42 results on '"Florence Mehl"'
Search Results
2. Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study
- Author
-
Shiying Li, Iulian Dragan, Van Du T. Tran, Chun Ho Fung, Dmitry Kuznetsov, Michael K. Hansen, Joline W. J. Beulens, Leen M. ‘t Hart, Roderick C. Slieker, Louise A. Donnelly, Mathias J. Gerl, Christian Klose, Florence Mehl, Kai Simons, Petra J. M. Elders, Ewan R. Pearson, Guy A. Rutter, and Mark Ibberson
- Subjects
multi-omics ,type 2 diabetes ,glycaemic deterioration ,metabolic syndrome ,lipidomics ,proteomics ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
IntroductionType 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised “bottom-up” approach, we attempt to group T2D patients based solely on -omics data generated from plasma.MethodsCirculating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics.ResultsFrom a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor.ConclusionsUsing an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.
- Published
- 2024
- Full Text
- View/download PDF
3. Identification of biomarkers for glycaemic deterioration in type 2 diabetes
- Author
-
Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A. Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J. M. Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J. Gerl, Amber A. van der Heijden, Lori L. Jennings, Michael K. Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W. Franks, Gareth E. Lim, Jennifer Estall, Mark Ibberson, Joline W. J. Beulens, Leen M ’t Hart, Ewan R. Pearson, and Guy A. Rutter
- Subjects
Science - Abstract
Abstract We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
- Published
- 2023
- Full Text
- View/download PDF
4. A Federated Database for Obesity Research: An IMI-SOPHIA Study
- Author
-
Carl Delfin, Iulian Dragan, Dmitry Kuznetsov, Juan Fernandez Tajes, Femke Smit, Daniel E. Coral, Ali Farzaneh, André Haugg, Andreas Hungele, Anne Niknejad, Christopher Hall, Daan Jacobs, Diana Marek, Diane P. Fraser, Dorothee Thuillier, Fariba Ahmadizar, Florence Mehl, Francois Pattou, Frederic Burdet, Gareth Hawkes, Ilja C. W. Arts, Jordi Blanch, Johan Van Soest, José-Manuel Fernández-Real, Juergen Boehl, Katharina Fink, Marleen M. J. van Greevenbroek, Maryam Kavousi, Michiel Minten, Nicole Prinz, Niels Ipsen, Paul W. Franks, Rafael Ramos, Reinhard W. Holl, Scott Horban, Talita Duarte-Salles, Van Du T. Tran, Violeta Raverdy, Yenny Leal, Adam Lenart, Ewan Pearson, Thomas Sparsø, Giuseppe N. Giordano, Vassilios Ioannidis, Keng Soh, Timothy M. Frayling, Carel W. Le Roux, and Mark Ibberson
- Subjects
federated database system ,obesity ,risk prediction ,remote statistical analysis ,bioinformatics ,Science - Abstract
Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.
- Published
- 2024
- Full Text
- View/download PDF
5. Regenerating islet-derived protein 3α: A promising therapy for diabetes. Preliminary data in rodents and in humans
- Author
-
Aurélie Le Lay, Erwann Philippe, Fanny Roth, Ana Rodriguez Sanchez-Archidona, Florence Mehl, Jessica Denom, Rashmi Prasad, Olof Asplund, Ola Hansson, Mark Ibberson, Fabrizio Andreelli, Lyse Santoro, Paul Amouyal, Gilles Amouyal, Christian Brechot, Laure Jamot, Céline Cruciani-Guglielmacci, and Christophe Magnan
- Subjects
Insulin resistance ,Glucose uptake ,Skeletal muscles ,Type 2 diabetes ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect.
- Published
- 2022
- Full Text
- View/download PDF
6. Systemic and central nervous system metabolic alterations in Alzheimer’s disease
- Author
-
Vera van der Velpen, Tony Teav, Héctor Gallart-Ayala, Florence Mehl, Ioana Konz, Christopher Clark, Aikaterini Oikonomidi, Gwendoline Peyratout, Hugues Henry, Mauro Delorenzi, Julijana Ivanisevic, and Julius Popp
- Subjects
Alzheimer’s disease ,Metabolomics ,Energy metabolism ,Tryptophan pathway ,CSF AD biomarkers ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer’s disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. Methods In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. Results Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1–42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1–42, or tau and phosphorylated Tau-181. Conclusions This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.
- Published
- 2019
- Full Text
- View/download PDF
7. Plasma triacylglycerols are biomarkers of β-cell function in mice and humans
- Author
-
Ana Rodríguez Sánchez-Archidona, Céline Cruciani-Guglielmacci, Clara Roujeau, Leonore Wigger, Justine Lallement, Jessica Denom, Marko Barovic, Nadim Kassis, Florence Mehl, Jurgen Weitz, Marius Distler, Christian Klose, Kai Simons, Mark Ibberson, Michele Solimena, Christophe Magnan, and Bernard Thorens
- Subjects
Triacylglycerols ,β-cell function ,Systems biology ,Type 2 diabetes ,PITPNC1 ,Biomarkers ,Internal medicine ,RC31-1245 - Abstract
Objectives: To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic β-cell deregulations or defects in the function of insulin target tissues. Methods: We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions, as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules. Results: We identified strong correlation between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for negative and positive correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In the liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the β-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification of PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion. Conclusion: TAGs emerge as biomarkers of a liver-to-β-cell axis that links hepatic β-oxidation to β-cell functional mass and insulin secretion.
- Published
- 2021
- Full Text
- View/download PDF
8. LC-HRMS data as a result of untargeted metabolomic profiling of human cerebrospinal fluid
- Author
-
Florence Mehl, Héctor Gallart-Ayala, Ioana Konz, Tony Teav, Aikaterini Oikonomidi, Gwendoline Peyratout, Vera van der Velpen, Julius Popp, and Julijana Ivanisevic
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Cerebrospinal fluid (CSF) is a key body fluid that maintains the homeostasis in central nervous system (CNS). As a biofluid whose content reflects the brain metabolic activity, the CSF is analyzed in the context of neurological diseases and is rarely collected from healthy subjects. For this reason, the metabolite variation associated with general phenotypic characteristics such as gender and age have hardly ever been studied. Here we present the hydrophilic interaction liquid chromatography-high resolution mass spectrometry (HILIC-HRMS) data as a result of untargeted metabolomics analysis of a cohort of elderly cognitively healthy volunteers (n = 32). 146 unambiguously identified water soluble metabolites (using accurate mass, retention time and MS/MS matching against spectral libraries) were measured and their abundances across all the subjects depending on their gender are provided in this article. Data tables are available at https://data.mendeley.com/datasets/c73xtsd4s5/1. it's published on mendeley, the DOI is DOI:10.17632/c73xtsd4s5.1. The data presented in this article are related to the research article entitled “A global HILIC-MS approach to measure polar human cerebrospinal fluid metabolome: Exploring gender-associated variation in a cohort of elderly cognitively healthy subjects” (Gallart-Ayala et al., 2018, In press).
- Published
- 2018
- Full Text
- View/download PDF
9. Molecular Biomarkers of Neovascular Age-Related Macular Degeneration With Incomplete Response to Anti-Vascular Endothelial Growth Factor Treatment
- Author
-
Irmela Mantel, Angelica Borgo, Jacopo Guidotti, Edwige Forestier, Olga Kirsch, Yasmine Derradji, Patrice Waridel, Frédéric Burdet, Florence Mehl, Claude Schweizer, and Raphaël Roduit
- Subjects
age-related macular degeneration (AMD) ,angiogenic factors ,Inflammation ,Soluble vascular cell adhesion molecule-1 (sVCAM-1) ,interleukin-6 (IL-6) ,bioactive interleukin-12 (IL-12p40) ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [ p = 0.001], interleukin-6 (IL-6) [ p = 0.009], bioactive interleukin-12 (IL-12p40) [ p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [ p = 0.004], and hepatocyte growth factor (HGF) [ p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [ p < 0.0001] and IL-6 [ p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. Data are available via ProteomeXchange with identifier PXD02247
