luminex xMAP technology in amniotic and cervical fluids

2008 ◽  
Vol 199 (6) ◽  
pp. S208
Author(s):  
Rose-Marie Holst ◽  
Bo Jacobsson ◽  
Henrik Hagberg ◽  
Ulla-Britt Wennerholm ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Preterm Labor ◽  
Spontaneous Preterm Birth ◽  
Xmap Technology

scholarly journals Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96901 ◽  
Author(s):  
Yujing Jan Heng ◽  
Craig Edward Pennell ◽  
Hon Nian Chua ◽  
Jonathan Edward Perkins ◽  
Stephen James Lye
Keyword(s):  
Gene Expression ◽  
Preterm Birth ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Whole Blood ◽  
Preterm Labor ◽  
Spontaneous Preterm Birth ◽  
Blood Gene Expression ◽  
Threatened Preterm Labor

scholarly journals Gut microbial-related metabolite trimethylamine-N-oxide and its precursor L-carnitine are associated with spontaneous preterm birth: a nested case-control study

2019 ◽  
Author(s):  
Xing Chen ◽  
Ning Huang ◽  
Chaoqun Liu ◽  
Yue Chen ◽  
Lulu Huang ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Preterm Labor ◽  
Case Control Study ◽  
Case Control ◽  
Normal Weight ◽  
Maternal Serum ◽  
Spontaneous Preterm Birth ◽  
Nested Case Control ◽  
Related Metabolite ◽  
Control Study

Abstract Background: Gut microbiota has been proven to disease susceptibility and may lead to increased risk of preterm birth. To date, the link of gut microbial-related metabolite trimethylamine-N-oxide (TMAO), L-carnitine, and betaine, with spontaneous preterm birth (sPTB) has not been established. This study aimed to investigate the association of TMAO, L-carnitine and betaine, with sPTB risk. Methods: A nested case-control study was designed including 129 sPTB cases and 258 controls based on Guangxi Birth Cohort Study. TMAO, L-carnitine, and betaine level in maternal serum were determined by liquid chromatography with mass spectrometry. Conditional logistic regression analyses were used to examine the association between maternal serum metabolites and sPTB. Stratified analyses were further conducted according to BMI and preterm prelabor rupture of membranes. Spline analyses were performed to explore the dose-response relationship between the metabolites and sPTB.Results: Statistically significant association with decreased sPTB risk was observed for the highest L-carnitine (OR: 0.47; 95% CI: 0.23, 0.95). In risk analyses stratified by BMI, similar results were observed in normal weight gravida (BMI: 18.5~23.9 kg/cm2). The significant subtype-specific association with TMAO (OR: 0.43; 95% CI: 0.20, 0.93) and L-carnitine (OR: 0.45; 95% CI: 0.21, 0.97) were observed for preterm labor but not PPROM. Spline regression analysis indicated non-linear associations with TMAO and sPTB risk (P for nonlinearity: 0.057). Significant associations of TMAO with sPTB were observed in normal weight gravida (P = 0.028) and preterm labor subtype (P = 0.025). No statistically significant associations with sPTB risk were observed for betaine (P > 0.05).Conclusions: TMAO and L-carnitine levels in maternal serum are inversely linked with sPTB risk. Discovery of the association between gut-microbiota initiated TMAO metabolism and sPTB may open new avenues for diagnose and therapy.

scholarly journals The short-chain fatty acids butyrate and propionate protect against inflammation-induced activation of mediators involved in active labor: implications for preterm birth

2020 ◽  
Vol 26 (6) ◽  
pp. 452-468 ◽  
Author(s):  
Hope Eveline Carter Moylan ◽  
Caitlyn Nguyen-Ngo ◽  
Ratana Lim ◽  
Martha Lappas
Keyword(s):  
Fatty Acids ◽  
Preterm Birth ◽  
Inflammatory Cytokines ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Fetal Membranes ◽  
Spontaneous Preterm Birth ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines ◽  
Chain Fatty Acids

Abstract Spontaneous preterm birth is a global health issue affecting up to 20% of pregnancies and leaves a legacy of neurodevelopmental complications. Inflammation has been implicated in a significant proportion of preterm births, where pro-inflammatory insults trigger production of additional pro-inflammatory and pro-labor mediators. Thus, novel therapeutics that can target inflammation may be a novel avenue for preventing preterm birth and improving adverse fetal outcomes. Short-chain fatty acids (SCFAs), such as butyrate and propionate, are dietary metabolites produced by bacterial fermentation of fiber in the gut. SCFAs are known to possess anti-inflammatory properties and have been found to function through G-coupled-receptors and histone deacetylases. Therefore, this study aimed to investigate the effect of SCFAs on pro-inflammatory and pro-labor mediators in an in vitro model of preterm birth. Primary human cells isolated from myometrium and fetal membranes (decidua, amnion mesenchymal and amnion epithelial cells) were stimulated with the pro-inflammatory cytokines tumor necrosis factor alpha (TNF) or interleukin 1B (IL1B). The SCFAs butyrate and propionate suppressed inflammation-induced expression of pro-inflammatory cytokines and chemokines, adhesion molecules, the uterotonic prostaglandin PGF2alpha and enzymes involved in remodeling of myometrium and degradation of the fetal membranes. Notably, propionate and butyrate also suppressed inflammation-induced prostaglandin signaling and myometrial cell contraction. These effects appear to be mediated through suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation. These results suggest that the SCFAs may be able to prevent myometrial contractions and rupture of membranes. Further in vivo studies are warranted to identify the efficacy of SCFAs as a novel anti-inflammatory therapeutic to prevent inflammation-induced spontaneous preterm birth.

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