433. Identifying novel biomarkers predictive of impending human labour

2008 ◽  
Vol 20 (9) ◽  
pp. 113
Author(s):  
Y. J. Heng ◽  
M. K. W. Di Quinzio ◽  
M. Permezel ◽  
G. E. Rice ◽  
H. M. Georgiou
Keyword(s):  
Predictive Value ◽  
Interleukin 1 ◽  
Fetal Membranes ◽  
Vaginal Fluid ◽  
Protease Inhibition ◽  
Fatty Acid Binding ◽  
Spontaneous Labour ◽  
Human Labour ◽  
Anti Inflammatory ◽  
Term Labour

Human labour is characterised by structural remodelling of the cervix and overlying fetal membranes, myometrial activation and parturition. We hypothesise that temporal biochemical alterations of the cervix and supracervical fetal membranes associated with impending labour may be reflected in the cervico-vaginal fluid (CVF). 2D PAGE proteomic analysis performed on serial CVF samples collected from women (n = 9) during late pregnancy and in spontaneous labour demonstrated 9 significantly altered protein spots (P < 0.05) in association with term labour. Seven different proteins were identified using electrospray ion-trap mass spectrometry (interleukin-1 receptor antagonist (IL-1ra), cystatin-A, glutathione S-transferase P, peroxiredoxin-2, thioredoxin, Cu,Zn superoxide dismutase, and epidermal fatty-acid binding protein). These proteins are involved in anti-inflammatory activity, protease inhibition, and oxidative stress defence. Validation of these potential biomarkers using ELISA is currently underway. Findings for the anti-inflammatory cytokine, IL-1ra are discussed. CVF was collected weekly from 106 women at 36 weeks' gestation up to and including spontaneous labour. The concentration of IL-1ra was 4-fold lower during labour compared with 15–21 and 22–28 days from labour (P < 0.05) and was also significantly lower (P < 0.05) at 0–7 days compared with 15–21 days before labour. After subdividing the women, the concentration of IL-1ra at 8–14 and 15–21 days before labour was 6-fold lower in women who had prelabour rupture of membranes at term followed by regular contractions compared with women who had spontaneous labour with intact membranes. Receiver-operator characteristic curve analysis indicated that IL-1ra best predicted term labour within 3 days of sampling with a cut-off value of 0.4 m g/mL (sensitivity 50.7%, specificity 72.2%, positive predictive value 36.1%, negative predictive value 82.6%). This IL-1ra validation study suggests that the decrease in IL-1ra in CVF during spontaneous term labour may be associated with proinflammatory-mediated remodelling of the fetal membranes leading to their rupture. (1) Di Quinzio et al. 2008, J. Proteome Res, 7:1916–1921. (2) Heng YJ et al. 2008, Am J Obstet Gynecol, In Press.

scholarly journals RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators

Reproduction ◽  
2016 ◽  
Vol 151 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Martha Lappas
Keyword(s):  
Protein Expression ◽  
Interleukin 1 ◽  
Signalling Pathway ◽  
Mrna Abundance ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Human Labour ◽  
Prostaglandin Endoperoxide Synthase ◽  
Sirna Knockdown ◽  
Term Labour

Inflammation plays a central role in the terminal process of human labour and delivery, including myometrial contractions. RAF1 proto-oncogene serine/threonine-protein kinase (RAF1) can activate ERK (official gene symbolMAPK1) and/or nuclear factor-kappa B (NF-κB) to regulate genes involved in inflammation. There are, however, no studies on the role of RAF1 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour and pro-inflammatory cytokines interleukin 1 beta (IL1B) and tumour necrosis factor (TNF) alpha on RAF1 protein expression in myometrium and ii) siRNA knockdown ofRAF1on pro-inflammatory and pro-labour mediators in human myometrial primary cells. Term labour was associated with an increase in RAF1 protein expression. Furthermore, RAF1 protein expression was increased in myometrial cells treated with IL1B and TNF, two likely factors contributing to preterm birth. Knockdown ofRAF1by siRNA in primary myometrial cells significantly decreased IL1B- and TNF-inducedIL1A, IL1B, IL6,(C-X-C motif) ligand 8 (CXCL8)and chemokine (C-C motif) ligand 2 (CCL2) mRNA abundance and IL6, IL8 and CCL2; prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels and prostaglandin PGF2αrelease; and NF-κB activation. Furthermore,RAF1knockdown was associated with decreased activation of ERK in the presence of IL1B but not TNF. Concordantly, the ERK inhibitor U0126 significantly decreased IL1B-inducedIL6,CXCL8,CCL2andPTGS2mRNA abundance; IL6, CXCL8, CCL2 and PGF2αrelease; and NF-κB activation. In conclusion, IL1B induces the expression and secretion of pro-labour mediators through the RAF1–MAPK1–NF-κB signalling pathway. TNF, on the other hand, regulates pro-labour mediators through the RAF1–NF-κB signalling pathway via an MAPK1-independent mechanism.