- Published
- 2020
- Full Text
- View/download PDF
10. MetaNetX/MNXref: unified namespace for metabolites and biochemical reactions in the context of metabolic models.
- Author
-
Sébastien Moretti, T. Van Du Tran, Florence Mehl, Mark Ibberson, and Marco Pagni
- Published
- 2021
- Full Text
- View/download PDF
11. Novel subgroups of type 2 diabetes based on multi-Omics profiling: an IMI-RHAPSODY Study
- Author
-
Shiying Li, Iulian Dragan, Chun Ho Fung, Dmitry Kuznetsov, Michael K. Hansen, Joline W.J. Beulens, Leen M. ’t Hart, Roderick C. Slieker, Louise A. Donnelly, Mathias J. Gerl, Christian Klose, Florence Mehl, Kai Simons, Petra JM Elders, Ewan R. Pearson, Guy A. Rutter, and Mark Ibberson
- Abstract
Type 2 diabetes is a complex, multifactorial disease with varying presentation and underlying pathophysiology. Recent studies using data-driven cluster analysis have led to a stratification of type 2 diabetes into novel subgroups based on six clinical measurements. Whether these subgroups truly correspond to the underlying phenotypic differences is nevertheless unclear. Here, we apply an unsupervised, data-driven clustering method (Similarity Network Fusion) to characterize type 2 diabetes in two independent cohorts involving 1,134 subjects in total based on integrated plasma lipidomics and peptidomics data without pre-selection. Logistic regression was then used to explore clustering based on ≥ 180 circulating lipids and 1,195 protein biomarkers, alongside clinical signatures. Two subgroups were identified, one of which associated with elevated C-peptide levels, diabetic complications and more severe insulin resistance compared to the other. GWAS analysis against 403 type 2 diabetes risk variants revealed associations of several SNPs with clusters and altered molecular profiles. We thus demonstrate that heterogeneity in type 2 diabetes can be captured by circulating omics alone using an unsupervised bottom-up approach. Such multiomics signatures could reflect pathological mechanisms underlying type 2 diabetes and thus may help inform on precision medicine approaches to disease management.
- Published
- 2022
12. Field-based metabolomic reveals alteration of the volatiles organic compounds produced by Lavandula species in the context of yellow decline disease
- Author
-
Émilie Stierlin, Florence Nicolè, Thomas Costes, Florence Mehl, Xavier Fernandez, and Thomas Michel
- Abstract
Introduction Fine lavender and lavandin are perfume and medicinal plants widely cultivated in Provence (south-east of France) for their essential oil and for the production of honey. The lavender monocultures are affected by a severe decline in France, due to the propagation of the yellow decline disease. This disease is caused by the Stolbur phytoplasma, a bacterium transmitted by a sap-sucking insect, Hyalesthes obsoletus. Objectives Main objective was to develop an untargeted metabolomic approach to highlight changes in the volatiles organic compounds produced by asymptomatic (“healthy”) and symptomatic (“infected”) plants. Methods Samples from fine lavender and lavandin aerial parts were collected in the field, then stored volatile compounds were extracted in the laboratory by ultrasound assisted extraction and analyzed by gas chromatography–mass spectrometry. Afterwards, multivariate statistical analysis has been performed using principal component analysis and partial least square regression as well as a multiblock statistical analysis by orthogonal partial least squares discriminant analysis to compare VOCs from fine lavender (variety 7713) and lavandin (variety abrial).Results Fifty stored VOCs, mainly oxygenated monoterpenes, from lavender and lavandin leaves and blooming head of the inflorescences were identified. Metabolism of several compounds were found to be altered by yellow decline such as β-farnesene overexpressed by symptomatic plants. Conclusion The developed metabolomic approach allowed the identification of specific volatile compounds produced by asymptomatic and symptomatic plants in a complex field environment.
- Published
- 2022
13. Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes
- Author
-
Cristina Legido-Quigley, Florence Mehl, Daniela Aust, Eyke Schöniger, Kai Simons, Mathias Lesche, Michele Solimena, Andreas Dahl, Marko Barovic, Nicole Kipke, Flavia Marzetta, Anke M. Schulte, Andreas-David Brunner, Matthias Mann, Daniela Friedland, Jürgen Weitz, Frédéric Burdet, Philippe Delerive, Christian Klose, Bernard Thorens, Mark Ibberson, Marius Distler, Mathias J. Gerl, Pierre Barbier Saint Hilaire, Leonore Wigger, Ezio Bonifacio, and Camille Kessler
- Subjects
Blood Glucose ,Proteomics ,endocrine system ,endocrine system diseases ,Lipide, Typ-2-Diabetes (T2D), Pankreasinseln, Multi-omics-Analyse ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Type 2 diabetes ,Biology ,Impaired glucose tolerance ,Islets of Langerhans ,03 medical and health sciences ,0302 clinical medicine ,Insulin-Secreting Cells ,Physiology (medical) ,Diabetes mellitus ,Living Donors ,Internal Medicine ,medicine ,Humans ,Insulin ,Metabolomics ,ddc:610 ,030304 developmental biology ,0303 health sciences ,geography ,geography.geographical_feature_category ,Gene Expression Profiling ,Pancreatic islets ,Transdifferentiation ,lipids, type 2 diabetes (T2D), pancreatic islets, multi-omics analysis ,Cell Biology ,Islet ,medicine.disease ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Pancreatectomy ,Cancer research ,Disease Susceptibility ,Beta cell ,Energy Metabolism ,Biomarkers - Abstract
Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers. Wigger, Barovic and Brunner et al. perform a multidimensional analysis of islets from metabolically characterized patients who had undergone pancreatectomy, observing remarkable heterogeneity between samples from individuals with type 2 diabetes, thus arguing against models of linear beta-cell dedifferentiation in diabetes.
- Published
- 2021
14. LC-HRMS data as a result of untargeted metabolomic profiling of human cerebrospinal fluid
- Author
-
Ioana Konz, Vera van der Velpen, Hector Gallart-Ayala, Gwendoline Peyratout, Aikaterini Oikonomidi, Florence Mehl, Julius Popp, Julijana Ivanisevic, and Tony Teav
- Subjects
0301 basic medicine ,Metabolite ,Physiology ,Context (language use) ,lcsh:Computer applications to medicine. Medical informatics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,Biochemistry, Genetics and Molecular Biology ,Metabolome ,Medicine ,Research article ,lcsh:Science (General) ,Body fluid ,Multidisciplinary ,business.industry ,3. Good health ,030104 developmental biology ,Metabolomic profiling ,chemistry ,Cohort ,lcsh:R858-859.7 ,business ,030217 neurology & neurosurgery ,lcsh:Q1-390 - Abstract
Cerebrospinal fluid (CSF) is a key body fluid that maintains the homeostasis in central nervous system (CNS). As a biofluid whose content reflects the brain metabolic activity, the CSF is analyzed in the context of neurological diseases and is rarely collected from healthy subjects. For this reason, the metabolite variation associated with general phenotypic characteristics such as gender and age have hardly ever been studied. Here we present the hydrophilic interaction liquid chromatography-high resolution mass spectrometry (HILIC-HRMS) data as a result of untargeted metabolomics analysis of a cohort of elderly cognitively healthy volunteers ( n = 32). 146 unambiguously identified water soluble metabolites (using accurate mass, retention time and MS/MS matching against spectral libraries) were measured and their abundances across all the subjects depending on their gender are provided in this article. Data tables are available at https://data.mendeley.com/datasets/c73xtsd4s5/1. it's published on mendeley, the DOI is DOI:10.17632/c73xtsd4s5.1. The data presented in this article are related to the research article entitled "A global HILIC-MS approach to measure polar human cerebrospinal fluid metabolome: Exploring gender-associated variation in a cohort of elderly cognitively healthy subjects" (Gallart-Ayala et al., 2018, In press).
