Day 2 :
Keynote Forum
Choon Nam ONG
National University of Singapore, Singapore
Keynote: Plasma metabolic profiles are associated with habitual dietary patterns
Time : 09:00-09:30
Biography:
Choon Nam ONG is the Director of the NUS Environmental Research Institute (NERI) and a professor at the Saw Swee Hock School of Public Health, National University of Singapore. He has published more than 300 papers in international peer-reviewed journals with an h-index of 75, and over 17,000 citations. His main research interest is Environmental Health Sciences and teaches in Toxicology and Environment Health, and nursing a lifelong passion of all matters related to environment on health. Since 1985, he has served as a consultant to the World Health Organization (WHO) on many occasions and was involved in 12 of its Health Criteria publications.He is an editorial board member of several international journals on environment and sustainability. He is a visiting professor to several overseas universities and serves as a Scientific Advisor to the China Center of Disease Control and Prevention (CDC). He was the recipient of Astra-Zeneca American Toxicology Society Award, 2002. Dr Ong also served as an advisor to the OECD, US National Water Research Institute, and has been consulted often by international health agencies on issues related to environmental health. He has been a member of the WHO Guidelines for Drinking Water Quality Expert Panel since 2003. His research group currently focuses on the use of metabolomics as a technology platform for biomedical and environmental research.
Abstract:
Dietary factors play important roles in human metabolism and influence the status of health. So far, few human studies have been focused on how diet affects the palsma metabolome. In this study, we investigated the differences in plasma metabolic profiles between habitual high meat and seafood (HMS) eaters and low meat and seafood (LMS) eaters using mass spectrometry-based metabolomics methods, aimed to reveal the link between plasma metabolic profiles and habitual dietary intake. Plasma metabolites were profiled and compared between 83 HMS eaters and 82 LMS eaters from a healthy cohort in Singapore. A total of 49 differential metabolites were found between the two dietary groups. The difference was mainly reflected by higher concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and AA/EPA/DHA-content phospholipids in HMS eaters than in LMS eaters, although there were also differences in levels of other metabolites, such as D-glucose, glycine, and urea. We observed strong correlations across a wide range of plasma metabolites and food variables. The strongest association was found for DHA levels with fish consumption (r = 0.535). Our study demonstrates that mass spectrometry-based metabonomics is a valid technique to dietary pattern analysis, and the findings illustrates that plasma metabolic profiles were associated with habitual diets.
Keynote Forum
Jian Zhi Hu
Pacific Northwest National Laboratory, USA
Keynote: NMR Metabolomics Studies of Mice Exposed to Ionizing Radiation
Time : 09:31-10:00
Biography:
Jian Zhi Hu received his Ph.D in 1994 and is currently a senior staff scientist and principal investigator of Pacific Norwest National Laboratory. He has published more than 170 papers in peer reviewed journals, delivered a large number of presentations, received two US R&D 100 awards and 10 US patents.
Abstract:
Ionizing radiation can be fatal to a living system and is a growing concern in the fields of medicine where diagnostic imaging techniques using X-rays are frequently used on patients, the space exploration where astronauts have a great chance of exposing to high energy space particle radiation and nuclear energy generation where an unfortunate accident may happen. In this work, NMR based metabolomics combined with multivariate data analysis are used to evaluate the metabolic changes in the C57BL/6 mice 4 and 11 days post whole body 3.0 Gy and 7.8 Gy gamma radiations, including proton irradiation, using various organs (liver, spleen, lung and heart) and blood. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) are employed for classification and identification of potential metabolite markers associated with gamma irradiation. Two different strategies for NMR spectral data reduction, i.e., spectral binning and spectral deconvolution are compared with normalization to constant sum and unit weight before multivariate data analysis. It is found that the combination of spectral deconvolution and normalization to unit weight is the best way for identifying discriminatory metabolites between the irradiation and control groups. Using this method, metabolite markers responsible for gamma radiation are identified on each organ and blood, separately. The possibility of accessingindividual organ injury due to ionizing radiation via minimally invasive blood will be discussed.
- Track : 17 Analytical Platforms in Metabolomics
Track : 19 Data Analysis & Systems Biology
Session Introduction
Kazuhiro Ogata
Yokohama City University Graduate School of Medicine, Japan
Title: Molecular Mechanism for modulationof a multiple transcriptionfactorcomplexformed on enhancer site upon phosphorylation
Time : 10:00-10:20
Biography:
K. Ogata has completed his PhD at the age of 27 years from Yokohama City University in 1992 and postdoctoral studies from RIKEN tsukuba institute. In 1997, He became the leader of the regulation of protein function project, Kanagawa Academy of Science and Technology (KAST), and from 2001,the professor and chair person of Department of Biochemistry, Yokohama City University Graduate School of Medicine.He has published papers in JMB, PNAS, NSMB, and Cell, and had been serving as an editorial board member of BBRC (2009-2010)
Abstract:
Transcriptional regulationis a fundamental mechanism for cell proliferation and differentiation. A major player in this process is a member of transcription factors (TFs).Activities of TFs are modulated by chemical modifications such as phosphorylation through cell signaling pathways directing cell functions. Molecular mechanisms of regulation for the functional high-order assemblyconsisting of multiple TFs and enhancer DNA (enhanceosome) under cellsignaling are largely unknown. So far, we investigated changes in assembly state of an enhance osome upon a TF’s phosphorylation, using crystallographical, biophysical, and molecular dynamic alanalyses. Here, wewill illustrate the case of Ets1 in non-phosphorylated and phosphorylated forms on its target gene enhancers with or withoutits partner TFs, Runx1/CBFï¢ or Pax5, as an example. A structure-function relationship of a TF-DNA assembly and an effect by phosphorylationwill be discussed.