Measurement of interleukin-1 alpha and interleukin-6 in pregnancy-associated tissues

1996 ◽  
Vol 8 (7) ◽  
pp. 1069 ◽  
Author(s):  
L Gunn ◽  
P Hardiman ◽  
S Tharmaratnam ◽  
D Lowe ◽  
T Chard
Keyword(s):  
Amniotic Fluid ◽  
Interleukin 1 ◽  
Elective Caesarean Section ◽  
Maternal Blood ◽  
Fetal Membranes ◽  
Fetal Blood ◽  
Tissue Extracts ◽  
Arterial Blood ◽  
Term Labour ◽  
In Pregnancy

The concentrations of interleukin-1 alpha (IL-1 alpha) and IL-6 in pregnancy-associated tissues were investigated in term labour and delivery in the absence of labour (elective Caesarean section). Samples of amniotic fluid, placenta, fetal membranes, umbilical venous and, where possible, umbilical arterial blood were collected at delivery (37-41 weeks of gestation). Maternal blood was sampled during labour. Fluid and tissue extracts were assayed for IL-1 alpha and IL-6 by radioimmunoassay. Placenta and membranes were examined histologically for evidence of infection. Concentrations of IL-1 alpha and IL-6 in amniotic fluid and membrane extract, and IL-1 alpha in maternal and fetal blood, were raised after the onset of labour. Concentrations of both cytokines in the placenta remained unchanged. There was a good correlation between concentrations of both cytokines in amniotic fluid and membranes. There was also a significant correlation between concentrations of IL-1 alpha and IL-6 in amniotic fluid, placenta and membranes. It is suggested that the fetal membranes or maternal decidua, but not the placenta, internal fetal or maternal tissues, are the main sources of IL-1 alpha and IL-6 during labour.

scholarly journals Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes

Reproduction ◽  
2013 ◽  
Vol 145 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Stella Liong ◽  
Megan K W Di Quinzio ◽  
Yujing J Heng ◽  
Gabrielle Fleming ◽  
Michael Permezel ◽  
...  
Keyword(s):  
Binding Protein ◽  
Fetal Membranes ◽  
Two Dimensional ◽  
Protease Inhibition ◽  
Premature Rupture ◽  
Fatty Acid Binding ◽  
Elastase Inhibitor ◽  
Membrane Rupture ◽  
Preterm Premature Rupture ◽  
Cervicovaginal Fluid

A significant obstetric complication facing contemporary materno–fetal medicine is preterm premature rupture of the fetal membranes (preterm PROM), which occurs in 30% of all preterm births. The objective of this study was to identify differentially expressed proteins in the cervicovaginal fluid of asymptomatic women before the clinical manifestation of preterm PROM. The preterm PROM group comprised of women with samples collected 6–23 days before PROM, who subsequently delivered preterm (n=5). Women who spontaneously delivered at term served as gestation-matched controls (n=10). Two-dimensional difference in-gel electrophoresis was used to distinguish differential expression between the pooled groups and fold changes were subsequently confirmed by two-dimensional PAGE of individual samples. Spots of interest were identified by mass spectrometry. Proteins that were significantly reduced with impending preterm PROM included the following: thioredoxin (2.7-fold), interleukin 1 receptor antagonist (1.7-fold), fatty acid-binding protein 5 (2.1-fold), cystatin A (dimer; 1.9-fold), monocyte/neutrophil elastase inhibitor (1.6-fold), squamous cell carcinoma antigen-1 (2.1-fold) and γ-glutamyl cyclotransferase (3.0-fold). By contrast, annexin A3 (3.7-fold) and vitamin D binding protein (3.9-fold) were significantly increased with impending preterm PROM. Western blot analysis was also performed on an independent cohort of preterm PROM and control samples to validate these candidate biomarkers. These proteins have known biological functions in oxidative balance, anti-inflammatory activity, metabolism or protease inhibition that may facilitate membrane rupture.