- Published
- 2018
15. Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study
- Author
-
Sheikh M, Kai Simons, Florence Mehl, Dina Mansour Aly, Marko Barovic, Peter Rossing, Frédéric Burdet, Timothy J. Pullen, Min Kim, Filip Ottosson, Iulian Dragan, t Hart Lm, Imre Pavo, Asger Wretlind, Michele Solimena, Joline W.J. Beulens, Petra J. M. Elders, Gudmundsdottir, Céline Fernandez, M.J. Gerl, Giuseppe N. Giordano, Muniangi-Muhitu H, Mikael Åkerlund, Efanov A, Louise A. Donnelly, Lopez-Noriega L, Diana Marek, Kevin L. Duffin, Hugo Fitipaldi, Christian Klose, Guy A. Rutter, Olle Melander, Emma Ahlqvist, Lori L. Jennings, Akalestou E, Michael K. Hansen, Adnan Ali, Gerard A Bouland, Tommi Suvitaival, Bernard Thorens, Gudnason, Georgiadou E, Niknejad A, Leif Groop, E R Pearson, Mickaël Canouil, Paul W. Franks, Mark Ibberson, Leclerc I, Lyssenko, Roderick C. Slieker, Dmitry Kuznetsov, van der Heijden Aa, Cristina Legido Quigley, Philippe Froguel, and Andreas Festa
- Subjects
Homocitrulline ,0303 health sciences ,geography ,geography.geographical_feature_category ,business.industry ,Insulin ,medicine.medical_treatment ,Type 2 diabetes ,Disease ,medicine.disease ,Islet ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,Diabetes mellitus ,Immunology ,COTL1 ,medicine ,business ,030304 developmental biology - Abstract
We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2;2 were also predictive of disease progression. Of ∼1,300 proteins examined in two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis. This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
- Published
- 2021
16. Plasma triacylglycerols are biomarkers of ß-cell function in mice and humans
- Author
-
Bernard Thorens, Michele Solimena, Christian Klose, Jürgen Weitz, Florence Mehl, Jessica Denom, Ana Rodriguez Sanchez-Archidona, Clara Roujeau, Mark Ibberson, Christophe Magnan, Marko Barovic, Céline Cruciani-Guglielmacci, Kai Simons, Nadim Kassis, Leonore Wigger, Marius Distler, and Justine Lallement
- Subjects
Male ,PC, phosphatidylcholines ,HFD, high-fat diet ,T2D, Type 2 diabetes ,medicine.medical_treatment ,PITPNC1 ,Type 2 diabetes ,Transcriptome ,Mice ,AUC, area under the curve ,LPC, lysophosphatidylcholines ,0302 clinical medicine ,Insulin-Secreting Cells ,Gene expression ,Insulin Secretion ,Internal medicine ,Cells, Cultured ,0303 health sciences ,Mice, Inbred BALB C ,geography.geographical_feature_category ,Chol, cholesterol ,OXPHOS, Oxidative phosphorylation ,ABHD6 ,Islet ,Cell biology ,Mice, Inbred DBA ,TAGs, triacylglycerols ,VDR, vitamin D receptor ,Original Article ,Sphingomyelin ,Systems biology ,medicine.drug ,LDL, low-density lipoproteins ,β-cell function ,030209 endocrinology & metabolism ,Biology ,GSIS, glucose-stimulated insulin secretion ,ER, endoplasmic reticulum ,03 medical and health sciences ,SMs, sphingomyelins ,WGCNA, weighted gene co-expression network analysis ,GO, Gene Ontology ,medicine ,KEGG, Kyoto encyclopedia of genes and genomes ,Animals ,Humans ,Lpl, lipoprotein lipase ,Carnitine ,PI, phosphatidylinositols ,Molecular Biology ,Triglycerides ,030304 developmental biology ,geography ,PCA, principal component analysis ,HDL, high-density lipoproteins ,Insulin ,RC, regular chow ,Cell Biology ,medicine.disease ,RC31-1245 ,CE, cholesteryl esters ,Mice, Inbred C57BL ,Biomarkers/blood ,Biomarkers/metabolism ,Glucose/metabolism ,Insulin-Secreting Cells/metabolism ,Triglycerides/blood ,Triglycerides/metabolism ,Biomarkers ,Triacylglycerols ,Glucose - Abstract
Objectives To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic β-cell deregulations or defects in the function of insulin target tissues. Methods We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions, as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules. Results We identified strong correlation between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for negative and positive correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In the liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the β-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification of PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion. Conclusion TAGs emerge as biomarkers of a liver-to-β-cell axis that links hepatic β-oxidation to β-cell functional mass and insulin secretion., Highlights • Plasma triacylglycerols correlated with genes controlling β-cell mass and function. • Plasma triacylglycerols correlated with genes controlling liver β-oxidation. • In humans, triacylglycerols also correlated with key regulators of insulin secretion. • Mouse and human data identified PITPNC1 as a candidate regulator of insulin secretion. • Triacylglycerols are biomarkers of the liver-to-β-cell axis and β-cell function.
- Published
- 2021
- Full Text
- View/download PDF
17. Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes:An IMI-RHAPSODY Study
- Author
-
Mathias J. Gerl, Hugo Fitipaldi, Michael K. Hansen, Mikael Åkerlund, Leif Groop, Roderick C. Slieker, Kai Simons, Guy A. Rutter, Ewan R. Pearson, Louise A. Donnelly, Peter Rossing, Gerard A Bouland, Min Kim, Mark Ibberson, Amber A. van der Heijden, Dmitry Kuznetsov, Christian Klose, Florence Mehl, Timothy J. Pullen, Giuseppe N. Giordano, Valeriya Lyssenko, Iulian Dragan, Emma Ahlqvist, Andreas Festa, Dina Mansour Aly, Paul W. Franks, Cristina Legido Quigley, Asger Wretlind, Petra J. M. Elders, Imre Pavo, Joline W. J. Beulens, Adnan Ali, Bernard Thorens, Leen M 't Hart, Tommi Suvitaival, Epidemiology and Data Science, General practice, APH - Health Behaviors & Chronic Diseases, APH - Methodology, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, MRC Programme Grant, and Wellcome Trust
- Subjects
Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Disease ,Type 2 diabetes ,Biology ,Cohort Studies ,03 medical and health sciences ,Endocrinology & Metabolism ,0302 clinical medicine ,Metabolomics ,Diabetes mellitus ,Internal Medicine ,medicine ,Cluster Analysis ,Humans ,PI3K/AKT/mTOR pathway ,11 Medical and Health Sciences ,030304 developmental biology ,Genetics ,0303 health sciences ,Pancreatic islets ,Genetics/Genomes/Proteomics/Metabolomics ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Cross-Sectional Studies ,Diabetes Mellitus, Type 2 ,Homogeneous ,Insulin Resistance ,Intracellular - Abstract
Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
- Published
- 2021
18. Replication and cross-validation of T2D subtypes based on clinical variables: an IMI-RHAPSODY study
- Author
-
Mikael Åkerlund, Imre Pavo, Peter Rossing, Adnan Ali, Min Kim, Bernard Thorens, Andreas Festa, Christian Klose, Florence Mehl, Mathias J. Gerl, Louise A. Donnelly, Dmitry Kuznetsov, Hugo Fitipaldi, Timothy J. Pullen, Gerard A Bouland, Kai Simons, Ewan R. Pearson, Michael K. Hansen, Iulian Dragan, Mark Ibberson, Cristina Legido Quigley, Emma Ahlqvist, Paul W. Franks, Leif Groop, Guy A. Rutter, Giuseppe N. Giordano, Dina Mansour Aly, Valeriya Lyssenko, Leen M 't Hart, Tommi Suvitaival, Roderick C. Slieker, Asger Wretlind, and Joline W.J. Beulens
- Subjects
Genetics ,Clinical variables ,nutritional and metabolic diseases ,Insulin resistant ,030209 endocrinology & metabolism ,Type 2 diabetes ,Biology ,medicine.disease ,Cross-validation ,03 medical and health sciences ,0302 clinical medicine ,SIDD ,Cohort ,Replication (statistics) ,Cluster (physics) ,medicine ,030212 general & internal medicine - Abstract
Aims/hypothesisFive clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes (T2D). In the current study we replicate and cross-validate these T2D clusters in three large cohorts using readily measured variables in the clinic.MethodsIn this cross-sectional study, 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide and HDL in three independent cohorts. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort’s cluster centres.ResultsFive distinct T2D clusters were identified and mapped back to the original four ANDIS clusters. Using C-peptide and HDL instead of HOMA-B and HOMA-S three of the clusters mapped with high sensitivity (80.6 – 90.7%) to the previously identified Severe Insulin Deficient (SIDD), Severe insulin resistant (SIRD) and Obese (MOD) clusters. The previously described ANDIS MARD cluster could be mapped to the two milder groups in our study – one characterised by high HDL, and the other having not any extreme characteristic (MDH cluster). When these two milder groups were combined they mapped well to the previously labelled MARD cluster (sensitivity 79.4%). In the cross-validation between cohorts, particularly the SIDD and MDH cluster cross-validated well with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity ranging from 36.1% to 92.3% where individuals shifted from SIRD to MD and vice versa.Conclusions/interpretationClusters based on C-peptide instead of HOMA measures result in clusters that resemble those based on HOMA measures, especially for SIDD, SIRD and MOD. By adding HDL, the MARD cluster based upon HOMA measures resulted in the current clustering in two clusters with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts.