Takeshi Kimura
Ajinomoto Co., Inc., Japan
Title: Development and commercialization of a plasma amino acid based risk diagnosis service
Time : 10:21-10:40
Biography:
Takeshi Kimura received his BSc in Cell and Molecular Biology and PhD in Biocheistry from University of London King’s Collage and became a Visiting Fellow and then Visiting Associate at LMB, NIDDK, NIH, Bethesda, MD, USA. He joined Ajinomoto Co., Inc. in 1989 and after heading the Washingto DC. Office, Basic Safety Research Group, Quality Assurance and External Scientific Affairs Department, R&D Planning Department., he became Member of the Board and Corporate Vice President in 2013. He is a Trustee for International Life Science Institute and Research Foundation, International Advisor to the Monell Chmical Senses Center amongst other external positions
Abstract:
From observations indicating that amino acids were a convenient metabolomic subset to investigate changes in metabolism associated with various physiological states, we have developed a technology package (“AminoIndex technology”) to generate biomarkers using plasma amino acid concentration data, and have commercialized a service based on this technology. In order to achieve commercialization, various problems ranging from sample handling, throughput, standardization and follow-up services had to be overcome and some of these issues, which may be relevant to other biomarker commercialization, will be addressed in the presentation. So far, “AminoIndex technology” has been used to generate risk biomarkers for gastric, lung, colorectal, prostate and breast cancer, and more recently for pancratic cancer, and since its launch as a biomarker service in April 2011 in Japan, it has been adopted by over 1000 hospitals and clinics as an optional blood test, and has led to the receipt of various awards in Japan. Research is ongoing to add other cancer risk biomarkers as well as biomarkers for other diseases risks and recent evidence indicate the possibility of generating biomarkers to predict the risk of developing a number of diseases four years in the future. We believe that in the near future, other validated metabolites and omics data could be added to the current analytical platform, increasing discriminative power. Although there are a number of issues still needing refinement, we believe that the “AminoIndex technology” platform can play a role in tailor-made nutrition and medicine.
Darby Tien-Hao Chang
National Cheng Kung University, Taiwan
Title: Studying Conformational Changes on GDP and GTP Binding with a Novel Visualization Platform
Time : 10:41-11:00
Biography:
Tien-Hao Chang received his B.S., M.S. and Ph.D. in Computer Science and Information Engineering from National Taiwan University. Currently he is a Professor of Department of Electrical Engineering, National Cheng Kung University. Dr. Chang focuses on machine learning and Systems Biology and has developed many analytical algorithms for protein/DNA sequences, structures, binding sites and interactions. He has co-worked with researchers in various fields such as computer science, life science, pharmacy and medicine and executed many cross-filed researches. Recently, he has expanded his interest and started to collaborate with specialists of industrial design, business, finance, data science and social science.
Abstract:
In many biological processes, proteins have important interactions with various molecules such as proteins, ions or ligands. Many proteins undergo conformational changes upon these interactions, where regions with large conformational changes are critical to the interactions. Several important proteins, such as the universal translation initiation factor (IF2/eIF5B), have been observed having large conformational changes on GDP and GTP binding. This work uses a novel platform, CCProf, to analyze conformational changes of entire proteins. This study analyzes protein conformational change with nine biological features, including potential binding target site, secondary structure, conservation, disorder propensity, hydropathy propensity, sequence domain, structural domain, phosphorylation site and catalytic site. All these information are integrated into a well-aligned view so that researchers can capture important relevance between different biological features visually. This analysis help researchers to study potential causes of conformational changes. The results of this work show two flexible regions with disorder-to-order transitions. The large conformational changes of these regions help to recognize multiple binding targets.
Jaleel Kareem Ahmed
Babylon University, Iraq
Title: Using chlorophyll as gamma absorber generated from uranium coated weapons to protect Iraqi children from cancer
Time : 11:01-11:20
Biography:
Jaleel Kareem Ahmed has completed his PhD from Baghdad University. He is the Dean of the Institute of Foundry and Hammering. He has registered 8 patents with 40 published papers and 3 books. He is a member in Who is Who network. He is a reviewer in Jon Wily and Sons and Editorial Board Member of Science Publishing Group and a member in Encyclopedia of Chemistry Scientists. He has got the Iraqi Scientist Medal. Currently, he is a Professor of physical chemistry in the College of Materials Engineering , Babylon University, Iraq.
