Key pointsr Maternal hypoxia is a common perturbation that may impair fetal development and programme sex specific disease outcomes in offspring.r There is growing interest in the role of the placenta in mediating the effects of maternal hypoxia on fetal development, particularly in late gestation during maximal fetal growth.r Multiple mechanisms have been proposed to play a role in hypoxia induced impairment of placental development. Here we investigated the role of glucocorticoids and glucose regulation.r This study shows that fetal sex determines placental adaptations to maternal hypoxia: while maternal hypoxia increased maternal glucose and corticosterone levels in both sexes, placental adaptations to impaired maternal physiology were more evident in female fetuses, in which factors responsible for the regulation of glucocorticoids and nutrient transport were most severely affected by maternal hypoxia.Abstract Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during midto late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults. Abbreviations Crh, corticotropin releasing hormone; Crhr1, corticotropin releasing hormone receptor 1; E, embryonic day; Flt1, Fms related tyrosine kinase 1; Glut1, glucose transporter 1; Glut3, glucose transporter 3; Hif1a, hypoxia inducible factor 1 alpha; Hsd11b2, 11 beta hydroxysteroid dehydrogenase type 2; Igf2, insulin like growth factor 2; Igf1r, insulin like growth factor 1 receptor; Igf2r, Insulin like g...

Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis induce activity in the cellular reduction-oxidation (redox) system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.

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Neurodegenerative conditions are characterised by a progressive loss of neurons, which is believed to be initiated by misfolded protein aggregations. During this time period, many physiological and metabolomic alterations and changes in gene expression contribute to the decline in neuronal function. However, these pathological effects have not been fully characterised. In this study, we utilised a metabolomic approach to investigate the metabolic changes occurring in the hippocampus and cortex of mice infected with misfolded prion protein. In order to identify these changes, the samples were analysed by ultrahigh-performance liquid chromatography-tandem mass spectroscopy. The present dataset comprises a total of 498 compounds of known identity, named biochemicals, which have undergone principal component analysis and supervised machine learning. The results generated are consistent with the prion-inoculated mice having significantly altered metabolic profiles. In particular, we highlight the alterations associated with the metabolism of glucose, neuropeptides, fatty acids, L-arginine/nitric oxide and prostaglandins, all of which undergo significant changes during the disease. These data provide possibilities for future studies targeting and investigating specific pathways to better understand the processes involved in neuronal dysfunction in neurodegenerative diseases.

Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.

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Exposure to stressful stimuli causes activation of the hypothalamic-pituitary-adrenal axis which rapidly releases high concentrations of glucocorticoid stress hormones, resulting in increased cellular metabolism and spontaneous oxygen and nitrogen radical formation. High concentrations of nitrogen radicals, including nitric oxide, cause damage to cellular proteins in addition to inhibiting components of the mitochondrial transport chain, leading to cellular energy deficiency. During stress exposure, pharmacological inhibition of nitric oxide production reduces indicators of anxiety- and depressive-like behavior in animal models. Therefore, the purpose of this review is to present an overview of the current literature on stress-evoked changes in the nitrergic system, particularly within neural tissue.