SIRT1 is a novel regulator of key pathways of human labor.
ABSTRACT Human sirtuin (SIRT) 1 and SIRT2, which possess nicotinamide adenosine dinucleotide (NAD(+))-dependent deacetylase activity, exhibit anti-inflammatory actions. However, there are no data available on SIRT1 and SIRT2 expression and regulation in human intrauterine tissues. Thus, the aim of this study was to characterize the localization and expression of SIRT1 and SIRT2 in 1) placenta and fetal membranes before and after term spontaneous labor onset, 2) prelabor fetal membranes from the supracervical site (SCS) and a distal site (DS), and 3) in response to proinflammatory stimuli. Further, the effect of SIRT activation using resveratrol and SRT1720 on prolabor mediators was also assessed. SIRT1 and SIRT2 were localized in the syncytiotrophoblast layer and the cytotrophoblasts of the placenta, amnion epithelium, trophoblast layer of the chorion, and decidual cells. Additionally, SIRT2 was found within the endothelial walls of placental vessels. SIRT2, but not SIRT1, staining was significantly lower in amnion and chorion obtained from the SCS compared to a DS. On the other hand, SIRT1, but not SIRT2, gene and/or protein expression was significantly lower in placenta, amnion, and chorion obtained after labor compared to prelabor. SIRT1 expression, but not SIRT2, was down-regulated by lipopolysaccharide (LPS) and proinflammatory cytokines TNF and IL1B. The SIRT1 activators resveratrol and SRT1720 significantly decreased LPS-induced TNF, IL6, and IL8 gene expression and release and PTGS2 mRNA expression and resultant prostaglandin (PG) E(2) and PGF(2α) release from human gestational tissues. In conclusion, SIRT1 possesses anti-inflammatory actions and thus may play a role in regulating pregnancy and parturition.
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ABSTRACT: Inflammation is associated with preterm birth, a worldwide healthcare issue. SLIT3 has a role in inflammation, and thus, the purpose of this study was to determine the effect of SLIT3 on labour mediators in human gestational tissues. SLIT3 protein expression was performed using immunohistochemistry in foetal membranes and myometrium with no labour and after labour. Foetal membranes were also obtained from a distal site (DS) and supracervical site (overlying the cervix; SCS). SLIT3 gene silencing was achieved using siRNA in primary amnion and myometrial cells. Pro-inflammatory and pro-labour mediators were evaluated by qRT-PCR, ELISA and gelatin zymography. SLIT3 expression was greater in foetal membranes from the SCS compared with DS and in myometrium after term spontaneous labour onset. SLIT3 siRNA in primary amnion and myometrial cells decreased IL-1β-induced pro-inflammatory cytokine gene expression and release (IL-6 and IL-8) and MMP-9 gene expression and release. In amnion cells, SLIT3 siRNA knockdown decreased IL-1β-induced COX-2 expression and prostaglandin PGE2 release. There was no effect of SLIT3 siRNA on IL-1β-induced NF-κB transcriptional activity. Our results demonstrate that SLIT3 is increased with labour, and both our amnion and our myometrial studies describe a pro-inflammatory effect of SLIT3 in these tissues.American Journal Of Reproductive Immunology 11/2013; · 3.32 Impact Factor
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ABSTRACT: Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that is involved in human parturition, especially in the context of infection-induced preterm birth. Caspase-1 is a key component of inflammasomes, which are activated upon infection to trigger the maturation of IL-1β. To determine the effect of human labour on caspase-1 activation in human foetal membranes and myometrium. In addition, the mechanisms by which inflammasome activation regulates IL-1β production were also be assessed. Higher caspase-1 gene and protein expression were detected in foetal membranes myometrium obtained from term labouring women when compared with samples taken from non labouring women. Lipopolysaccharide induced the transcription and secretion of IL-1β from foetal membranes and myometrium; both events were dependent on nuclear factor kappa B (NF-κB). However, levels of extracellular IL-1β were greatly increased by subsequent treatment with the potassium-proton ionophore Adenosine triphosphate (ATP) or nigericin; an effect that was dependent on active caspase-1. Additionally, ATP induced IL-1β secretion via the purinergic P2X7 receptor, whereas the pannexin-1 channel was required for nigericin induced IL-1β secretion. Taken together, these results demonstrate that caspase-1 activation is increased with human labour in foetal membranes and myometrium, and is required for infection-induced IL-1β secretion.American Journal Of Reproductive Immunology 11/2013; · 3.32 Impact Factor
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ABSTRACT: Diet in human health is no longer simple nutrition, but in light of recent research, especially nutrigenomics, it is linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease especially lack of vitamins and minerals is well known, but more recently, epidemiological studies suggest a role of fruits and vegetables, as well as essential fatty acids and even red wine (French paradox), in protection against disease. In the early 1990s, various research groups started considering the use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-L-carnitine, creatine, coenzyme Q10) as possible candidates in neuroprotection. They were of course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention are now mainstream and commercial health claims being made are subject to regulation in most countries. Apart from efficacy and finding, the right dosages, the safety, and especially the level of purification and lack of contamination are all issues that are important as their use becomes widespread. From the mechanistic point of view, most of the time these substances replenish the body's deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects. Free radicals and neuroinflammation processes underlie many neurodegenerative conditions, even Parkinson's disease and Alzheimer's disease. Curcumin, carotenoids, acetyl-L-carnitine, coenzyme Q10, vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions. In summary, augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., induction of health-promoting genes and reduction of the expression of disease-promoting genes, could be incorporated into neuroprotective strategies of the future.Molecular Neurobiology 06/2013; · 5.47 Impact Factor