Abstract:
Chlorophyll extracted from celery using 50% water – methyl alcohol as a solvent. By this method the concentration of chlorophyll (was 21% with yellowish-green color). This solution showed strongly absorption at 400 – 210 nm and maximum was at the end of ultra violet region. This absorption appeared in water, methyl alcohol, and acetone, but strongest absorption was in water. No emission spectra was detected in the ultra-violet region which means that chlorophyll absorbs radiation and dissipate it as a heat. Several samples of the above solution was irradiated by gamma ray from cesium-137 with energy of 0.7 Mev for different intervals ( 0.5, 1, 2, 4, 24 hours). The color of the solution disappeared after two hours radiation while the pH decreases from 6.38 for non-irradiated to 4.17 after 24 hours radiation with liberation of carbon dioxide which indicates destroying of chlorophyll but the absorption at 400 – 210 nm still exists which reflects the high stability of the group magnesium-four nitrogen atoms (tetrapyrrole) its energy about 3500 kJ mol-1. Calculation showed that the dosage of two hours radiation in which color of the solution disappeared (Compton effect) was 5.6 killogray (1 gray = 1 Joule per 1 kg sample) absorbed by chlorophyll before color disappear is enough to kills 1120 people weight 75 kg each within 14 days when the whole bodies exposure at one time. The glass containers and their plastic covers of the irradiated samples for 4 and 24 hours changed their color to violet may be due to the rearrangement of their physical structures. Others interesting points will appear in the full article. Capsules used as carrier for the chlorophyll to take it by children
Shrikant Mane
Yale University School of Medicine, USA
Title: Recent advancements in Mendelian genomics and data management at the Yale Center for Genome Analysis
Time : 09:55-10:20
Biography:
Shrikant Mane completed his PhD at The University of Bombay and Postdoctoral studies from The Johns Hopkins University School of Medicine. He is the Director of Yale Center for Genome Analysis, one of the most scientifically productive and accomplished Genome Centers. He has published more than 100 papers in reputed journals and has been serving as an ad hock reviewer of several journals. He is currently one of the principle investigators of a $12 million grant from NIH/NHGRI to establish The Yale Center for Genome Analysis
Abstract:
The Yale Center for Genome Analysis (YCGA) is a state-of-the-art DNA Sequencing Center launched in 2010 to provide an open access centralized facility for services, equipment and expertise required for carrying out large-scale sequence analysis studies. Since its inception in 2010, YCGA has emerged as one of the leaders in the field of identification of disease associated genetic factors. Our group foresaw scientific opportunities for the development and use of exome sequencing in Mendelian genetics and was the first to develop the method for exome capture on the Nimblegen/Roche platform. We were also the first to demonstrate the biological utility of exome sequencing for clinical diagnostic applications. Currently, YCGA is a part of the NHGRI supported Yale Center for Mendelian Genomics that uses NGS and computational approaches to discover the genes and variants that underlie Mendelian conditions. In the last four years, the use of next-gen sequencing has led to the publications of >200 articles in peer reviewed journals, including >40 in high profile journals such as Science, Nature, Cell, New England Journal of Medicine and Nature Genetics reporting new variants in various disorders, including hypertension, autism, several types of cancers, Gaucher disease, skin disorders, and cortical malfunctions, all using exome analysis. The presentation will focus on recent discoveries in Mendelian disorders made at YCGA, its computer infrastructure and the current challenges and solutions developed for data analysis and management.
Caihong Wei
Chinese Academy of Agricultural Sciences (CAAS), China
Title: Genome-wide analysis reveals population structure and selection in Chinese indigenous sheep breeds and reveals adaptation to high- altitude hypoxia in Tibetan sheep
Biography:
Caihong Wei has completed his PhD from Gansu Agrigultrural University. She is a key specialist of National Mutton Sheep Industry Technology System, a associated research fellow and a master tutor at the Chinese Academy of Agricultural Sciences (CAAS). She has published more than 16 papers in reputed journals and two monographs.