- Published
- 2020
19. Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes
- Author
-
Philippe Delerive, Michele Solimena, Camille Kessler, Nicole Kipke, Mark Ibberson, Flavia Marzetta, Ezio Bonifacio, Matthias Mann, Andreas-David Brunner, Mathias Lesche, Daniela Aust, Andreas Dahl, Marko Barovic, Daniela Friedland, Frédéric Burdet, Anke M. Schulte, Eyke Schöniger, Kai Simons, Leonore Wigger, Jürgen Weitz, Bernard Thorens, Florence Mehl, Cristina Legido Quigley, and Marius Distler
- Subjects
endocrine system ,geography ,geography.geographical_feature_category ,endocrine system diseases ,Type 2 diabetes ,Biology ,Islet ,medicine.disease ,Impaired glucose tolerance ,Transcriptome ,Lipidomics ,Cancer research ,medicine ,Beta cell ,Gene ,Microdissection - Abstract
Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.
- Published
- 2020
20. MetaNetX/MNXref - unified namespace for metabolites and biochemical reactions in the context of metabolic models
- Author
-
Florence Mehl, Mark Ibberson, Sébastien Moretti, Marco Pagni, and Van Du T. Tran
- Subjects
Databases, Factual ,Data curation ,AcademicSubjects/SCI00010 ,Flat file database ,Computer science ,Metabolic network ,Context (language use) ,computer.file_format ,Biology ,Models, Biological ,World Wide Web ,Resource (project management) ,Metabolome ,Genetics ,Database Issue ,Biochemical reactions ,SPARQL ,Namespace ,RDF ,computer ,Data Curation ,Metabolic Networks and Pathways - Abstract
MetaNetX/MNXref is a reconciliation of metabolites and biochemical reactions providing cross-links between major public biochemistry and Genome-Scale Metabolic Network (GSMN) databases. The new release brings several improvements with respect to the quality of the reconciliation, with particular attention dedicated to preserving the intrinsic properties of GSMN models. The MetaNetX website (https://www.metanetx.org/) provides access to the full database and online services. A major improvement is for mapping of user-provided GSMNs to MXNref, which now provides diagnostic messages about model content. In addition to the website and flat files, the resource can now be accessed through a SPARQL endpoint (https://rdf.metanetx.org).
- Published
- 2020
21. Molecular Biomarkers of Neovascular Age-Related Macular Degeneration With Incomplete Response to Anti-Vascular Endothelial Growth Factor Treatment
- Author
-
Raphaël Roduit, Florence Mehl, Yasmine Derradji, Irmela Mantel, Claude Schweizer, Angelica Borgo, Edwige Forestier, Jacopo Guidotti, Olga Kirsch, Frédéric Burdet, and Patrice Waridel
- Subjects
0301 basic medicine ,angiogenic factors ,hepatocyte growth factor (HGF) ,Inflammation ,Pharmacology ,interleukin-6 (IL-6) ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Adjuvant therapy ,Pharmacology (medical) ,Soluble vascular cell adhesion molecule-1 (sVCAM-1) ,age-related macular degeneration (AMD) ,bioactive interleukin-12 (IL-12p40) ,plasminogen ctivator inhibitor type 1 (PAI-1) ,Original Research ,business.industry ,Standard treatment ,lcsh:RM1-950 ,Macular degeneration ,medicine.disease ,Complement system ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,030221 ophthalmology & optometry ,Increased inflammatory response ,Hepatocyte growth factor ,medicine.symptom ,business ,medicine.drug ,Retinopathy - Abstract
The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [ p = 0.001], interleukin-6 (IL-6) [ p = 0.009], bioactive interleukin-12 (IL-12p40) [ p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [ p = 0.004], and hepatocyte growth factor (HGF) [ p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [ p < 0.0001] and IL-6 [ p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. Data are available via ProteomeXchange with identifier PXD02247
- Published
- 2020
22. Author Correction: Mechanistic insights into bacterial metabolic reprogramming from omics-integrated genome-scale models
- Author
-
Vladimir Sentchilo, Anush Chiappino-Pepe, Noushin Hadadi, Hector Gallart-Ayala, Vikash Pandey, Julijana Ivanisevic, Florence Mehl, Marian Morales, and Jan Roelof van der Meer
- Subjects
Genome ,Systems Analysis ,Bacteria ,Biochemical Phenomena ,Applied Mathematics ,Metabolic reprogramming ,Genome scale ,Adaptation, Biological ,Computational Biology ,Computational biology ,Biology ,Omics ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Computer Science Applications ,Environmental sciences ,Biodegradation, Environmental ,lcsh:Biology (General) ,Modeling and Simulation ,Pseudomonas ,Drug Discovery ,Author Correction ,lcsh:QH301-705.5 ,Metabolic Networks and Pathways - Abstract
Understanding the adaptive responses of individual bacterial strains is crucial for microbiome engineering approaches that introduce new functionalities into complex microbiomes, such as xenobiotic compound metabolism for soil bioremediation. Adaptation requires metabolic reprogramming of the cell, which can be captured by multi-omics, but this data remains formidably challenging to interpret and predict. Here we present a new approach that combines genome-scale metabolic modeling with transcriptomics and exometabolomics, both of which are common tools for studying dynamic population behavior. As a realistic demonstration, we developed a genome-scale model of Pseudomonas veronii 1YdBTEX2, a candidate bioaugmentation agent for accelerated metabolism of mono-aromatic compounds in soil microbiomes, while simultaneously collecting experimental data of P. veronii metabolism during growth phase transitions. Predictions of the P. veronii growth rates and specific metabolic processes from the integrated model closely matched experimental observations. We conclude that integrative and network-based analysis can help build predictive models that accurately capture bacterial adaptation responses. Further development and testing of such models may considerably improve the successful establishment of bacterial inoculants in more complex systems.
- Published
- 2020
23. Systemic and central nervous system metabolic alterations in Alzheimer's disease
- Author
-
Gwendoline Peyratout, Christopher Clark, Ioana Konz, Tony Teav, Aikaterini Oikonomidi, Hugues Henry, Julius Popp, Florence Mehl, Vera van der Velpen, Mauro Delorenzi, Hector Gallart-Ayala, and Julijana Ivanisevic
- Subjects
0301 basic medicine ,Apolipoprotein E ,Male ,Kynurenine pathway ,lcsh:RC346-429 ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,Kynurenic acid ,CSF AD biomarkers ,Medicine ,Phosphorylation ,Aged, 80 and over ,Neurodegeneration ,Tryptophan ,Brain ,Middle Aged ,Neurology ,Female ,Tryptophan pathway ,Alzheimer’s disease ,medicine.medical_specialty ,Cognitive Neuroscience ,tau Proteins ,Creatine ,lcsh:RC321-571 ,03 medical and health sciences ,Insulin resistance ,Alzheimer Disease ,Internal medicine ,Carnitine ,Metabolomics ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Amyloid beta-Peptides ,business.industry ,Research ,Energy metabolism ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,Case-Control Studies ,Neurology (clinical) ,Clinical Neurology ,business ,030217 neurology & neurosurgery ,Biomarkers ,Quinolinic acid - Abstract
Background Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer’s disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. Methods In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. Results Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1–42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1–42, or tau and phosphorylated Tau-181. Conclusions This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.
- Published
- 2019
24. Merged Targeted Quantification and Untargeted Profiling for Comprehensive Assessment of Acylcarnitine and Amino Acid Metabolism
- Author
-
Hugues Henry, Hector Gallart-Ayala, Vera van der Velpen, Julijana Ivanisevic, Tony Teav, and Florence Mehl
- Subjects
Metabolite ,Energy metabolism ,010402 general chemistry ,Mass spectrometry ,01 natural sciences ,Mass Spectrometry ,Analytical Chemistry ,chemistry.chemical_compound ,Limit of Detection ,Carnitine ,Humans ,Sample preparation ,Amino acid metabolism ,Amino Acids ,Derivatization ,chemistry.chemical_classification ,Brain Chemistry ,Chromatography ,Hydrophilic interaction chromatography ,010401 analytical chemistry ,Brain ,Reproducibility of Results ,0104 chemical sciences ,Amino acid ,chemistry ,Isotope Labeling ,Calibration ,Metabolome ,Hydrophobic and Hydrophilic Interactions ,Chromatography, Liquid - Abstract
Acylcarnitines and amino acids are key players in energy metabolism; however, analytical methods for comprehensive and straightforward quantitative profiling of these metabolites, without derivatization or use of ion-pairing agents, are lacking. We therefore developed a hydrophilic interaction chromatography (HILIC)-based high-resolution mass spectrometry (HRMS) method for the simultaneous quantification of acylcarnitines and amino acids in a single run, while taking advantage of HRMS data acquired in full-scan mode to screen for additional derivatives and other polar metabolites. A single-step metabolite extraction with internal standard mixture (in methanol) warranted high-throughput sample preparation whose applicability was demonstrated on a panel of human biofluids (i.e., blood plasma, CSF, and urine) and brain tissue. Method accuracy was within 90-106% of validated NIST reference plasma concentrations for the panel of measured amino acids. Amino acid and acylcarnitine extraction recoveries were 87-100% on average, depending on the concentration range spiked. The coefficient of variation (CV) was 1-10% and 1-25% for intra- and interday measurements, respectively, with the highest CVs for the metabolites at the limit of quantification, depending on the biofluid. Acylcarnitine and amino acid signatures or chemical composition barcodes of the different biofluids and human brain tissue were acquired and biofluid- and tissue-associated differences were discussed in the context of their respective physiological roles. Significant differences were observed in the amino acid profiles, whereas acylcarnitine composition did not show biofluid-characteristic or brain region-specific pattern. The retrospective exploration of full-scan all-ion-fragmentation data allowed us to extract the information on unsaturated and hydroxylated acylcarnitine species, amines, and purine and pyrimidine metabolites. This merged targeted and untargeted approach provides an innovative strategy for simultaneous and comprehensive assessment of acylcarnitine and amino acid metabolism in clinical research studies using relevant biofluids and tissue extracts.
