Obstetrics and Gynaecology - Research Publications

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Subject: inflammation × Author: Barker, Gillian ×

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    Dietary phytophenols curcumin, naringenin and apigenin reduce infection-induced inflammatory and contractile pathways in human placenta, foetal membranes and myometrium
    Lim, R ; Barker, G ; Wall, CA ; Lappas, M (OXFORD UNIV PRESS, 2013-07)
    A tenet of contemporary obstetrics is that a significant proportion of preterm births involve bacterial infection. Bacterial endotoxin induces pro-inflammatory cytokines, prostaglandins and proteases via the pro-inflammatory pathway nuclear factor-κB (NF-κB), which plays a key role in initiating uterine contractions and rupture of foetal membranes. In non-gestational tissues, the phytophenols curcumin, naringenin and apigenin exert anti-inflammatory properties via inhibition of NF-κB. The aim of this study was to determine whether these treatments regulate pro-inflammatory and pro-labour mediators in human gestational tissues. Placenta, foetal membranes and myometrium were treated with curcumin, naringenin and apigenin in the presence of lipopolysaccharide (LPS) or interleukin (IL)-1β. In placenta and foetal membranes, all treatments significantly reduced LPS-stimulated release and gene expression of pro-inflammatory cytokines IL-6 and IL-8; placenta decreased cyclooxygenase (COX-2) mRNA expression, subsequent release of prostaglandins PGE2 and PGF2α and expression and activity of matrix-degrading enzyme matrix metalloproteinase (MMP)-9. In myometrial cells, all treatments attenuated IL-1β-induced COX-2 expression, release of PGE2 and PGF2α and expression and activity of MMP-9. Although naringenin significantly attenuated IL-1β-induced IL-6 and IL-8 mRNA expression and release, there was no effect of curcumin and apigenin. LPS-stimulated release of 8-isoprostane, a marker of oxidative stress, was attenuated by all treatments. NF-κB p65 DNA-binding activity was also decreased using these treatments. In conclusion, curcumin, naringenin and apigenin exert anti-inflammatory properties in human gestational tissues by inhibiting the transcriptional activity of NF-κB. Further studies should be undertaken to define a possible implication of these natural spices in the management of preterm labour and delivery.
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    A Novel Role for FOXO3 in Human Labor: Increased Expression in Laboring Myometrium, and Regulation of Proinflammatory and Prolabor Mediators in Pregnant Human Myometrial Cells
    Lim, R ; Barker, G ; Lappas, M (OXFORD UNIV PRESS INC, 2013-06)
    Preterm birth is the leading factor causing neonatal mortality and morbidity. Inflammation plays a central role in stimulating uterine contractility, which is responsible for approximately one-third of all preterm births. Recent studies have shown that the transcription factor Forkhead box O3 (FOXO3) regulates inflammation in nongestational tissues such as adipocytes and hepatocytes. Thus, in this study, we sought to determine the effect of 1) human term labor on myometrial FOXO3 expression and 2) FOXO3 inhibition and FOXO3 overexpression on proinflammatory and prolabor mediators in human myometrial cells. Higher FOXO3 gene and protein expression were detected in myometrium obtained from women in labor when compared to samples taken from nonlaboring women. Myometrial cells were isolated from pregnant human myometrium, and FOXO3 silencing was achieved using siRNA and overexpression using a cDNA clone. We found that the loss of FOXO3 in myometrial cells was associated with a significant decrease in IL1B-induced IL6 and IL8 expression and production, cyclooxygenase ([COX]-2, official symbol PTGS2) expression and subsequent prostaglandin (PGE2 and PGF2alpha) release, and matrix metalloproteinase 9 (MMP9) and mRNA expression and activity. Conversely, FOXO3 overexpression increased cytokine expression and secretion, prostaglandin production, and MMP9 expression in myometrial cells treated with IL1B. In summary, we have identified FOXO3 as an upstream mediator of inflammation in human myometrium. Thus, FOXO3 may present an alternative therapeutic target for preventing preterm birth and its associated morbidity and mortality.
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    2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue
    Oliva, K ; Barker, G ; Rice, GE ; Bailey, MJ ; Lappas, M (BIOSCIENTIFICA LTD, 2013-08)
    Gestational diabetes mellitus (GDM) is a significant risk factor for the type 2 diabetes epidemic in many populations. Maternal adipose tissue plays a central role in the pathophysiology of GDM. Thus, the aim of this study was to determine the effect of GDM on the proteome of adipose tissue. Omental adipose tissue was obtained at the time of term Caesarean section from women with normal glucose tolerance (NGT) or GDM. 2D-difference gel electrophoresis (DIGE), followed by mass spectrometry, was used to identify protein spots (n = 6 patients per group). Western blotting was used for confirmation of six of the spot differences (n = 6 patients per group). We found 14 proteins that were differentially expressed between NGT and GDM adipose tissue (≥ 1.4-fold, P < 0.05). GDM was associated with an up-regulation of four proteins: collagen alpha-2(VI) chain (CO6A2 (COL6A2)), fibrinogen beta chain (FIBB (FGB)), lumican (LUM) and S100A9. On the other hand, a total of ten proteins were found to be down-regulated in adipose tissue from GDM women. These were alpha-1-antitrypsin (AIAT (SERPINA 1)), annexin A5 (ANXA5), fatty acid-binding protein, adipocyte (FABP4), glutathione S-transferase P (GSTP (GSTP1)), heat-shock protein beta-1 (HSP27 (HSPB1)), lactate dehydrogenase B chain (LDHB), perilipin-1 (PLIN1), peroxiredoxin-6 (PRX6 (PRDX6)), selenium-binding protein 1 (SBP1) and vinculin (VINC (VCL)). In conclusion, proteomic analysis of omental fat reveals differential expression of several proteins in GDM patients and NGT pregnant women. This study revealed differences in expression of proteins that are involved in inflammation, lipid and glucose metabolism and oxidative stress and added further evidence to support the role of visceral adiposity in the pathogenesis of GDM.