Abstract:
Traditionally, Chinese indigenous sheep were classified geographically and morphologically into three groups: Mongolian, Kazakh and Tibetan. Herein, we evaluate the population structure and genome selection among 140 individuals from ten representative Chinese indigenous sheep breeds: Ujimqin, Hu, Tong, Large-Tailed Han and Lop breed (Mongolian group); Duolang and Kazakh (Kazakh group); and Diqing, Plateau-type Tibetan, and Valley-type Tibetan breed (Tibetan group). We analyzed the population structure using principal component analysis (PCA), STRUCTURE and a Neighbor-Joining (NJ)-tree. In PCA plot, the Tibetan and Mongolian groups were clustered as expected; however, Duolang and Kazakh (Kazakh group) were segregated. STRUCTURE analyses suggested two subpopulations: one from North China (Kazakh and Mongolian groups) and the other from the Southwest (Tibetan group). In the NJ-tree, the Tibetan group formed an independent branch and the Kazakh and Mongolian groups were mixed. We then used the di statistic approach to reveal selection in Chinese indigenous sheep breeds. Among the 599 genome sequence windows analyzed, 16 (2.7%) exhibited signatures of selection in four or more breeds. We detected three strong selection windows involving three functional genes: RXFP2, PPP1CC and PDGFD. PDGFD, one of the four subfamilies of PDGF, which promotes proliferation and inhibits differentiation of preadipocytes, was significantly selected in fat type breeds by the Rsb (across pairs of populations) approach. Two consecutive selection regions in Duolang sheep were obviously different to other breeds. One region was in OAR2 including three genes (NPR2, SPAG8 and HINT2) the influence growth traits. The other region was in OAR 6 including four genes (PKD2, SPP1, MEPE, and IBSP) associated with a milk production quantitative trait locus. We also identified known candidate genes such as BMPR1B, MSRB3, and three genes (KIT, MC1R, and FRY) that influence lambing percentage, ear size and coat phenotypes, respectively. Tibetan sheep have lived at Tibetan plateau for thousands of years. They have adapted to the extreme environment of high altitude hypoxia through a long period of natural selection. Seven sheep breeds, can be clustered highland and lowland respectively, living at different area of China. FST and XP-EHH approaches were used to identify the regions harboring local positive selection between these two groups.We found 171 SNPs containing 152 genes with signals of positive selection in the highland sheep, with 21 of these candidate genes as being associated with high-altitude adaptation. Such as EPAS1, NF1, LONP1, DPP4, SOD1, PPARG, SOCS2 are involved in responses to hypoxia. Mutations of twelve are identified in exons at EPAS1, especially, one of which happened to a quite conserved site in the EPAS1 3’UTR domain. The relationship between blood-related phenotypes and EPAS1 genotypes on additional highland sheep at this loci reveals that the homozygous mutation is associated with the improved mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular volume (MCV), which may help us to better understand physiological adaptability on Tibetan sheep. Taken together, our results not only provide the evidence on the genetic diversity of the highland sheep but also suggest potential mechanism for adaptation to hypoxia of high-altitude as well as the role of EPAS1 in the adaptive processes.
Yashwant Kumar Rao
GSVM Medical College, India
Title: Rapid analysis of hemoglobin variants in beta-thalassemia by HPLC in northern India
Biography:
Yashwant Kumar Rao has completed his MD from King George’s Medical University Lucknow UP, India. He is currently the Head of Department of Pediatrics GSVM Medical College Kanpur, a premier Medical institution of India. He has published more than 25 papers in reputed journals and has been serving as an Editorial Board Member of reputed journals.
Abstract:
Introduction: Beta-thalassemia is the most common and hereditary blood disorder worldwide, most of which are characterized by base substitution or small deletion or insertion of one or two nucleotides in the globin gene. Today due to the mixture of gene pool, this disorder is now not confined to any particular ethical group/races but each group represents its own sets of mutations. High Performance Liquid Chromatography forms a rapid, sensitive and precise method for detecting abnormal hemoglobin fractions. About 55 cases of Beta-thalassemia have been studied for various hemoglobin variants from Kanpur and adjoining areas. Material & Method: The study was performed on Agilent 1220 Infinity LC (Agilent Technologies) a High Performance Liquid Chromatography using EZChrom Elite for Beta-thalassemia. Result: Abnormal hemoglobin variants were analyzed for 55 cases of Beta-thalassemia on High Performance Liquid Chromatography. There were about 18 cases of Beta-thalassemia major and 37 cases of Beta-thalassemia carriers. The frequency observed in our study was HbA1c (0.14), HbF (0.7), HbE (0.45), HbD (0.34), HbS (0.45), and HbA2 (0.52). Conclusion: Automated High Performance Liquid Chromatography is an appropriate approach for the screening and presumptive identification of patients as well as carriers of Beta-thalassemia prior to DNA studies for definitive diagnosis.
Biography:
I have completed my M.SC. degree in medical Biochemistry since 2014 from Addis Ababa University,School of Medicine,department of Biochemistry and am working at Addis Ababa University,School of Medicine,department of Biochemistry as lecturer as well as as young researcher. I published three publication at reputable journals and doing research specially on Glycomics of Ethiopian society for biomarker of many types of cancers.
Abstract:
Glycomics refers to the broad study of complex carbohydrates, or glycans, in the form of oligosaccharide polymers, N- and O-linked glycoproteins, glycolipids, and proteoglycans. The process of adding these sugars to protein or lipid carriers is termed glycosylation. Normal physiological functions attributed to glycosylation include cellular mechanisms involving cell–cell adhesion, cell motility, inflammation, signal transduction, pathogen–host interactions, and viral entry. However, alterations to any of these processes can easily be linked to various ailments or oncogenesis and cancer progression, and similarly to other fundamental processes like embryogenesis, fertilization and stem cell differentiation. Glycomics composition and concentrations in human varies from individual to individuals since it depends on the food consumption habit, ethnicity, environmental factors and cultural diversity in continents or countries population. The aim of this study to analysis the Ethiopian normal population glycomics profile index which pave the way for new development glycomics-based clinically useful Cancer biomarker for early detection and therapeutic targets by using a variety of approaches and technologies. This research also requires extensive collaborations across institutions with different skills and facilities to accelerate glycan profile in Ethiopia which helps national cancer institute to detect and diagnose cancer at early stages. To complete this, we propose to evaluate the levels of normal glycoproteins in blood samples from healthy voluntary blood donors collected at Tikur Anbessa Specialized Hospital of Addis Ababa University (AAU), Ethiopia. Patients clinically suspected of any chronic diseases will be excluded. Blood drawn from consented normal adult persons (250 physiological persons) will be analyzed by glycobloating technologies both locally at AAU and abroad at Okayama University (Tokyo, Japan).
