Metabolomic Signature of Patients With Narcolepsy

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000013128
Author(s):  
Dauvilliers Yves ◽  
Lucie Barateau ◽  
Benita Middleton ◽  
Daan Van Der Veen ◽  
Debra J Skene
Keyword(s):  
Arachidonic Acid ◽  
Metabolic Pathways ◽  
Slow Wave Sleep ◽  
Arachidonic Acid Metabolism ◽  
Metabolic Phenotype ◽  
Metabolic Disturbances ◽  
Brain Disorder ◽  
Metabolite Concentrations ◽  
Obese Subjects

Background and Objective:Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10-20% higher than the general population, with one third being obese (BMI>30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and non-obese patients with narcolepsy type 1 remain unknown. The aim of the study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.Methods:We used a targeted liquid chromatography-mass spectrometry metabolomics approach to measure 141 circulating, low molecular weight metabolites in drug-free fasted plasma samples from 117 NT1 patients (including 41 obese subjects) compared with 116 BMI-matched controls (including 57 obese subjects).Results:Common metabolites driving the difference between NT1 and controls, irrespective of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long chain lysophosphatidylcholine acyls, one sphingolipid, 12 phosphatidylcholine diacyls and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences, in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolisms. The metabolites driving these differences were glutamate, sarcosine and ornithine (glycine and serine metabolism), glutamate and PC aa C34:4 (arachidonic acid metabolism) and glutamate, serotonin and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e. slow wave sleep duration, sleep latency and periodic leg movement) and metabolite concentrations seen in the controls were lost.Discussion:These results represented the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1.Classification of Evidence:This study provides Class II evidence that a distinct metabolic profile can differentiate patients with Narcolepsy Type 1 from patients without the disorder.

scholarly journals Metabolic Profiling Revealed Dysregulated Arachidonic Acid Metabolism and Tryptophan Metabolism in the Lungs from Canines with Pacing-induced Heart Failure

2020 ◽  
Author(s):  
Junhan Zhao ◽  
Jing Wang ◽  
Shengwen Yang ◽  
Ran Jing ◽  
Xi Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Arachidonic Acid ◽  
Metabolic Pathways ◽  
Sham Group ◽  
Acid Metabolism ◽  
Congestion Management ◽  
Arachidonic Acid Metabolism ◽  
Tryptophan Metabolism ◽  
Negative Ion ◽  
Metabolic Signatures

Abstract Background: Lung has critical pathophysiological connections to heart and lung congestion presents one of the hallmark features of heart failure (HF). This study aimed to explore the metabolic signatures and disturbances in lungs under HF condition and provide insights on the pathophysiology of the lungs under HF condition from the perspective of metabolism.Methods: In this study, we established a rapid pacing induced HF canine model and applied a comprehensive untargeted metabolomics method to comparatively assessed the metabolomics profiles in the lung tissues from HF group and sham group. Results: Distinct metabolic signatures were identified in the lungs between beagles in HF group and sham group. 81 dysregulated metabolites were identified as differential metabolites (adjusted P <0.05, FC≥2 or≤0.5) in positive ion mode and 80 dysregulated metabolites in negative ion mode, indicating a profound metabolic alteration in the lungs under HF condition. In pathway analysis, arachidonic acid metabolism and tryptophan metabolism were identified as the most significant dysregulated metabolic pathways in the lungs from HF beagles.Conclusions: In this study, we identified profound metabolic variation and dysregulated metabolic pathways, which may deepen our understanding on the pathophysiology of the lungs under HF condition from the perspective of metabolism and open new avenues in lung congestion management in HF.

scholarly journals Level of Arachidonic Acid and State of Peroxidation Processes in Patients with Aspirin-Intolerant Polypous Rhinosinusitis

2016 ◽  
Vol 23 (4) ◽  
pp. 2016410
Author(s):  
Ivanna Koshel
Keyword(s):  
Arachidonic Acid ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Serum Proteins ◽  
Arachidonic Acid Metabolism ◽  
Oxidative Modification ◽  
Key Enzyme ◽  
Protein Peroxidation ◽  
Genetic Block ◽  
Peroxidation Processes

