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Dynamic changes in binding interaction networks of sex steroids establish their non-classical effects.

ABSTRACT: Non-classical signaling in the intracellular second messenger system plays a pivotal role in the cytoprotective effect of estradiol. Estrogen receptor is a common target of sex steroids and important in mediating estradiol-induced neuroprotection. Whereas the mechanism of genomic effects of sex steroids is fairly understood, their non-classical effects have not been elucidated completely. We use real time molecular dynamics calculations to uncover the interaction network of estradiol and activator estren. Besides steroid interactions, we also investigate the co-activation of the receptor. We show how steroid binding to the alternative binding site of the non-classical action is facilitated by the presence of a steroid in the classical binding site and the absence of the co-activator peptide. Uncovering such dynamic mechanisms behind steroid action will help the structure-based design of new drugs with non-classical responses and cytoprotective potential.

SUBMITTER: Balint M

PROVIDER: S-EPMC5665952 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Dynamic changes in binding interaction networks of sex steroids establish their non-classical effects.

Bálint Mónika M Jeszenői Norbert N Horváth István I Ábrahám István M IM Hetényi Csaba C

Scientific reports 20171101 1

Non-classical signaling in the intracellular second messenger system plays a pivotal role in the cytoprotective effect of estradiol. Estrogen receptor is a common target of sex steroids and important in mediating estradiol-induced neuroprotection. Whereas the mechanism of genomic effects of sex steroids is fairly understood, their non-classical effects have not been elucidated completely. We use real time molecular dynamics calculations to uncover the interaction network of estradiol and activat ...[more]

PMID: 29093525

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Project description:ContextSleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes.ObjectiveTo determine mechanisms contributing to impaired bone health in youth following SG.Methods12-month longitudinal observational study in a multidisciplinary tertiary-care hospital, including 64 youth 13-25 years old with moderate-to-severe obesity (51 females); 30 underwent SG and 34 were nonsurgical (NS) controls. SG was undertaken after a combined decision-making process between treatment team and patient. The main outcome measures were fasting blood for enteric peptides, sex steroids, sclerostin, and bone turnover markers (N-terminal propeptide of type 1 procollagen [P1NP] and C-terminal cross-linking telopeptide [CTX]); dual-energy X-ray absorptiometry measures of areal bone mineral density (aBMD) and body composition; high resolution peripheral quantitative computed tomography; measures of volumetric BMD (vBMD); microfinite element analysis of strength estimates (distal radius and tibia).ResultsSG had greater reductions in body mass index (BMI) z-scores, serum estrone, and the free androgen index (FAI) (P ≤ .046), and greater increases in sclerostin, P1NP, and CTX (P ≤ .010) than NS controls. Fasting ghrelin decreased in SG vs NS (P < .0001); fasting peptide YY did not change. Most changes were driven by female SG participants. Among females (the majority of study participants), after controlling for baseline age and race, reductions in total hip aBMD Z-scores were positively associated with changes in BMI, lean mass, estrone, FAI, and ghrelin, and inversely with changes in sclerostin.. Decreases in total vBMD of the radius and tibia were associated positively with decreases in BMI. Increases in CTX were associated with decreases in BMI, lean mass, and ghrelin, and increases in sclerostin.ConclusionBone loss after SG in youth is associated with changes in body composition, sex steroids, sclerostin, and enteric peptides. These are potential targets for future preventative or therapeutic strategies.

Project description:BackgroundThe gut microbiota impacts on a range of host biological processes, and the imbalances in its composition are associated with pathology. Though the understanding of contribution of the many factors, e.g. gender, diet and age, in the development of gut microbiota has been well established, the dynamic changes of the phylogenetic composition and the interaction networks along with the age remain unclear in pigs.ResultsHere we applied 16S ribosomal RNA gene sequencing, enterotype-like clustering (Classification of the gut microbiome into distinct types) and phylogenetic co-occurrence network to explore the dynamic changes of pig gut microbiome following the ages with a successive investigation at four ages in a cohort of 953 pigs. We found that Firmicutes and Bacteroidetes are two predominant phyla throughout the experimental period. The richness of gut microbiota was significantly increased from 25 to 240 days of age. Principal coordinates analysis showed a clear difference in the gut microbial community compositions between pre-weaning piglets and the pigs at the other three age groups. The gut microbiota of pre-weaning piglets was clearly classified into two enterotypes, which were dominated by Fusobacterium and p-75-a5, respectively. However, Prevotella and Treponema were the main drivers of the enterotypes for pigs at the age of 80, 120 and 240 days. Besides the piglets, even some adult pigs switched putative enterotypes between ages. We confirmed that the topological features of phylogenetic co-occurrence networks, including scale, stability and complexity were increased along with the age. The biological significance for modules in the network of piglets were mainly associated with the utilization of simple carbohydrate and lactose, whereas the sub-networks identified at the ages of 80, 120 and 240 days may be involved in the digestion of complex dietary polysaccharide. The modules related to the metabolism of protein and amino acids could be identified in the networks at 120 and 240 days. This dynamic change of the functional capacities of gut microbiome was further supported by functional prediction analysis.ConclusionsThe present study provided meaningful biological insights into the age-based dynamic shifts of ecological community of porcine gut microbiota.

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Dynamic changes in binding interaction networks of sex steroids establish their non-classical effects.

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Dynamic changes in binding interaction networks of sex steroids establish their non-classical effects.

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