- Published
- 2019
25. Dataset-Mechanistic insights into bacterial metabolic reprogramming from omics-integrated genome-scale models
- Author
-
Noushin Hadadi, Vikash Pandey, Anush Chiappino-Pepe, Marian Morales, Hector Gallart-Ayala, Florence Mehl, Julijana Ivanisevic, Vladimir Sentchilo, and Jan R. van der Meer
- Abstract
Data needed to reproduce the results from the manuscript "Mechanistic insights into bacterial metabolic reprogramming from omics-integrated genome-scale models" byNoushin Hadadi, Vikash Pandey, Anush Chiappino-Pepe, Marian Morales, Hector Gallart-Ayala, Florence Mehl, Julijana Ivanisevic, Vladimir Sentchilo and Jan R. van der Meer. The dataset includes: Models folder that contains TFA reconstructions/models as well as REMI models where we integrated different type of constraints based on gene expression data and metabolomics data using the REMI method. We provide scripts and simulation data so that one can reproduce the reported results. Scripts folder contains scripts for generating models, alternative analysis, and biomass building blocks (BBBs) analysis. Stationary vs exponential comparison Sand vs liquid comparison BBB Analysis Simdata folder contains the mat files of alternative solutions obtained from REMi models, BBB analysis for exponential vs stationary and sand vs liquid as well as the edgR analysis results of the differentially expressed genes.
- Published
- 2019
- Full Text
- View/download PDF
26. Mechanistic insights into bacterial metabolic reprogramming from omics-integrated genome-scale models
- Author
-
Noushin Hadadi, Jan Roelof van der Meer, Hector Gallart-Ayala, Julijana Ivanisevic, Florence Mehl, Anush Chiappino-Pepe, Marian Morales, Vladimir Sentchilo, and Vikash Pandey
- Subjects
Growth phase ,pathways ,Metabolic reprogramming ,Microbial metabolism ,Genome scale ,Systems analysis ,Pseudomonas veronii ,Computational biology ,Biology ,Genome ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Metabolic modeling ,Microbiome ,lcsh:QH301-705.5 ,030304 developmental biology ,0303 health sciences ,Applied Mathematics ,tool ,Dynamic population ,biology.organism_classification ,Environmental sciences ,Computer Science Applications ,lcsh:Biology (General) ,Modeling and Simulation ,network ,Adaptation ,030217 neurology & neurosurgery - Abstract
Understanding the adaptive responses of individual bacterial strains is crucial for microbiome engineering approaches that introduce new functionalities into complex microbiomes, such as xenobiotic compound metabolism for soil bioremediation. Adaptation requires metabolic reprogramming of the cell, which can be captured by multi-omics, but this data remains formidably challenging to interpret and predict. Here we present a new approach that combines genome-scale metabolic modeling with transcriptomics and exometabolomics, both of which are common tools for studying dynamic population behavior. As a realistic demonstration, we developed a genome-scale model of Pseudomonas veronii 1YdBTEX2, a candidate bioaugmentation agent for accelerated metabolism of mono-aromatic compounds in soil microbiomes, while simultaneously collecting experimental data of P. veronii metabolism during growth phase transitions. Predictions of the P. veronii growth rates and specific metabolic processes from the integrated model closely matched experimental observations. We conclude that integrative and network-based analysis can help build predictive models that accurately capture bacterial adaptation responses. Further development and testing of such models may considerably improve the successful establishment of bacterial inoculants in more complex systems.
- Published
- 2019
27. OP0053 CERAMIDES AND DIHYDROCERAMIDES LEVELS ARE ASSOCIATED WITH THE INFLAMMATORY RESPONSE IN A MURINE MODEL OF GOUT
- Author
-
Nicola L. Harris, Florence Mehl, Véronique Chobaz, Hector Gallart-Ayala, and Alexander So
- Subjects
medicine.medical_specialty ,Normal diet ,medicine.drug_class ,business.industry ,Antibiotics ,Inflammation ,medicine.disease ,Sphingolipid ,Gout ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Hyperuricemia ,medicine.symptom ,Metabolic syndrome ,business - Abstract
Background The metabolic syndrome is strongly associated with gout and hyperuricemia in man. Patients with gout commonly report acute flares after eating particular foods and it is suspected that metabolic changes, apart from serum urate levels, influence the triggering of the inflammatory response to MSU crystals. Objectives By studying the metabolic changes that impact on the response to MSU crystals in a murine model of gout, we hope to identify the dietary effect on metabolites that are associated with the inflammatory response to MSU crystals. Methods Male mice (C57Bl/6) were fed either a normal diet (ND) or high fat diet HFD (DIO D12492) for >6 weeks. During the last 4 weeks of feeding, half the mice in each group were treated with antibiotics (Enrofloxacin 0.25% + co-amoxicillin) to induce a germ-free state. At day 0, mice were injected i-p with 1mg of MSU crystals. Mice were sacrificed 6h after i-p injection. Serum, plasma and peritoneal exudate samples were collected at sacrifice and plasma obtained 3 weeks before sacrifice. Untargeted and targeted liquid chromatography – mass spectrometry based-metabolomics approach was performed on serum and plasma samples. IL1 and IL6 were measured in serum and peritoneal exudates by ELISA. Animal experimental authorization was obtained for these experiments. Results Mice fed a HFD had a greater serum and peritoneal IL6 response to MSU. In an untargeted analysis, multiple metabolic alterations were observed related to diet. Targeted analyses of sphingolipids were performed. Both diet and inflammation (MSU injection) altered plasma sphingolipid levels. No effect of antibiotics was observed. MSU injection induced marked changes in the sphingolipid profile (38.2% of explained variance), while diet had a lesser effect (16.2% of explained variance). Mice fed an HFD had significantly higher serum IL6 before and peritoneal IL6 levels after MSU injection than mice fed a ND. DhCer C16:0 and Cer C16:0 levels decreased significantly after MSU injection. Pre-MSU levels of DhCer C16:0 and Cer C16:0 showed significantly negative correlations with IL6p levels after i-p injection in HFD animals. Conclusion The sphingolipid profile was significantly changed by diet and inflammation. In mice given a HFD, the levels of particular ceramides were significantly correlated with subsequent inflammatory response as assessed by IL6 secretion, suggesting that they may play a role in modulating the inflammatory response to MSU. These same ceramides and their derivatives have been linked to susceptibility to diabetes and cardiovascular diseases1,2. Further investigation of these sphingolipids in gout in man is warranted. References [1] Wigger L, et al. Cell Rep. 2017 Feb 28;18(9):2269-2279. doi: 10.1016/j.celrep.2017.02.019 [2] Summers SA. Cell Metab. 2018 Feb 6;27(2):276-280. doi: 10.1016/j.cmet.2017.12.003 Disclosure of Interests Alexander So Consultant for: SOBI, Grunenthal, Speakers bureau: Grunenthal, Florence Mehl: None declared, Nicola Harris: None declared, Veronique Chobaz: None declared, Hector Gallart-Ayala: None declared
- Published
- 2019
28. Longitudinal monitoring of endogenous steroids in human serum by UHPLC-MS/MS as a tool to detect testosterone abuse in sports
- Author
-
Martial Saugy, Raul Nicoli, Norbert Baume, Federico Ponzetto, Florence Mehl, Julien Boccard, and Serge Rudaz
- Subjects
Serum ,Adult ,Male ,medicine.medical_specialty ,Urinary system ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Endogeny ,Urine ,Pharmacology ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,Steroid ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Multiway data analysis ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Humans ,Testosterone ,Longitudinal Studies ,Circadian rhythm ,Androstenedione ,Transdermal ,Doping in Sports ,ddc:615 ,Steroid profile ,Chemistry ,010401 analytical chemistry ,Testosterone doping ,UHPLC-MS/MS ,Steroids ,Substance Abuse Detection ,Testosterone (patch) ,0104 chemical sciences ,Endocrinology - Abstract
The detection of testosterone abuse in sports is routinely achieved through the 'steroidal module' of the Athlete Biological Passport by GC-MS(/MS) quantification of selected endogenous anabolic androgenic steroids (EAAS) from athletes' urines. To overcome some limitations of the "urinary steroid profile" such as the presence of confounding factors (ethnicity, enzyme polymorphism, bacterial contamination, and ethanol), ultrahigh performance liquid chromatography (UHPLC) measurements of blood concentrations of testosterone, its major metabolites, and precursors could represent an interesting and complementary strategy. In this work, two UHPLC-MS/MS methods were developed for the quantification of testosterone and related compounds in human serum, including major progestogens, corticoids, and estrogens. The validated methods were then used for the analyses of serum samples collected from 19 healthy male volunteers after oral and transdermal testosterone administration. Results from unsupervised multiway analysis allowed variations of target analytes to be assessed simultaneously over a 96-h time period. Except for alteration of concentration values due to the circadian rhythm, which concerns mainly corticosteroids, DHEA, and progesterone, significant variations linked to the oral and transdermal testosterone administration were observed for testosterone, DHT, and androstenedione. As a second step of analysis, the longitudinal monitoring of these biomarkers using intra-individual thresholds showed, in comparison to urine, significant improvements in the detection of testosterone administration, especially for volunteers with del/del genotype for phase II UGT2B17 enzyme, not sensitive to the main urinary marker, T/E ratio. A substantial extension of the detection window after transdermal testosterone administration was also observed in serum matrix. The longitudinal follow-up proposed in this study represents a first example of 'blood steroid profile' in doping control analysis, which can be proposed in the future as a complement to the 'urinary module' for improving steroid abuse detection capabilities.