The main peculiarity of aspirin-intolerant polypous rhinosinusitis pathogenesis is the presence of “genetic block” of constitutive cyclooxygenase being the key enzyme of the arachidonic acid metabolism. It justifies the necessity of studying its metabolic peculiarities.The objective of the research was to determine the level of arachidonic acid as well as the state of lipid and protein peroxidation processes in patients with aspirin-intolerant polypous rhinosinusitis.Materials and methods. The levels of arachidonic acid, malondialdehyde and oxidative modification of serum proteins were studied in 20 patients with aspirin-intolerant polypous rhinosinusitis and 7 healthy individuals.Results. Significantly elevated levels of arachidonic levels were observed. The search for alternative metabolic pathways stimulated lipid and protein peroxidation processes and led to the increase in the levels of malondialdehyde and oxidative modification of serum proteins. The peculiarities of biochemical changes indicated pro-inflammatory orientation of lipid metabolism.Conclusions. The obtained data confirmed the hypothesis of “genetic block” of the arachidonic acid metabolism as the main pathogenetic component of aspirin-intolerant polypous rhinosinusitis and allowed us to clearly interpret biochemical picture of the disease.

scholarly journals Proteomic And Metabolomic Analyses Reveal The Full Spectrum of Inflammatory and Lipid Metabolic Abnormalities In Dyslipidemia

2020 ◽  
Author(s):  
Hui DU ◽  
Yifei RAO ◽  
Ronghua LIU ◽  
Kesui DENG ◽  
Yongmei GUAN ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Lipid Metabolism ◽  
Linoleic Acid ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Arachidonic Acid Metabolism ◽  
Antioxidant Defenses ◽  
Alpha Linolenic Acid ◽  
Full Spectrum ◽  
Potential Biomarker

Abstract Background: Dyslipidemia is a common, chronic metabolic disease associated with cardiovascular complications. Due to the multiplicity of etiological factors, the pathogenesis of dyslipidemia is still unclear.Methods: In this study, we combined proteomics and metabolomics methods to analyze the plasma of patients with dyslipidemia and healthy subjects. ITRAQ markers, combined with LC-MS/MS proteomics technology and the UHPLC/ Orbitfast-X Tribrid system, were used to establish the metabolite profile in clinical dyslipidemia.Results: A total of 137 differentially expressed proteins were identified, mainly related to biological processes such as protein activation cascades, adaptive immune responses, complement activation, acute inflammatory responses and regulation of acute inflammatory responses. These proteins are involved in the regulation of important metabolic pathways, such as immunity and inflammation, coagulation and hemostasis, lipid metabolism, and oxidation and antioxidant defenses. Analysis of clinical metabolites showed there were 69 different metabolites in plasma, mainly related to glycerolipid, sphingolipid, porphyrin, alpha-linolenic acid, linoleic acid and arachidonic acid metabolism, suggesting that regulation of inflammation and lipid metabolism may be disturbed in patients with dyslipidemia. Among these, significant changes were observed in indole-3-propionic acid (IPA), which is considered a potential biomarker of dyslipidemia. Conclusions: Combined analysis of proteins and metabolites showed that arachidonic acid, linoleic acid and lipid metabolic pathways were closely related to dyslipidemia. IPA may be a potential biomarker.The information provided in this study may provide new insights into the pathogenesis of dyslipidemia and related diseases, as well as potential intervention targets.

scholarly journals Comparative metabonomic investigations of Schistosoma japonicum from SCID mice and BALB/c mice: clues to developmental abnormality of schistosome in the immunodeficient host

2018 ◽  
Author(s):  
Rong Liu ◽  
Wen-jun Cheng ◽  
Hong-bin Tang ◽  
Qin-ping Zhong ◽  
Zhen-ping Ming ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Schistosoma Japonicum ◽  
Metabolic Pathways ◽  
Growth And Development ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Scid Mice ◽  
Sphingolipid Metabolism ◽  
Metabolic Profiles ◽  
Male And Female

