Browse
Submit Data
Databases
API
Help

Dataset Information

6 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metabolomics analysis and modeling suggest a lysophosphocholines-PAF receptor interaction in fibromyalgia.

ABSTRACT: Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14:0/0:0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16:0/0:0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14:0/0:0) and PC(16:0/0:0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.

SUBMITTER: Caboni P

PROVIDER: S-EPMC4169547 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Increased susceptibility to bladder inflammation in smokers: targeting the PAF-PAF receptor interaction to manage inflammatory cell recruitment.

Project description:Chronic bladder inflammation can result in a significant reduction in quality of life. Smoking remains a leading preventable risk factor in many diseases. Despite the large amount of evidence supporting the risks of smoking, roughly 45 million people in the United States remain smokers. The impact of cigarette smoking on inflammation is well established, but how smoking promotes bladder inflammation is currently unknown. The aim of this study was to determine if cigarette smoke exposure impacts inflammatory cell adherence to bladder endothelial cells and if targeting the platelet-activating factor (PAF)-PAF receptor (PAFR) interaction could be beneficial in managing bladder inflammation. In response to cigarette smoke extract (CSE) incubation, bladder endothelial cells from human or mouse displayed increased PAF accumulation, decreased PAF-AH activity, and increased inflammatory cell adherence. Inhibition of endothelial cell calcium-independent phospholipase A2β (iPLA2β) with (S)-BEL, to block PAF production, prevented adherence of inflammatory cells. Pretreatment of inflammatory cells with PAFR antagonists, ginkgolide B or WEB2086 significantly reduced the number of adhered cells to bladder endothelium. Wild-type mice exposed to cigarette smoke displayed increased presence of inflammatory infiltration which was absent in iPLA2β(-/-) mice and those exposed to room air. In conclusion, cigarette smoke exposure increases endothelial cell PAF accumulation and increased inflammatory cell adherence. Inhibition of PAF accumulation or PAFR antagonism markedly attenuated inflammatory cell adherence to bladder endothelial cells. The results detailed in this study highlight to potential therapeutic targets for managing bladder inflammation.

| S-EPMC4760457 | biostudies-other

Modeling the complete chemokine-receptor interaction.

Project description:Chemokines are soluble, secreted proteins that induce chemotaxis of leukocytes and other cells. Migratory cells can sense the chemokine concentration gradient following chemokine binding and activation of chemokine receptors, a subset of the G protein-coupled receptor (GPCR) superfamily. Chemokine receptor signaling plays a central role in cell migration during inflammatory responses as well as in cancer and other diseases. Given their important role in mediating essential pathologic and physiologic processes, chemokines and their receptors are attractive targets for therapeutic development. A better understanding of the molecular basis of chemokine-GPCR interactions will aid in the understanding of the mechanistic basis for chemokine function in disease-related processes, as well as aid in the design of new therapeutics. High resolution protein structures are critical for determining these mechanisms and investigating the interactions between approximately 50 chemokines and 20 chemokine receptors. Currently, three unique structures of chemokine-GPCR complexes have been determined and have greatly broadened our knowledge of this large protein-protein interaction. While these structures represent only a small fraction of clinically relevant chemokines and receptors, they can be exploited as scaffolds for homology modeling to understand the chemokine-GPCR interactions. This chapter presents a specialized methodology to construct and validate models of chemokine-GPCR complexes using the Rosetta software suite.

| S-EPMC6790067 | biostudies-literature

Metabolomics and psychological features in fibromyalgia and electromagnetic sensitivity.

Project description:Fibromyalgia (FM) as Fibromyalgia and Electromagnetic Sensitivity (IEI-EMF) are a chronic and systemic syndrome. The main symptom is represented by strong and widespread pain in the musculoskeletal system. The exact causes that lead to the development of FM and IEI-EMF are still unknown. Interestingly, the proximity to electrical and electromagnetic devices seems to trigger and/or amplify the symptoms. We investigated the blood plasma metabolome in IEI-EMF and healthy subjects using 1H NMR spectroscopy coupled with multivariate statistical analysis. All the individuals were subjected to tests for the evaluation of psychological and physical features. No significant differences between IEI-EMF and controls relative to personality aspects, Locus of Control, and anxiety were found. Multivariate statistical analysis on the metabolites identified by NMR analysis allowed the identification of a distinct metabolic profile between IEI-EMF and healthy subjects. IEI-EMF were characterized by higher levels of glycine and pyroglutamate, and lower levels of 2-hydroxyisocaproate, choline, glutamine, and isoleucine compared to healthy subjects. These metabolites are involved in several metabolic pathways mainly related to oxidative stress defense, pain mechanisms, and muscle metabolism. The results here obtained highlight possible physiopathological mechanisms in IEI-EMF patients to be better defined.

| S-EPMC7686375 | biostudies-literature

Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.