- Published
- 2015
29. P4‐193: IDENTIFICATION AND COMPREHENSIVE CHARACTERIZATION OF CNS AND SYSTEMIC METABOLIC ALTERATIONS IN ALZHEIMER'S DISEASE
- Author
-
Tony Teav, Hector Gallart-Ayala, Aikaterini Oikonomidi, Hugues Henry, Vera van der Velpen, Julijana Ivanisevic, Julius Popp, Florence Mehl, Gwendoline Peyratout, and Ioana Konz
- Subjects
Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,business.industry ,Health Policy ,Medicine ,Identification (biology) ,Neurology (clinical) ,Disease ,Computational biology ,Geriatrics and Gerontology ,business - Published
- 2018
30. A global HILIC-MS approach to measure polar human cerebrospinal fluid metabolome: Exploring gender-associated variation in a cohort of elderly cognitively healthy subjects
- Author
-
Gwendoline Peyratout, Julijana Ivanisevic, Vera van der Velpen, Tony Teav, Florence Mehl, Julius Popp, Aikaterini Oikonomidi, Ioana Konz, and Hector Gallart-Ayala
- Subjects
0301 basic medicine ,Male ,Taurine ,Metabolite ,Pharmacology ,01 natural sciences ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,ddc:616.89 ,Cerebrospinal fluid ,Metabolomics ,Metabolome ,Environmental Chemistry ,Humans ,Cognitive Dysfunction ,Spectroscopy ,Aged ,Cerebrospinal Fluid ,Body fluid ,Sex Characteristics ,Fatty acid metabolism ,Hydrophilic interaction chromatography ,010401 analytical chemistry ,Middle Aged ,Healthy Volunteers ,0104 chemical sciences ,030104 developmental biology ,chemistry ,Female ,Chromatography, Liquid - Abstract
Cerebrospinal fluid (CSF) is a key body fluid that maintains the homeostasis in central nervous system (CNS). As a biofluid whose content reflects the brain metabolic activity, the CSF has been profiled in the context of neurological diseases to provide novel insights into the disease mechanisms. However, a global high-throughput approach to measure a broad diversity of polar metabolites present in CSF is lacking. Although still perceived as challenging and less reproducible, hydrophilic interaction liquid chromatography (HILIC) has recently evolved to offer the unprecedented coverage capacity of water-soluble metabolome. Here, we present a global HILIC high-resolution mass spectrometry-based (HRMS) approach that combines the profiling in acidic pH ESI (+) and basic pH ESI (-) mode to extend the coverage of CSF polar metabolome. This approach allowed us to annotate and measure a broad range of central carbon metabolites (implicated in glycolysis, TCA cycle, nucleotide, amino acid and fatty acid metabolism) in CSF collected from cognitively healthy elderly volunteers (n = 32), using a single extraction method. Metabolite annotation was achieved using the accurate mass, RT and MS/MS criteria, allowing for the characterization of 146 measurable metabolites. Exploration of characterized individual CSF profiles allowed for a discovery of intriguing gender-associated differences, with significantly higher acylcarnitine levels in men and higher taurine levels women. With this case study, we demonstrate the value of combined HILIC ESI ± HRMS profiling to assess CSF metabolome in clinical research studies.
- Published
- 2018
31. Integrating metabolomic data from multiple analytical platforms for a comprehensive characterisation of lemon essential oils
- Author
-
Estelle Delort, Jean-Luc Wolfender, Lucie Baroux, Florence Mehl, Julien Boccard, Philippe Merle, Guillaume Marti, Horst Sommer, and Serge Rudaz
- Subjects
Chemometrics ,Metabolomics ,Untargeted metabolomics ,Chemistry ,Flavour ,Organoleptic ,Lemon oil ,Context (language use) ,General Chemistry ,Biochemical engineering ,Food Science ,Extractor - Abstract
Citrus cold pressed oils are of great importance to the flavour and fragrance industry. Because of their high added value, careful attention must be paid to ensure the oils’ genuineness and authenticity. Characterising their chemical complexity in a holistic perspective constitutes a potent way to relate specific compounds to the organoleptic properties of interest and to assess their quality. In this context, a complete characterisation using untargeted metabolomics represents an analytical challenge. The present study takes advantage of multiblock data modelling to integrate heterogeneous signals collected from GC-FID, 1H-NMR, UHPLC-TOF/MS- (negative mode) and UHPLC-TOF/MS+ (positive mode) platforms to obtain a complete characterisation of 64 samples of cold pressed lemon oil (CPLO). Two statistical approaches (MB-PLS-DA and Consensus OPLS-DA) were used to classify the samples according to their extraction processes [i.e. Sfumatrice, Food Machinery Corporation Inline Extractor (FMC), Brown Oil Extractor (BOE), Pelatrice, or mixed FMC + Pelatrice]. Furthermore, the multiblock strategy allows links between variables from different analytical methods to be drawn easily and facilitates the identification of compounds. Because citrus oils extracted using the Sfumatrice process constitute the reference quality from an organoleptic point of view, these samples were characterised thoroughly and are reported to contain less fatty acids but more sesquiterpenes and furocoumarins compared with products obtained using other extraction processes.
- Published
- 2014
32. Comprehensive profiling and marker identification in non-volatile citrus oil residues by mass spectrometry and nuclear magnetic resonance
- Author
-
Jean-Luc Wolfender, Julien Boccard, Benjamin Debrus, Guillaume Marti, Horst Sommer, Laurence Marcourt, Florence Mehl, Philippe Merle, Lucie Baroux, Estelle Delort, and Serge Rudaz
- Subjects
Citrus ,Magnetic Resonance Spectroscopy ,Citropten ,Mass spectrometry ,Mass Spectrometry ,Analytical Chemistry ,Chemometrics ,chemistry.chemical_compound ,Metabolomics ,Plant Oils ,Flavor ,ddc:615 ,Cold-pressed lemon oils ,Chromatography ,Discriminant Analysis ,1H NMR ,General Medicine ,Classification ,Bergamottin ,Furocoumarins ,UHPLC–TOF-MS ,chemistry ,Geographic origin ,Proton NMR ,MS–NMR correlation analysis ,Biomarkers ,Food Science - Abstract
The detailed characterization of cold-pressed lemon oils (CPLOs) is of great importance for the flavor and fragrance (FF) industry. Since a control of authenticity by standard analytical techniques can be bypassed using elaborated adulterated oils to pretend a higher quality, a combination of advanced orthogonal methods has been developed. The present study describes a combined metabolomic approach based on UHPLC-TOF-MS profiling and (1)H NMR fingerprinting to highlight metabolite differences on a set of representative samples used in the FF industry. A new protocol was set up and adapted to the use of CPLO residues. Multivariate analysis based on both fingerprinting methods showed significant chemical variations between Argentinian and Italian samples. Discriminating markers identified in mixtures belong to furocoumarins, flavonoids, terpenoids and fatty acids. Quantitative NMR revealed low citropten and high bergamottin content in Italian samples. The developed metabolomic approach applied to CPLO residues gives some new perspectives for authenticity assessment.