AbstractIt has been discovered that the development of schistosome is hampered in immunodeficient mice, e.g. nude mice lacking T-lymphocytes and the severe combined immune deficient (SCID) mice lacking both T- and B-lymphocytes. However, it’s still unresolved about the underlying regulatory mechanisms of the retarded growth and development of schistosomes in their immunodeficient definitive host. In this study, therefore, five replicates of male or female Schistosoma japonicum samples with twenty male or female worms in each sample, were collected from SCID mice or BALB/c mice at five weeks post infection and used to perform metabonomic analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform, for elucidating the growth and development regulation of schistosome in their definitive hosts from the metabolomic aspect. Based on the identified 1015 ion features in ESI+ mode and 342 ion features in ESI-mode, multivariate modelling methods including the Principal Component Analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) identified distinct metabolic profiles that clearly differentiated both male and female worms in SCID mice from those in BALB/c mice, respectively. Common and uniquely perturbed metabolites and their involved metabolic pathways were identified in male and female worms from SCID mice when compared with those from BALB/c mice. The results also revealed that more differential metabolites were found in female worms (one metabolite was up-regulated and forty metabolites were down-regulated) than male worms (nine metabolites were up-regulated and twenty metabolites were down-regulated) between SCID mice and BALB/c mice. The top five increased metabolites of male worms in SCID mice when compared with those in BALB/c mice were PC(22:6/20:1), L-allothreonine, L-serine, glycerophosphocholine and 5-aminoimidazole ribonucleotide. And the top five decreased metabolites of male worms in SCID mice when compared with those in BALB/c mice were PC(16:0/0:0), PAF C-16, PE(18:1/0:0), adenosine and butenoyl PAF. Most of the differential metabolites of female worms in SCID mice had lower levels when compared with the normal female worms in BALB/c mice, except for retinyl ester with a higher level. The top five decreased metabolites of female worms in SCID mice when compared with those in BALB/c mice were adrenic acid, 5-phosphoribosylamine, PC(16:0/0:0), PC(22:6/20:1) and ergothioneine. The involved metabolic pathways of the differential metabolites in male worms between SCID mice and BALB/c mice mainly included taurine and hypotaurine metabolism, glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, alpha-linolenic acid metabolism, etc. The involved metabolic pathways of differential metabolites in female worms included mainly pyrimidine metabolism, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, etc. These findings suggested a correlation between the retarded growth and development of schistosome in SCID mice and their perturbed metabolic profiles, which also provided a new insight into the regulation mechanisms of growth and development of S. japonicum worms from the metabolic level, and provided clues for discovery of drugs or vaccines against the parasites and parasitic disease.Author summaryThe growth and development of schistosome has been discovered hampered in the immunodeficient hosts. But it remains unresolved about the molecular mechanisms involved in this. In this study, we tested and compared the metabolic profiles of the male and female Schistosoma japonicum worms collected from SCID mice or BALB/c mice at five weeks post infection using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform. There were 1015 ion features in ESI+ mode and 342 ion features in ESI-mode were identified, and distinct metabolic profiles were found to clearly differentiate both male and female worms in SCID mice from those in BALB/c mice, respectively. The results also found more differential metabolites in female worms than in male worms between SCID mice and BALB/c mice. The enriched metabolic pathways of the differential metabolites in male worms between SCID mice and BALB/c mice included taurine and hypotaurine metabolism, glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, alpha-linolenic acid metabolism, etc. And the enriched metabolic pathways of differential metabolites in female worms included pyrimidine metabolism, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, etc. The findings in this study suggested an association between the developmentally stunted schistosome and their perturbed metabolites and metabolic pathways, which provided a new insight into the regulation mechanisms of growth and development of S. japonicum worms from the metabolic level, and clues for discovery of drugs or vaccines against the parasites and disease.

scholarly journals 3019 Metabolomic Markers of Methotrexate Response in Juvenile Idiopathic Arthritis

2019 ◽  
Vol 3 (s1) ◽  
pp. 109-110
Author(s):  
Ryan Sol Funk ◽  
Mara Becker
Keyword(s):  
Arachidonic Acid ◽  
Juvenile Idiopathic Arthritis ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Plasma Metabolites ◽  
Plasma Samples ◽  
Metabolic Markers

OBJECTIVES/SPECIFIC AIMS: In this study, a semi-targeted metabolomics approach is used to identify metabolic markers of methotrexate (MTX) response in juvenile idiopathic arthritis (JIA) and in vitro. METHODS/STUDY POPULATION: A comparative metabolomic analysis was used to identify metabolomic markers and metabolic pathways associated with MTX activity in vitro and in vivo. Cell-based studies assessed metabolomic profiles in K562 erythroblastoid cells with or without MTX treatment. In vivo analysis utilized plasma samples from JIA patients treated with MTX (n=30) and included samples collected prior to the initiation of MTX and after 3-months of MTX treatment. Plasma samples were from an IRB-approved single center prospective cohort study of biomarkers of MTX response in patients with JIA and were stratified based on American College of Rheumatology pediatric (ACR Pedi) response criteria. Semi-targeted global metabolomic profiles including over 800 metabolites across three analytical platforms at the NIH West Coast Metabolomics Center at UC-Davis and were analyzed by univariate and multivariate analysis using MetaboAnalyst 3.0. RESULTS/ANTICIPATED RESULTS: In K562 cells, MTX treatment was associated with statistically significant changes in 550 of the 850 intracellular metabolites detected (false discovery rate less than 0.05). Major metabolic pathways inhibited by MTX included branched-chain amino acid metabolism, purine and pyrimidine biosynthesis, and lipid metabolism including the inhibition of arachidonic acid metabolism. In patients with JIA, far fewer plasma metabolites were significantly altered following the initiation of MTX and included only 15 of the 833 plasma metabolites detected. Interestingly, MTX treatment was associated with the inhibition of arachidonic acid synthesis, inhibition of purine metabolism, and a dramatic reduction in plasma levels of various exogenous metabolites. In particular, MTX treatment was associated reductions in known metabolic markers of intestinal microbiota metabolism, including: biotin and dehydrocholic acid. Further, stratification of patients based on ACR Pedi response demonstrated that clinical response was associated with a greater reduction in plasma dehydrocholic acid levels following the initiation of MTX. DISCUSSION/SIGNIFICANCE OF IMPACT: This work demonstrates that MTX therapy is associated with a number of biochemical changes in vitro and in vivo, including: inhibition of purine metabolism, inhibition of arachidonic acid metabolism, and an apparent inhibition of gut microbiota metabolism. Most notably, inhibition of gut microbiota metabolism appears to demonstrate a relationship with the observed clinical efficacy of MTX in JIA.