Project description:The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.

| S-EPMC8382200 | biostudies-literature

Mouse and human eosinophils degranulate in response to platelet-activating factor (PAF) and lysoPAF via a PAF-receptor-independent mechanism: evidence for a novel receptor.

Project description:Platelet-activating factor (PAF [1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine]) is a phospholipid mediator released from activated macrophages, mast cells, and basophils that promotes pathophysiologic inflammation. Eosinophil responses to PAF are complex and incompletely elucidated. We show in this article that PAF and its 2-deacetylated metabolite (lysoPAF) promote degranulation (release of eosinophil peroxidase) via a mechanism that is independent of the characterized PAFR. Specifically, we demonstrate that receptor antagonists CV-3988 and WEB-2086 and pertussis toxin have no impact on PAF- or lysoPAF-mediated degranulation. Furthermore, cultured mouse eosinophils from PAFR(-/-) bone marrow progenitors degranulate in response to PAF and lysoPAF in a manner indistinguishable from their wild-type counterparts. In addition to PAF and lysoPAF, human eosinophils degranulate in response to lysophosphatidylcholine, but not phosphatidylcholine, lysophosphatidylethanolamine, or phosphatidylethanolamine, demonstrating selective responses to phospholipids with a choline head-group and minimal substitution at the sn-2 hydroxyl. Human eosinophils release preformed cytokines in response to PAF, but not lysoPAF, also via a PAFR-independent mechanism. Mouse eosinophils do not release cytokines in response to PAF or lysoPAF, but they are capable of doing so in response to IL-6. Overall, our work provides the first direct evidence for a role for PAF in activating and inducing degranulation of mouse eosinophils, a crucial feature for the interpretation of mouse models of PAF-mediated asthma and anaphylaxis. Likewise, we document and define PAF and lysoPAF-mediated activities that are not dependent on signaling via PAFR, suggesting the existence of other unexplored molecular signaling pathways mediating responses from PAF, lysoPAF, and closely related phospholipid mediators.

| S-EPMC3406327 | biostudies-literature

Predictive Modeling for Metabolomics Data.

Project description:In recent years, mass spectrometry (MS)-based metabolomics has been extensively applied to characterize biochemical mechanisms, and study physiological processes and phenotypic changes associated with disease. Metabolomics has also been important for identifying biomarkers of interest suitable for clinical diagnosis. For the purpose of predictive modeling, in this chapter, we will review various supervised learning algorithms such as random forest (RF), support vector machine (SVM), and partial least squares-discriminant analysis (PLS-DA). In addition, we will also review feature selection methods for identifying the best combination of metabolites for an accurate predictive model. We conclude with best practices for reproducibility by including internal and external replication, reporting metrics to assess performance, and providing guidelines to avoid overfitting and to deal with imbalanced classes. An analysis of an example data will illustrate the use of different machine learning methods and performance metrics.

| S-EPMC7423323 | biostudies-literature

ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor.

Project description:The diminished level of platelet-activating factor acetylhydrolase (PAFAH) in milk causes an enhanced level of platelet activating factor (PAF) in the skin, leading to a severe hair loss phenotype during neonatal pup's lactation. The deletion of very-low-density-lipoprotein receptor (VLDLR) prevents the expression and secretion of PAFAH. Here we revealed that deletion of Roundabout 4 (ROBO4) in mice ameliorated hair loss phenotype via reducing PAF concentration in skin. As a consequence, the neonatal pups with ROBO4 deletion lactated by mother with VLDLR deletion showed normal hair phenotype during lactation. In details,ROBO4 deletion reduced the protein but not mRNA expression of two PAF synthetic enzymes LPCAT1/LPCAT2 in macrophage as well as the expression of PAF receptor in both macrophage and ocular tissue, but increased PAFAH protein in serum. On the other hand, RNA expression profile analysis in macrophages revealed that the genes involving in oxidative phosphorylation and ribosome obviously decreased their expression in response to ROBO4 deletion. Moreover, through High Performance Liquid Chromatography (HPLC) analysis, we found that ATP concentration also reduced in ROBO4 deletion macrophages. Because ribosome and energy are very important factors for the mRNA translation, we then tested whether ROBO4 deletion affects LPCAT1/LPCAT2 mRNA translation using polyribosome assay. As expected, the mRNA level of LPCAT1/LPCAT2 significantly decreased in polyribosome in ROBO4 deletion macrophage comparing to that of wild type. Additionally, mice with ROBO4 deletion suppressed LPS-induced IL-6 expression as well as the phosphorylation of p44/42 and p65, but enhanced the AKT phosphorylation. Collectively, ROBO4 deletion alleviates PAF- and LPS-mediated inflammation. And above results also indicate PAF signal might be a crosstalk point of ROBO4- and VLDLR-activated pathways.