- Published
- 2014
33. Hemisynthesis and odour properties of δ-hydroxy-γ-lactones and precursors derived from linalool
- Author
-
Florence Mehl, Robert Faure, Emile M. Gaydou, Nicolas Vanthuyne, and Isabelle Bombarda
- Subjects
chemistry.chemical_classification ,Allylic rearrangement ,Natural product ,Stereochemistry ,General Medicine ,Food chemistry ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Linalool ,Dihydroxylation ,Molecule ,Organic chemistry ,Sharpless asymmetric dihydroxylation ,Lactone ,Food Science - Abstract
γ -Lactones are aromatic molecules which constitute the aroma or flavour of many natural products. Functionalized γ -lactones have attracted attention in recent years due to their synthetic importance as building blocks in bioactive natural product synthesis. Furthermore the δ -hydroxy- γ -lactone motif is the core structure of bioactive natural products. To synthesise lactones, an attractive method consists of subjecting β , γ - or γ , δ -unsaturated ester to a Sharpless asymmetric dihydroxylation. Hemisynthesis of such lactones was here realised in two steps from a monoterpenic alcohol, linalool. First, the allylic terpenol was submitted to a Johnson–Claisen rearrangement to produce γ , δ -unsaturated esters. These γ , δ -unsaturated esters were then subjected to an asymmetric dihydroxylation to give the corresponding γ , δ -unsaturated dihydroxyesters which can directly cyclise to the δ -hydroxy- γ -lactones. Five new products were isolated and characterised by 1D- and 2D-NMR. The odour evaluation of lactones and their precursors revealed interesting properties.
- Published
- 2010
34. Optimization of the Microwave-Assisted Ortho Ester Claisen Rearrangement: Application to Monoterpenols
- Author
-
Emile M. Gaydou, Carine Franklin, Isabelle Bombarda, and Florence Mehl
- Subjects
Claisen rearrangement ,Solvent ,chemistry.chemical_compound ,Chemistry ,Perillyl alcohol ,Reagent ,Organic Chemistry ,Nerol ,Organic chemistry ,Sigmatropic reaction ,Microwave assisted ,Carroll rearrangement - Abstract
Two monoterpenols, perillyl alcohol and nerol, have been converted into their γ,δ-unsaturated ester derivatives following a modified process of microwave-assisted ortho ester Claisen rearrangement. The yields obtained (>90%) are better than those previously obtained. The optimized process needs less reaction time (5 min), smaller amount of reagent, and no solvent.
- Published
- 2010
35. Exploring the hidden biosynthetic potential of fungi – Evaluation of epigenetic modifications through metabolomics
- Author
-
Florence Mehl, Katia Gindro, M Perisic, YS Wong, J-L Wolfender, Julien Boccard, and PM Allard
- Subjects
Pharmacology ,Metabolomics ,Complementary and alternative medicine ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Computational biology ,Epigenetics ,Biology ,Bioinformatics ,Analytical Chemistry - Published
- 2014
36. Comparison of liquid chromatography and supercritical fluid chromatography coupled to compact single quadrupole mass spectrometer for targeted in vitro metabolism assay
- Author
-
Davy Guillarme, Dany Spaggiari, Szabolcs Fekete, Vincent Desfontaine, Florence Mehl, Serge Rudaz, and Alexandre Grand-Guillaume Perrenoud
- Subjects
Analyte ,Chromatography ,Chemistry ,In vitro metabolism ,Organic Chemistry ,Analytical chemistry ,Chromatography, Supercritical Fluid ,General Medicine ,In Vitro Techniques ,Biochemistry ,High-performance liquid chromatography ,Method development ,Analytical Chemistry ,Triple quadrupole mass spectrometer ,Sequential method ,Cytochrome P-450 Enzyme System ,Tandem Mass Spectrometry ,Supercritical fluid chromatography ,Quadrupole mass analyzer ,Chromatography, High Pressure Liquid ,Chromatography, Liquid - Abstract
The goal of this study was to evaluate the combination of powerful chromatographic methods and compact single quadrupole MS device for simple in vitro cytochrome P450 (CYP) inhibition assay, instead of more expensive triple quadrupole MS/MS detectors. For this purpose, two modern chromatographic approaches (ultra-high pressure liquid chromatography (UHPLC) and ultra-high performance supercritical fluid chromatography (UHPSFC)) were tested in combination with simple MS detector. To show the applicability for an in vitro CYP-mediated metabolism assay using the cocktail approach, a method was first developed in UHPLC–MS to separate a mixture of 8 probe substrates and 8 CYP-specific metabolites. A screening procedure was initially applied to determine the best combination of a column, an organic modifier and a mobile-phase pH, followed by fine tuning of the conditions ( i.e. , gradient profile, temperature and pH) using HPLC modelling software. A similar sequential method development procedure was also evaluated for UHPSFC–MS. For method development, where peak tracking is necessary, the use of single quadrupole MS was found to be extremely valuable for following the investigated analytes. Ultimately, a baseline separation of the 16 compounds was achieved in both UHPLC–MS and UHPSFC–MS with an analysis time of less than 7 min. In a second series of experiments, sensitivity was evaluated, and LOQ values were between 2 and 100 ng/mL in UHPLC–MS, while they ranged from 2 to 200 ng/mL in UHPSFC–MS. Based on the concentrations employed for the current in vitro phase I metabolism assay, these LOQ values were appropriate for this type of application. Finally, the two analytical methods were applied to in vitro CYP-dependent metabolism testing. Two well-known phytochemical inhibitors, yohimbine and resveratrol, were investigated, and reliable conclusions were drawn from these experiments with both UHPLC–MS and UHPSFC–MS. At the end, the proposed strategy of optimized chromatography combined with simple MS device has been shown to potentially compete with the widely used combination of generic chromatography and highly selective MS/MS device for simple in vitro CYP inhibition assays. In addition, our analytical method may be easier to use in a routine environment; the instrument cost is significantly reduced and the two developed methods fit for purpose.
- Published
- 2014
37. Chemometric analysis of mid infrared and gas chromatography data of Indonesian nutmeg essential oils
- Author
-
Florence Mehl, Josiane Molinet, Nathalie Dupuy, Yveline Le Dréau, Fanny Nanlohy, Jacky Kister, Laboratoire d'Instrumentation et Sciences Analytiques (LISA), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Chromatography ,biology ,010405 organic chemistry ,Chemistry ,Chemometric treatment ,010401 analytical chemistry ,Mid infrared ,Nutmeg ,Nutmeg essential oil ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,law.invention ,13. Climate action ,law ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,Geographical origin ,MID-IR ,GC–MS ,Gas chromatography ,Maturity ,Gas chromatography–mass spectrometry ,Agronomy and Crop Science ,Essential oil - Abstract
International audience; Nutmeg, provided by tree native to Moluccas, is widely interesting for Indonesia essential oil production.21 hydrocarbon and oxygenated compounds are controlled by industrial perfumers in nutmeg samples.Samples of nutmeg essential oils (n = 26) from different geographic origins (Sanger, Siau and Minahasa forthe Sulawesi region and Ambon and Ternate for little islands of the Molucca region) show high variationof concentrations of these compounds. The evolution of composition during the extraction of essentialoil was studied and has shown the importance of this parameter for the nutmeg essential oil quality.Chemometric treatment of gas chromatographic–mass spectrometry (GC–MS) data was assessed forthe differentiation of geographical origin and maturity of the nutmeg. Results were compared to thoseobtained by MID-IR analysis. Chemometric MID-IR spectra treatments conduce to similar results thanthose obtained by GC–MS which is a time consuming analytical technique. Therefore, MID-IR associatedto chemometric analyses constitutes a robust and helpful fast method for authentication of nutmegessential oils.