Mafalda Gomes
Centro Hospitalar do Porto Portugal
Title: About the Fetal Risks from Diagnostic use of Radiation during Pregnancy: a systematic review and proposal of a clinical protocol
Biography:
Mafalda Gomes has completed her Degree in Basic Health Sciences in the Faculty of Medicine of the University of Porto, the best Medical School in Portugal, in 2012. Engaged in one of the biggest Hospitals in the country, she gained clinical experience in Hospital S. João, with internships in Hospital Pedro Hispano and Póvoa de Varzim-Vila do Conde Hospital Center. In 2015 she finished her Master Degree in Medicine in the same Faculty of Medicine.
Abstract:
Aim: Analyze existing literature about the fetal risks of radiation exposure, producing a clinical protocol to guide radiation exposure in a clinical setting. Methods: An initial query was made on PubMed: “Diagnostic radiography in pregnancy AND radiation”, with the limits “published from January 1st 1993 to December 31st 2013, in English or Portuguese”. The articles that presented our aim were analyzed according to their MESH terms and created the final query: “((radiation) AND pregnancy) AND diagnostic imaging”. Research on April 15th of 2014, with the same limits, on PubMed gathered 688 articles; on SCOPUS 245 additional articles. After reading the title and abstract 298 articles remained. 179 allowed access to full text and were analyzed according to inclusion and exclusion criteria. A total of 103 articles were used and an additional one regarding In utero radiation exposure from atomic bombs. The PRISMA statement was followed. Results: Deterministic effects like pregnancy loss, congenital malformations, growth retardation and neurobehavioral abnormalities have threshold doses greater 100-200 mGy, being the risk considered negligible at 50 mGy. No diagnostic exam exceeds this limit. The most crucial time to avoid radiation exposure is from the 8th to the 15th week of gestation. The risk of carcinogenesis is slightly higher than the general population, although very similar. Intravenous contrast is discouraged, except in highly-selected patients. Conclusion: Measures to diminish radiation are essential and affect the fetal outcome. Nonionizing procedures should be considered whenever possible and every radiology center should have its own data on fetal radiation exposure.
Mohammad Reza Naghavi
University of Tehran, Iran
Title: Application of nano-particles in purification of pharmaceutical metabolites from plants
Time : 10:45-11:10
Biography:
Mohammad Reza Naghavi has completed his PhD from University of Tehran. He has published more than 130 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Abstract:
Pharmaceutical plant-derived metabolites such as Paclitaxel (Taxol), artemisinin, morphine, codeine, thebaine, etc are valuable plant-derived drugs showing activity against various human and animal diseases. Accordingly, the development of a more effective process for separation and purification of plant-derived metabolites is an important subject. Today, nano-structured materials are used in various fields including separation of materials in nanometer dimensions for water purification and chemical, food and pharmaceutical industry. The present research attempted to develop a new purification method using nano-particles, for mass production of plant-derived metabolites. The proficiency of a number of magnetic carbon-based nano-adsorbents was evaluated in pre-purification process of the crude paclitaxel extract obtained from fresh needles of yew tree (Taxus baccata L.). By considering decolorization efficiency, purity of taxol, recovery and reusability of adsorbents, Fe3O4Nps/GO (50 g/L) in dichloromethane was selected as the best medium for re-purification of paclitaxel. Our findings displayed promising applications of Fe3O4Nps/GO, as a cost effective nano-adsorbent, to provide a suitable vehicle toward improvement of paclitaxel pre-purification. This method was developed aiming at increasing yield and purity, also reducing solvent usage and the size and complexity of the HPLC operations for purification of metabolites.
- Special Session
Session Introduction
Eugenia Trushina
Mayo Clinic College of Medicine, USA
Title: Mitochondrial complex I as a target for neuroprotection
Time : 11:41-12:40
Biography:
Eugenia Trushina has completed her PhD from Saratov State University, Russia and Post-doctoral studies from Mayo Clinic College of Medicine, USA. She is an Associate Professor in the Departments of Neurology and Pharmacology at the Mayo Clinic Rochester, USA. Her scientific interests include the investigation of early molecular mechanisms of neurodegeneration, the role of mitochondria in particular. Translational aspect of her work includes the development of blood-based metabolic biomarkers and mitochondria-targeted small molecule therapeutics for Alzheimer’s disease. She is a recipient of the NIH, BrightFocus, GHR, ADDF, and Mayo Clinic Research Awards.
