Metabolomics Analysis and Modeling Suggest a Lysophosphocholines-PAF Receptor Interaction in Fibromyalgia |
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Authors: | Pierluigi Caboni Barbara Liori Amit Kumar Maria Laura Santoru Shailendra Asthana Enrico Pieroni Antonella Fais Benedetta Era Enrico Cacace Valeria Ruggiero Luigi Atzori |
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Affiliation: | 1. Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.; 2. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.; 3. Biomedicine Department, CRS4, Cagliari, Italy.; 4. Department of Medical Sciences “Mario Aresu”, University of Cagliari, Cagliari, Italy.; Imperial College London, United Kingdom, |
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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. |
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