Effect of spontaneous term labour on the expression of the NR4A receptors nuclear receptor related 1 protein (Nurr1), neuron-derived clone 77 (Nur77) and neuron-derived orphan receptor 1 (NOR1) in human fetal membranes and myometrium

2016 ◽  
Vol 28 (7) ◽  
pp. 893 ◽  
Author(s):  
Martha Lappas
Keyword(s):  
Nuclear Receptor ◽  
Muramyl Dipeptide ◽  
Orphan Receptor ◽  
Diaminopimelic Acid ◽  
Fetal Membrane ◽  
Fetal Membranes ◽  
Membrane Rupture ◽  
Human Labour ◽  
Term Labour ◽  
Bacterial Products

Inflammation has been implicated in the mechanisms responsible for human labour. Emerging evidence indicates that nuclear receptor subfamily 4A (NR4A) receptors regulate the transcription of genes involved in inflammation. The aim of the present study was to determine the effect of spontaneous term labour, Toll-like receptor (TLR) ligands and nucleotide-binding oligomerisation domain-containing (NOD) ligands on the expression of nuclear receptor related 1 protein (Nurr1), neuron-derived clone 77 (Nur77) and neuron-derived orphan receptor 1 (NOR1) in human fetal membranes and myometrium. Human fetal membranes and myometrium were collected from term non-labouring women and women after spontaneous labour onset. Tissue explants were used to determine the effect of the bacterial products lipopolysaccharide (LPS; TLR4 ligand), flagellin (TLR5 ligand), fibroblast-stimulating lipopeptide (FSL-1) (TLR2 ligand), γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) (NOD1 ligand) or minimal peptidoglycan muramyl dipeptide (MDP; NOD2 ligand) on Nurr1, Nur77 and NOR1 expression. Term labour was associated with significantly higher Nurr1 and Nur77, but not NOR1, expression in fetal membranes and myometrium. LPS and MDP increased Nurr1, Nur77 and NOR in fetal membranes; flagellin increased Nurr1 in fetal membranes and the myometrium, as well as NOR1 in the myometrium; and FSL-1 increased Nurr1 expression in fetal membranes. In summary, human labour and bacterial products increase Nurr1, Nur77 and/or NOR1 expression in human fetal membranes and myometrium. This increase in NR4A receptors may contribute to the expression of proinflammatory and pro-labour genes associated with fetal membrane rupture and myometrial contractions.

scholarly journals KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium

Reproduction ◽  
2015 ◽  
Vol 149 (5) ◽  
pp. 413-424 ◽  
Author(s):  
Martha Lappas
Keyword(s):  
Mrna Expression ◽  
Interleukin 1 ◽  
Poly I:C ◽  
Human Myometrium ◽  
Viral Dsrna ◽  
Myometrial Cells ◽  
Human Labour ◽  
Foetal Membranes ◽  
Term Labour ◽  
Klf5 Expression

The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFκB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1β), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1β, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1β-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE2 and PGF2α. KLF5 silencing also significantly reduced flagellin- and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1β-, flagellin- and poly(I:C)-stimulated NFκB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation- and infection-induced pro-labour mediators.

scholarly journals Is myometrial inflammation a cause or a consequence of term human labour?

2017 ◽  
Vol 235 (1) ◽  
pp. 69-83 ◽  
Author(s):  
Natasha Singh ◽  
Bronwen Herbert ◽  
Gavin R Sooranna ◽  
Nicolas M Orsi ◽  
Lydia Edey ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mrna Expression ◽  
Inflammatory Cell ◽  
Preterm Labour ◽  
Cytokine Mrna ◽  
Protein Levels ◽  
Cytokine Mrna Expression ◽  
Spontaneous Labour ◽  
Human Labour ◽  
Term Labour

Myometrial inflammation is thought to have a pivotal role in the onset of term and some forms of preterm labour. This is based on the comparison of samples taken from women undergoing term elective CS prior to the onset of labour with those taken from women in established labour. Consequently, it is not clear whether myometrial inflammation is a cause or a consequence of labour. Our objective is to test the hypothesis that myometrial inflammation is a consequence of the onset of labour. To test this hypothesis, we have obtained myometrial samples from women at various stages of pregnancy and spontaneous labour and studied the activation of the AP-1 (c-Jun) and NFκB (p65) systems, cytokine mRNA expression and protein levels and inflammatory cell infiltration and activation. We found that the activation of p65 declined from preterm to term not in labour samples and thereafter increased in early and established labour. Cytokine mRNA expression and protein levels increased in established labour only. Using flow cytometry of myometrial tissue, we found that the number of neutrophils did increase with the onset of labour, but on tissue section, these were seen to be intravascular and not infiltrating into the myometrium. These data suggest that myometrial inflammation is a consequence rather than a cause of term labour.