- Published
- 2013
38. Differentiation of lemon essential oil based on volatile and non-volatile fractions with various analytical techniques: a metabolomic approach
- Author
-
Jean-Luc Wolfender, Vilfredo Raymo, Philippe Merle, Guillaume Marti, Horst Sommer, Maria Inés Velazco, Florence Mehl, Estelle Delort, Julien Boccard, Serge Rudaz, Benjamin Debrus, and Lucie Baroux
- Subjects
Chemometrics OPLS ,Citrus ,Magnetic Resonance Spectroscopy ,Argentina ,Gc fid ms ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,law.invention ,Chemometrics ,Metabolomics ,law ,GC-FID-MS ,Oils, Volatile ,Plant Oils ,Food science ,Essential oil ,Mathematics ,ddc:615 ,Cold-pressed lemon oils ,Volatile Organic Compounds ,Chromatography ,1H-NMR ,Lemon oil ,Discriminant Analysis ,General Medicine ,Classification ,Italy ,Spain ,Geographic origin ,Multivariate Analysis ,UHPLC-TOF-MS ,Production processes ,FT-MIR ,Food Science - Abstract
Due to the importance of citrus lemon oil for the industry, fast and reliable analytical methods that allow the authentication and/or classification of such oil, using the origin of production or extraction process, are necessary. To evaluate the potential of volatile and non-volatile fractions for classification purposes, volatile compounds of cold-pressed lemon oils were analyzed, using GC-FID/MS and FT-MIR, while the non-volatile residues were studied, using FT-MIR, (1)H-NMR and UHPLC-TOF-MS. 64 Lemon oil samples from Argentina, Spain and Italy were considered. Unsupervised and supervised multivariate analyses were sequentially performed on various data blocks obtained by the above techniques. Successful data treatments led to statistically significant models that discriminated and classified cold-pressed lemon oils according to their geographic origin, as well as their production processes. Studying the loadings allowed highlighting of important classes of discriminant variables that corresponded to putative or identified chemical functions and compounds.
- Published
- 2012
39. ChemInform Abstract: Optimization of the Microwave-Assisted Orthoester Claisen Rearrangement: Application to Monoterpenols
- Author
-
Isabelle Bombarda, Florence Mehl, Emile M. Gaydou, and Carine Franklin
- Subjects
Claisen rearrangement ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,General Medicine ,Orthoester ,Microwave assisted - Published
- 2010
40. Synthesis and in vitro evaluation of tropane halogenated-derivatives against malaria, sleeping sickness, chagas disease and leishmaniasis
- Author
-
Paul Cos, Sylvian Cretton, Yves Allenbach, Philippe Christen, Louis Maes, Trixie Ann Bartholomeusz, An Matheeussen, and Florence Mehl
- Subjects
Chagas disease ,Erythrocytes ,Halogenation ,Stereochemistry ,Acylation ,Trypanosoma cruzi ,Plasmodium falciparum ,Trypanosoma brucei brucei ,Antiprotozoal Agents ,Trypanosoma brucei ,Antimalarials ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Cricetinae ,parasitic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Leishmania infantum ,Cells, Cultured ,biology ,Pharmacology. Therapy ,Tropane ,Fibroblasts ,medicine.disease ,biology.organism_classification ,Trypanocidal Agents ,Chemistry ,chemistry ,Macrophages, Peritoneal ,Tropanes - Abstract
A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3α-ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 µM), 8 (IC50 = 6.7 µM), 5 (IC50 = 8.1 µM) and 7 (IC50 = 9.5 µM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 µM), 11 (IC50 = 5.6 µM) and 9 (IC50 = 5.8 µM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5.
41. Evaluation of chemical contamination of surfaces during the preparation of chemotherapies in 24 hospital pharmacies
- Author
-
Farshid Sadeghipour, Florence Mehl, Lucie Bouchoud, Pascal Bonnabry, Marianne Gex-Fabry, M. Mattiuzzo, Susanne Nussbaumer, Serge Rudaz, Ludivine Falaschi, and Sandrine Fleury-Souverain
- Subjects
Toxicology ,ddc:615 ,medicine.medical_specialty ,Biosafety ,business.industry ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Contamination ,Hospital pharmacy ,business ,Surgery ,Epirubicin ,medicine.drug - Abstract
Purpose To evaluate the chemical contamination of surfaces by cytotoxic agents during preparation of injectable chemotherapies in hospital pharmacies. Methods 526 wipe samples collected in 24 Swiss hospital pharmacies were analysed using a validated liquid chromatography–mass spectrometry/mass spectrometry method able to quantify 10 cytotoxic agents: cytarabine, gemcitabine, cyclophosphamide, ifosfamide, methotrexate, etoposide phosphate, irinotecan, doxorubicin, epirubicin and vincristine. Information on chemotherapies produced, equipment and production processes used were collected from all the hospital pharmacies on a voluntary basis in order to investigate their association with contamination rates. Results In two pharmacies, no trace of the 10 cytotoxic agents was detected. Chemical contamination was found in the other 22 hospital pharmacies, with combined total contamination of the 10 cytotoxic agents ranging from 8 ng to more than 41 000 ng per sample. Most contaminated samples came from inside biosafety cabinets, but some came from other clean room areas and logistics rooms. Statistically significant associations were observed between contamination rates and sampling locations, the number of chemotherapies prepared per year and types of cleaning solutions used. Conclusions This study demonstrated that most of the hospital pharmacies tested had some contamination of surfaces by different cytotoxic agents. Even if highest levels of contamination were mainly detected inside biosafety cabinets, technicians were also exposed to cytotoxic agents detected in logistical and storage areas. Protective measures should therefore be maintained or even reinforced in these areas in order to limit technicians' risks of exposure when handling cytotoxic products.
42. Comparison of liquid chromatography and supercritical luidchromatography coupled to compact single quadrupole massspectrometer for targeted in vitro metabolism assay
- Author
-
Spaggiari, Dany, florence mehl, Desfontaine, Vincent, Grand-Guillaume-Perrenoud, Alexandre, Fekete, Szabolcs, Rudaz, Serge, and Guillarme, Davy
- Subjects
MS-supported automated method development ,Cocktail approach ,ddc:615 ,UHPLC–MS ,Compact single quadrupolea ,In vitro metabolism ,UHPSFC–MS - Abstract
The goal of this study was to evaluate the combination of powerful chromatographic methods and com-pact single quadrupole MS device for simple in vitro cytochrome P450 (CYP) inhibition assay, insteadof more expensive triple quadrupole MS/MS detectors. For this purpose, two modern chromatographicapproaches (ultra-high pressure liquid chromatography (UHPLC) and ultra-high performance supercrit-ical fluid chromatography (UHPSFC)) were tested in combination with simple MS detector. To show theapplicability for an in vitro CYP-mediated metabolism assay using the cocktail approach, a method wasfirst developed in UHPLC–MS to separate a mixture of 8 probe substrates and 8 CYP-specific metabolites.A screening procedure was initially applied to determine the best combination of a column, an organicmodifier and a mobile-phase pH, followed by fine tuning of the conditions (i.e., gradient profile, temper-ature and pH) using HPLC modelling software. A similar sequential method development procedure wasalso evaluated for UHPSFC–MS. For method development, where peak tracking is necessary, the use ofsingle quadrupole MS was found to be extremely valuable for following the investigated analytes. Ulti-mately, a baseline separation of the 16 compounds was achieved in both UHPLC–MS and UHPSFC–MSwith an analysis time of less than 7 min. In a second series of experiments, sensitivity was evaluated,and LOQ values were between 2 and 100 ng/mL in UHPLC–MS, while they ranged from 2 to 200 ng/mLin UHPSFC–MS. Based on the concentrations employed for the current in vitro phase I metabolism assay,these LOQ values were appropriate for this type of application. Finally, the two analytical methods wereapplied to in vitro CYP-dependent metabolism testing. Two well-known phytochemical inhibitors, yohim-bine and resveratrol, were investigated, and reliable conclusions were drawn from these experimentswith both UHPLC–MS and UHPSFC–MS. At the end, the proposed strategy of optimized chromatographycombined with simple MS device has been shown to potentially compete with the widely used combi-nation of generic chromatography and highly selective MS/MS device for simple in vitro CYP inhibitionassays. In addition, our analytical method may be easier to use in a routine environment; the instrumentcost is significantly reduced and the two developed methods fit for purpose.
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.