Abstract:
Neurodegenerative diseases are characterized by progressive neuronalloss that affects individuals’ cognitive and motor functions. Examples include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Molecular mechanisms of neurodegeneration are not completely understood hindering the development of efficacious therapeutic treatments. The number of people living with dementia around the world is now estimated at 44 million, and is expected to rise to 76 million by 2030 and to 136 million by 2050. In the USA, AD currently affects more than 5 million Americans, with numbers expected to be 13.8 million by the year 2050. This is a terrible epidemic with no effective treatment and with multiple failed clinical trials focused on prevention of amyloid beta production. Alternative approaches are urgently needed. Despite different etiology of neurodegenerative diseases, they share some of the molecular mechanisms including protein aggregation, loss of mitochondrial function and increased oxidative stress. However, treatments with mitochondria-enhancing compounds or antioxidants did not provide a relief and failed clinical trials. In the recent years, a counterintuitive approach where a reduction of mitochondrial function using pharmacological inhibitors or genetic manipulations of the electron transport chain has been shown to induce positive cellular adaptation enhancing health and life span in model organisms and in humans. We demonstrated that mild inhibition of mitochondrial complex I with small molecules reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three preclinical animal models of AD. Modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to oxidative stress. Metabolic signatures obtained in plasma and brain tissue of AD mice treated with these small molecules allowed monitoring target engagement and confirms the proposed mechanism. I will discuss current stage of the development of mitochondria-targeted small molecule-based therapeutics, progress in the understanding of the molecular mechanism, and strategies for successful translation of this approach to humans.
- Track : 1 Metabolomic Profiling
Track : 8 Clinical Metabolomics & Lipidomics
Track : 9 Cancer Therapeutic Approaches
Chair
Petras Dzeja
Metabolomics NMRS Core, Mayo Clinic, USA
Co-Chair
Björn Riefke
Bayer Pharma AG, Germany
Session Introduction
Eugenia Trushina
Mayo Clinic College of Medicine, USA
Title: Metabolic and Epigenetic Alterations in Patients with Alzheimer’s Disease
Biography:
Dr. Trushina has completed her PhD at the age of 29 years from Saratov State University, Russia and postdoctoral studies from Mayo Clinic College of Medicine, USA. She is an Associate Professor in the Departments of Neurology and Pharmacology at the Mayo Clinic Rochester, USA. Dr. Trushina scientific interests include the investigation of early molecular mechanisms of neurodegeneration, the role of mitochondria in particular. Translational aspect of her work includes the development of blood-based metabolic biomarkers and mitochondria-targeted small molecule therapeutics for Alzheimer’s Disease. Dr. Trushina is a recipient of the NIH, BrightFocus, GHR, ADDF, and Mayo Clinic Research Awards.
Abstract:
The number of people living with dementia is estimated at 44 million worldwide, and is expected to rise to 76 million by 2030 and to 136 million by 2050. Alzheimer’s Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods, novel therapeutic approaches, and methods to monitor efficacy of experimental therapeutics. Targeted metabolomics with the overall goal to determine changes in mitochondria- and energy-related metabolites was conducted in CSF and plasma from males and females with mild cognitive impairment (MCI), AD and control patients involved in the Mayo Clinic Study of Aging. Panels of metabolites that include amino acids, fatty acids, lipids and components of the TCA cycle revealed that metabolic changes in females were more pronounced and correlated strongly with the disease compared to males. Analysis of metabolic fluxes in TCA cycle in human fibroblasts from late onset AD male and female patients using Glucose and Glutamine stable isotope tracers confirmed stronger inhibition of fluxes in female patients. Epigenetic changes were also more pronounced in female patients suggesting a link to altered energy metabolism. Overall, our data demonstrate that metabolic changes associated with the development and progression of AD differ between males and females where females are affected to the greater extent.
Hsien-Yeh Hsu
National Yang-Ming University, Taiwan
Title: Fucoidan inhibitory function in cancer in vivo and in vitro: Role in the development of human anti-cancer therapeutic intervention
Time : 10:41-11:00
Biography:
Hsien-Yeh Hsu, a molecular/cellular biologist, obtained Doctoral degree from Cornell University, USA. Later, he worked in various biotechnology companies in Boston, USA. In 1990, he returned to university, and later became Assistant Professor in Weill Cornell Medical College, NYC, USA. In 1997, he joined National Yang-Ming University, Taiwan. Currently, as Professor, he works at Department of Biotechnology and Laboratory Science in Medicine, and also as Research Fellow in Genomics Research Center, Academia Sinica. He is working on polysaccharides obtained from brown algae and medicinal mushroom Ganoderma lucidum, and focusing on anti-cancer functions in human clinical experiments. Moreover, he is engaged on examining anti-cancer therapeutic intervention and on developing anti-cancer drugs.
Abstract:
Fucoidan, a polysaccharide extracted from brown seaweeds, reduces proliferation in a battery of tumor cells. In recent, we demonstrated that fucoidan reduces tumor size both in LLC1 lung cancer-xenograft male C57BL/6 mice and in 4T1 breast cancer-xenograft female Balb/c mice. As it is known, transforming growth factor β receptors (TGFRs) play important roles in the regulation of epithelial-mesenchymal transition (EMT) as well as of proliferation/progression and metastasis in cancer cells. Using these cancer cells, we found that fucoidan effectively up-regulates epithelial markers, down-regulates mesenchymal markers, and also decreases expression of transcriptional repressors Snail, Slug, and Twist. In addition, we found fucoidan inhibits TGFR-mediated migration and invasion of cancer cells. Moreover, we found fucoidan decreases TGFRI and TGFRII proteins in vivo and in vitro. To elucidate the mechanism by which fucoidan decreases TGFRI/II proteins in cancer cells, we found that fucoidan enhances ubiquitination proteasome pathway (UPP)-mediated degradation/ubiquitination of TGFRs. We further demonstrated fucoidan promotes Smurf2 and Smad7 to conjugate TGFRs, resulting in TGFR degradation. Together, we are the first to identify a novel mechanism for fucoidan anti-tumor activity, namely decreasing tumor growth by modulating TGFR proteins degradation, leading to reduction of TGFR-mediated signaling, and further inhibition of cancer cells in vivo and in vitro. Our current findings indicate that fucoidan is a potential therapeutic agent or dietary supplementation for cancers, acting via Smurf2-dependent ubiquitin degradation of TGFRs affecting the TGFR/Smad/Snail, Slug, Twist, and EMT axes.