Antioxidant and Anti-inflammatory Activities of Organic and Aqueous Extracts of Northeast Algerian Marrubium vulgare

2018 ◽  
Vol 16 (S1) ◽  
pp. S119-S129
Author(s):  
I. Namoune ◽  
B. Khettal ◽  
A.M. Assaf ◽  
S. Elhayek ◽  
L. Arrar
Keyword(s):  
Ethyl Acetate ◽  
Methanolic Extract ◽  
Ethyl Acetate Extract ◽  
Interleukin 1 ◽  
Total Phenolic ◽  
Dependent Manner ◽  
Aqueous Extracts ◽  
Traditional Use ◽  
Marrubium Vulgare ◽  
Anti Inflammatory

Marrubium vulgare (Lamiaceae) is frequently used in traditional medicine to treat many illnesses from ancient times. Its beneficial effects include antibacterial, antioedematogenic, and analgesic activities. This study was designed to evaluate the antioxidant and anti-inflammatory activities of organic and aqueous extracts of the leaves, the flowers, the stems, and the roots of Marrubium vulgare. The total phenolic and flavonoid contents as well as the antioxidant and the anti-inflammatory effects of methanol, chloroform, ethyl acetate, and aqueous extracts have been investigated by using different in-vitro methods. It was found that the ethyl acetate extract from Marrubium vulgare stems had the highest total phenolic content, while the ethyl acetate extract from the leaves yielded a high concentration of flavonoids. The ethyl acetate extract from the stems exhibited the highest activity in scavenging of 2,2-diphenyl- 1-picrylhydrazyl (DPPH), as well as in protecting erythrocytes. The leaves aqueous extract exhibited the highest ferrous chelating activity and its methanolic extract was found to be the strongest inhibitor of lipid peroxidation in β-carotene bleaching assay. The leaves chloroform extracts as well as the flowers methanol, chloroform, and ethyl acetate extracts were found to decrease the pro-inflammatory tumor necrosis factor alpha (TNF-α) cytokine levels in a dose-dependent manner. On the other hand, the flowers methanolic extract and the leaves methanol, ethyl acetate, and aqueous extracts decreased the interleukin-1 beta (IL- 1β) release. It was also found that the methanol extract from the flowers and the chloroform extract from the stems of Marrubium vulgare inhibited interleukin-8 (IL-8) release. This study provides a scientific basis for the traditional use of Marrubium vulgare as an anti-inflammatory agent and for the plant to be considered as an important resource of natural antioxidants.

Predictive value of pro- and anti-inflammatory cytokines in assessing severity and outcome of acute pancreatitis

2005 ◽  
Vol 24 (4) ◽  
pp. 253-257 ◽  
Author(s):  
Darko Mirkovic ◽  
Maja Surbatovic ◽  
Nikola Filipovic ◽  
Sonja Radakovic
Keyword(s):  
Acute Pancreatitis ◽  
Inflammatory Cytokines ◽  
Predictive Value ◽  
Anti Inflammatory

scholarly journals Aristolochia trilobata: Identification of the Anti-Inflammatory and Antinociceptive Effects

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 111
Author(s):  
Dayana da Costa Salomé ◽  
Natália de Morais Cordeiro ◽  
Tayná Sequeira Valério ◽  
Darlisson de Alexandria Santos ◽  
Péricles Barreto Alves ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Interleukin 1 ◽  
Antinociceptive Effect ◽  
Cholinergic Receptor ◽  
Hot Plate ◽  
Nitric Oxide Synthase Inhibitor ◽  
Antinociceptive Effects ◽  
Anti Inflammatory ◽  
Skin Affection ◽  
Synthase Inhibitor

Aristolochia trilobata, popularly known as “mil-homens,” is widely used for treatment of stomach aches, colic, asthma, pulmonary diseases, diabetes, and skin affection. We evaluated the antinociceptive and anti-inflammatory activities of the essential oil (EO) and the main constituent, 6-methyl-5-hepten-2-yl acetate (sulcatyl acetate, SA). EO and SA (1, 10, and 100 mg/kg, p.o.) were evaluated using chemical (formalin-induced licking) and thermal (hot-plate) models of nociception or inflammation (carrageenan-induced cell migration into the subcutaneous air pouch, SAP). The mechanism of antinociceptive activity was evaluated using opioid, cholinergic receptor antagonists (naloxone and atropine), or nitric oxide synthase inhibitor (L-NAME). EO and SA presented a central antinociceptive effect (the hot-plate model). In formalin-induced licking response, higher doses of EO and SA also reduced 1st and 2nd phases. None of the antagonists and enzyme inhibitor reversed antinociceptive effects. EO and SA reduced the leukocyte migration into the SAP, and the cytokines tumor necrosis factor and interleukin-1 (TNF-α and IL-1β, respectively) produced in the exudate. Our results are indicative that EO and SA present peripheral and central antinociceptive and anti-inflammatory effects.

Sign in / Sign up

Export Citation Format

Share Document