scholarly journals High-Throughput Untargeted Serum Metabolomics Analysis of Hyperuricemia Patients by UPLC-Q-TOF/MS

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Nankun Qin ◽  
Yue Jiang ◽  
Wenjun Shi ◽  
Liting Wang ◽  
Lingbo Kong ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Linoleic Acid ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Sphingolipid Metabolism ◽  
Tryptophan Biosynthesis ◽  
Linoleic Acid Metabolism ◽  
Phenylalanine Metabolism ◽  
Tof Ms

Hyperuricemia (HUA) as a metabolic disease is closely associated with metabolic disorders. The etiology and pathogenesis of HUA are not fully understood, so there is no radical cure so far. Metabolomics, a specialized study of endogenous small molecule substances, has become a powerful tool for metabolic pathway analysis of selected differential metabolites, which is helpful for initially revealing possible development mechanisms of various human diseases. Twenty HUA patients and 20 healthy individuals participated in the experiment, and ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was employed to investigate serum samples to find differential metabolites. The statistical techniques used were principal component analysis and orthogonal partial least-squares discriminant analysis. The differences in metabolomics results of samples after pretreatment with different solvents were compared, 38, 20, 26, 28, 33, 50, and 40 potential differential metabolites were found, respectively, in HUA patient samples, and each group involved different metabolic pathways. Repetitive metabolites were removed, 138 differential metabolites in HUA serum were integrated for analysis, and the human body was affected by 7 metabolic pathways of glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and α-linolenic acid metabolism. In this work, the metabolomics approach based on UPLC-Q-TOF/MS was employed to investigate serum metabolic changes in HUA patients, 138 potential differential metabolites related to HUA were identified, which provided associations of lipids, amino acids, fatty acids, organic acids, and nucleosides profiles of HUA individuals. Metabolic pathways involved in glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and a-linolenic acid metabolism shed light on the understanding of the etiology and pathogenesis process of HUA.

Testosterone Potentiation of Ionophore and ADP Induced Platelet Aggregation : Relationship to Arachidonic Acid Metabolism

1981 ◽  
Vol 46 (02) ◽  
pp. 538-542 ◽  
Author(s):  
R Pilo ◽  
D Aharony ◽  
A Raz
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Unsaturated Fatty Acids ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Arachidonic Acid Metabolism ◽  
Ionophore A23187 ◽  
Low Concentrations ◽  
Induced Aggregation

SummaryThe role of arachidonic acid oxygenated products in human platelet aggregation induced by the ionophore A23187 was investigated. The ionophore produced an increased release of both saturated and unsaturated fatty acids and a concomitant increased formation of TxA2 and other arachidonate products. TxA2 (and possibly other cyclo oxygenase products) appears to have a significant role in ionophore-induced aggregation only when low concentrations (<1 μM) of the ionophore are employed.Testosterone added to rat or human platelet-rich plasma (PRP) was shown previously to potentiate platelet aggregation induced by ADP, adrenaline, collagen and arachidonic acid (1, 2). We show that testosterone also potentiates ionophore induced aggregation in washed platelets and in PRP. This potentiation was dose and time dependent and resulted from increased lipolysis and concomitant generation of TxA2 and other prostaglandin products. The testosterone potentiating effect was abolished by preincubation of the platelets with indomethacin.

Regulation of arachidonic acid metabolism in human amnion

1985 ◽  
Vol 110 (1_Suppla) ◽  
pp. S53-S54
Author(s):  
ST. NIESERT ◽  
M. D. MITCHELL ◽  
M. L. CASEY ◽  
P. C. MACDONALD
Keyword(s):  
Arachidonic Acid ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Human Amnion
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