Ashkan Emadi
University of Maryland School of Medicine, USA
Title: Interference with glutamine metabolism: a novel approach for treatment of acute myeloid leukemia
Time : 11:01-11:20
Biography:
Dr. Emadi received his M.D. at Tehran University of Medical Sciences and his Ph.D. in Organic Chemistry at the Illinois Institute of Technology. He developed novel methodologies for the regiospecific synthesis of multiple naphthoquinone derivatives related to the natural product conocurvone, and was granted “Highest Standards of Academic Achievement Award”. Following completion of his Ph.D., he completed his internship and residency in Internal Medicine at the University of Kentucky and the University of Cincinnati, respectively. Subsequently, Dr. Emadi was trained in Hematology and Medical Oncology Fellowship Program at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center. Dr. Emadi joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center as an Associate Professor of Medicine, Pharmacology and Experimental Therapeutics at the University of Maryland School Of Medicine and serves as Director of the ACGME-accredited Hematology and Oncology Fellowship Program. He previously served as medical officer at the Division of Hematology Products (DHP), United States Food and Drug Administration (FDA), and as visiting scientist at Division of Adult Hematology, Department of Internal Medicine, School of Medicine, Johns Hopkins University. Dr. Emadi has experience and in-depth understanding of the multiple aspects of cancer drug development including basic organic chemistry and molecular synthesis, in vitro and in vivo studies, and all phases of clinical trials as well as regulatory science.
Abstract:
In contrast to normal cells, rapidly dividing leukemia cells reprogram their nutritional requirements to match an increased metabolic demand. The two main nutrient sources for growth and survival of cancer cells are glucose and glutamine. Depletion of glutamine or interruption of its cellular processes can be detrimental to leukemia cells but not normal cells. Asparaginases deplete amino acids asparagine and glutamine and are FDA-approved drugs for the treatment of acute lymphoblastic leukemia (ALL). The anti-leukemia effect of asparaginases in acute myeloid leukemia (AML) is not established. Here we describe the preclinical effect of different asparaginase products on the survival of AML cells with or without isocitrate dehydrogenase (IDH) mutations, which culminates in glutamine depletion resulting in disruption of protein synthesis downstream of mammalian target of rapamycin (mTOR) causing strong apoptotic and autophagic responses. The clinical experience with asparaginase in AML patients will also be discussed. Moreover, the cytotoxic effect of pharmacologic inhition of glutaminase, the enzyme that converts glutamine to ammonia and glutamate, will be reported in AML cells with different mutational status.
I-Chen Peng
National Cheng Kung University, Taiwan
Title: Myc induces expression of glutamine synthetase through promoter demethylation
Time : 11:21-11:40
Biography:
I-Chen Peng is an assistant professor of Department of Life Sciences at National Cheng Kung University, Taiwan. She received her Ph.D. in the Biochemistry and Molecular Biology Graduate Program from University of California at Riverside, USA, and the post-doctoral training in the Department of Molecular Genetics & Microbiology at Stony Brook University in New York, USA. She has published several papers in reputed journals. Dr. Peng joined the faculty in the Department of Life Sciences at National Cheng Kung University in 2014. Dr. Peng’s research focuses on targeting lipid and glutamine metabolism to treat obesity and obesity-related diseases.
Abstract:
The proto-oncoprotein Myc is known to promote glutamine usage by up-regulating glutaminase (GLS), which converts glutamine to glutamate that is catabolized in the tricarboxylic acid (TCA) cycle. Here we report that in a number of human and murine cells and cancers, Myc overexpression leads to elevated expression of glutamate-ammonia ligase (GLUL), also termed glutamine synthetase (GS), which catalyzes the de novo synthesis of glutamine from glutamate and ammonia. Elevated expression of GS promotes cell survival under glutamine limitation, while silencing of GS leads to decreased cell proliferation and xenograft tumor growth. Stable isotope based metabolite tracing shows that GS overexpression increases glutamine synthesis, cataplerotic flux at the ï¡-ketoglutarate (ï¡KG) step of the TCA cycle, and contributes to nucleotide synthesis and amino acid transport. Mechanistically, Myc binds to the promoter of thymine DNA glycosylase (TDG) and upregulates its expression, which leads to active demethylation of the GS promoter and its increased expression. These results demonstrate an unexpected role of Myc in promoting glutamine synthesis, and suggest a previously uncovered molecular connection between DNA demethylation and glutamine metabolism in Myc-driven cancers.
