An adverse early-life environment is associated with long-term disease consequences. Adversity early in life is hypothesized to elicit developmental adaptations that serve to improve fetal and postnatal survival and prepare the organism for a particular range of postnatal environments. These processes, although adaptive in their nature, may later prove to be maladaptive or disadvantageous if the prenatal and postnatal environments are widely discrepant. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids is one model of early-life adversity that contributes substantially to the propensity of developing disease. Moreover, early-life glucocorticoid exposure has direct clinical relevance because synthetic glucocorticoids are routinely used in the management of women at risk of early preterm birth. In this regard, reports of adverse events in human newborns have raised concerns about the safety of glucocorticoid treatment; synthetic glucocorticoids have detrimental effects on fetal growth and development, childhood cognition, and long-term behavioral outcomes. Experimental evidence supports a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development and changes in placental function, and many of these alterations appear to be permanent. Because the placenta is the conduit between the maternal and fetal environments, it is likely that placental function plays a key role in mediating effects of fetal glucocorticoid exposure on hypothalamic-pituitary-adrenal axis development and long-term disease risk. Here we review recent insights into how the placenta responds to changes in the intrauterine glucocorticoid environment and discuss possible mechanisms by which the placenta mediates fetal hypothalamic-pituitary-adrenal development, metabolism, cardiovascular function, and reproduction.

/pdf/early-life-glucocorticoid-exposure-the-hypothalamic-5frst8cnfi.pdf

Early-Life Glucocorticoid Exposure: The Hypothalamic-Pituitary-Adrenal Axis, Placental Function, and Long-term Disease Risk

Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.

/pdf/nutrient-sensor-signaling-pathways-and-cellular-stress-in-1ycojc1lhh.pdf

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction

https://www.pure.ed.ac.uk/ws/files/19739411/Maternal_Distress_Associates_with_Placental_Genes.pdf

Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex.

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimer’s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways.

/pdf/orexin-receptors-exert-a-neuroprotective-effect-in-alzheimer-25cqjlcna6.pdf

Orexin receptors exert a neuroprotective effect in Alzheimer’s disease (AD) via heterodimerization with GPR103

To date, microarray analyses have led to the discovery of numerous individual 'molecular signatures' associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses. In this study, we conduct analyses-based on gene regulatory network-to reveal distinct and common biomarkers across cancer types. Using microarray data of triple-negative and medullary breast, ovarian and lung cancers applied to a combination of glasso and Bayesian networks (BNs), we derived a unique network-containing genes that are uniquely involved: small proline-rich protein 1A (SPRR1A), follistatin like 1 (FSTL1), collagen type XII alpha 1 (COL12A1) and RAD51 associated protein 1 (RAD51AP1). RAD51AP1 and FSTL1 are significantly overexpressed in ovarian cancer patients but only RAD51AP1 is upregulated in lung cancer patients compared with healthy controls. The upregulation of RAD51AP1 was mirrored in the bloods of both ovarian and lung cancer patients, and Kaplan-Meier (KM) plots predicted poorer overall survival (OS) in patients with high expression of RAD51AP1. Suppression of RAD51AP1 by RNA interference reduced cell proliferation in vitro in ovarian (SKOV3) and lung (A549) cancer cells. This effect appears to be modulated by a decrease in the expression of mTOR-related genes and pro-metastatic candidate genes. Our data describe how an initial in silico approach can generate novel biomarkers that could potentially support current clinical practice and improve long-term outcomes.

/pdf/identification-of-cancer-biomarkers-of-prognostic-value-dj1o82j722.pdf

Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): A novel role of RAD51AP1 for ovarian and lung cancers

DEPTOR [DEP-domain-containing and mTOR (mammalian target of rapamycin)-interacting protein] is a modulator of mTOR signalling that binds to mTORC (mTOR complex) 1 and mTORC2. However, to date, the precise functions of DEPTOR are not fully elucidated, particularly in reproductive tissues where mTOR acts as a placental nutrient sensor. Pregnancy is associated with major physiological and psychosocial changes and adaptation to these changes is crucial for normal fetal development. In the present study, we tested the hypothesis that maternal stress can affect mTOR signalling at term, and, as a result, influence placental growth. We first investigated the expression of DEPTOR, mTOR, rictor (rapamycin-insensitive companion of mTOR) and raptor (regulatory associated protein of mTOR) from human placentas (n = 23) using Q-PCR (quantitative PCR), and correlated these data to days of pregnancy and maternal stress, as well as placental and fetal weight. Maternal and fetal cortisol levels were also measured. JEG-3 and BeWo cells, used as placental in vitro models, were treated with cortisol and DEPTOR expression was assessed using Q-PCR. DEPTOR appears to be the predominant transcript in the human placenta compared with mTOR, rictor and raptor in both term (n = 13) and preterm (n = 10) placentas as assessed by Q-PCR. There was a significantly lower level only of log-DEPTOR gene expression in the high stress group (−1.34) than in the low stress group (0.07; t20 = 2.41, P = 0.026). Interestingly, mothers with high stress had significantly elevated levels of cortisol (8555 pg/ml) compared with those with low stress (4900 pg/ml). We then tested the hypothesis that cortisol can directly affect DEPTOR expression. When BeWo cells were treated with cortisol 10, 100 and 1000 nM, the expression of DEPTOR was significantly down-regulated by 50, 41 and 39 % (all P < 0.05) respectively when compared with basal levels. Treatment of JEG-3 cells with cortisol, led to a significant decrease of DEPTOR expression at 100 nM (39 %, P < 0.05) and at 1000 nM (73 %, P < 0.01). These novel findings are indicative of a higher order of complexity of DEPTOR signalling in the human placenta that is affected by maternal stress, which could affect pregnancy outcome.

/pdf/placental-deptor-as-a-stress-sensor-during-pregnancy-33ixjwbhn3.pdf

Placental DEPTOR as a stress sensor during pregnancy.

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Placental DEPTOR as a stress sensor during pregnancy.