| S-EPMC7053341 | biostudies-literature

Mouse 11?-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

Project description:Mouse (m) 11?-hydroxysteroid dehydrogenase type 2 (11?HSD2) was homology-modeled, and its structure and ligand-receptor interaction were analyzed. The modeled m11?HSD2 showed significant 3D similarities to the human (h) 11?HSD1 and 2 structures. The contact energy profiles of the m11?HSD2 model were in good agreement with those of the h11?HSD1 and 2 structures. The secondary structure of the m11?HSD2 model exhibited a central 6-stranded all-parallel ?-sheet sandwich-like structure, flanked on both sides by 3-helices. Ramachandran plots revealed that only 1.1% of the amino acid residues were in the disfavored region for m11?HSD2. Further, the molecular surfaces and electrostatic analyses of the m11?HSD2 model at the ligand-binding site exhibited that the model was almost identical to the h11?HSD2 model. Furthermore, docking simulation and ligand-receptor interaction analyses revealed the similarity of the ligand-receptor bound conformation between the m11?HSD2 and h11?HSD2 models. These results indicate that the m11?HSD2 model was successfully evaluated and analyzed. To the best of our knowledge, this is the first report of a m11?HSD2 model with detailed analyses, and our data verify that the mouse model can be utilized for application to the human model to target 11?HSD2 for the development of anticancer drugs.

| S-EPMC3236009 | biostudies-literature

Genetic analysis, structural modeling, and direct coupling analysis suggest a mechanism for phosphate signaling in Escherichia coli.

Project description:BackgroundProper phosphate signaling is essential for robust growth of Escherichia coli and many other bacteria. The phosphate signal is mediated by a classic two component signal system composed of PhoR and PhoB. The PhoR histidine kinase is responsible for phosphorylating/dephosphorylating the response regulator, PhoB, which controls the expression of genes that aid growth in low phosphate conditions. The mechanism by which PhoR receives a signal of environmental phosphate levels has remained elusive. A transporter complex composed of the PstS, PstC, PstA, and PstB proteins as well as a negative regulator, PhoU, have been implicated in signaling environmental phosphate to PhoR.ResultsThis work confirms that PhoU and the PstSCAB complex are necessary for proper signaling of high environmental phosphate. Also, we identify residues important in PhoU/PhoR interaction with genetic analysis. Using protein modeling and docking methods, we show an interaction model that points to a potential mechanism for PhoU mediated signaling to PhoR to modify its activity. This model is tested with direct coupling analysis.ConclusionsThese bioinformatics tools, in combination with genetic and biochemical analysis, help to identify and test a model for phosphate signaling and may be applicable to several other systems.

| S-EPMC4423584 | biostudies-literature

DNA methylation analysis in women with fibromyalgia

Project description:FM is a complex syndrome with physiological, genetics and environmental factors involved. It can present changes in functional neuroimaging, in cortical excitability measurements performed by transcranial magnetic stimulation and in grey matter density. Similarly, it has been shown that patients with FM have abnormal autonomic control, inflammatory profile and dysfunctional hypothalamic–pituitary–adrenal axis leading to disruptive sleep and fatigue. We characterized clinical and neurophysiological parameters and peripheral blood DNA methylation profiles of patients with FM and compared them to sex and age matched healthy controls. We hypothesized that these exploratory analyses could provide mechanistic insights into the pathophysiology of FM and possibly contribute to the future development of biological markers of diagnosis.We showed that patients with fibromyalgia have different (mainly hypo-) methylated CpG sites related to genes implicated in immune system and response to external stress pathways and that this methylation profile is related to a dysfunctional connectivity in pain network, adding evidence to consider fibromyalgia as a DOHAD disorder.

2017-08-10 | GSE85506 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data