Jian Zhi Hu
Pacific Northwest National Laboratory, USA
Title: Slow-MAS NMR Metabolomics
Time : 11:41-12:00
Biography:
Jian Zhi Hu received his Ph.D in 1994 and is currently a senior staff scientist and principal investigator of Pacific Norwest National Laboratory. He has published more than 170 papers in peer reviewed journals, delivered a large number of presentations, received two US R&D 100 awards and 10 US patents.
Abstract:
Metabolomics studies on tissues are of significance since a disease is often associated with a specific tissue or organ malfunction. It is, therefore, expected that the changes in metabolic profile is more dramatic in the diseased tissue than body fluids. It is likely that tissue specific metabolic profiling provides a unique window of investigating the biochemistry associated with a particular disease in great detail than possible using global body fluids. In this work, we will report a non-destructive magic angle spinning NMR metabolomics technique that is capable of high resolution and high sensitivity metabolic profiling on biological samples, in particular tissue samples, with sample volume from as small as 200 nanoliters (nL) to as large as a milliliter or more using a single probe and using only a few minutes. This has been achieved by combining the techniques of high resolution slow-MAS 1H NMR technique and a switchable inductively coupled static micro-RF coil-LC resonator and by rotating the specimen at a sample spinning rate of 40 to 200 Hz about the magic angle axis. The nanoliter capability has the potential to follow the metabolic changes through a continued investigation on a single small laboratory animal over a long period of time using minimally invasive blood and tissue biopsy samples. While the milliliter capability would allow minimally destructive studies of intact biological object with size as large as >1 cm3. Examples of applications will be reported.
Mats Gustav Borén
Denator, Sweden
Title: Prevention of metabolite change due to enzymatic post-sample activity using heat based enzyme inactivation
Time : 12:01-12:20
Biography:
Mats Borén completed his PhD at the Swedish University of Agricultural Sciences. He is currently the Head of Development at Denator, the heat stabilization and sample preservation company, based in Uppsala, Sweden . He has published more than 25 papers in reputed journals primarily on the subjects of sample quality and changes post-sampling.
Abstract:
The removal of a biological sample induce a cascade of reactive changes causing alterations to the molecular profile of the sample. This is particularly true for metabolomic studies where sample preservation is key for the relevance of the analytical results. In order to avoid this and enable analysis of a molecular state closer to in vivo state, heat induced protein denaturation has been introduced as a means to preserve sample conmposition and quality1 A study has been done to evaluate the inclusion of heat stabilization in the sample preparation prior to lipid analysis. The study was performed on mouse livers from 30 healthy mice, randomized in 5 groups of 6 animals designed to compare snap freezing at -80°C to 3 heat stabilization conditions (freezing just after heat stabilization, after 1 hour and after 3 hours) and to a negative control samples maintained at room temperature during 10 minutes before freezing. For each mouse livers polar metaboltes were extracted using MeOH and PBS buffers and analyzed using NMR to generate a global metabolite profile. Representative lipids profiles were generated and compared between the different treatment groups. Analysis demonstrate that for frozen samples, MeOH extraction results are intermediate between PBS extraction and heat stabilization, suggesting that whatever the method of extraction, there is metabolic changes for frozen samples, but also that results with heat stabilization are indeed “better” than freezing. A new biological sample preservation procedure based on heat stabilization for improved metabolomics profiling has been developed.
Ching-wan Lam
The University of Hong Kong, Hong Kong
Title: Clinical metabonomics for biomarker discovery of malignant pleural effusions (MPE)
Time : 12:21-12:40
Biography:
Professor Lam obtained his MBChB from The Chinese University of Hong Kong in 1991 and FRCPA in 1997 from The Royal College of Pathologists of Australasia with a double scope of practice in Chemical Pathology and Genetics. He is a Fellow of The Australasian Association of Clinical Bicohemists. He obtained his PhD in 2000 from The Chinese University of Hong Kong. He obtained FRCP(Glas) from The Royal College of Physicians and Surgeons of Glasgow in 2012. Professor Ching-Wan Lam is TheEditor, Clinical Chimica Acta, an official journal of The International Federation of Clinical Chemistry and Laboratory Medicine.
Abstract:
Aim: Clinical metabonomics has been widely used in advanced laboratory medicine for the study of disease mechanism and biomarker discovery. Here, we will extend the use of clinical metabonomics to develop new screening test for malignant pleural effusions (MPE). Methods: 32 malignant and 18 non-malignant PE samples will be analyzed using reversed-phase liquid chromatography-tandem mass spectrometry (LC-MS/MS). Biomarkers for MPE will be determined by metabolome-wide association studies (MWAS) using Receiver Operating Characteristic Curve Explorer and Tester (ROCCET). All markers will be filtered using a metabolome-wide significance level (MWSL) at p-value ≤ 2×10−5. Results: 2731 and 3137 markers were detected in positive and negative ESI spectra respectively. Free fatty acids (FFAs) 16:0, 18:1 and 18:2 were significantly increased in MPE. FFA 18:1 (oleic acid) showed the largest area-under-ROC of 0.96 (95% CI: 0.87–1.00) with sensitivity of 84% and specificity of 100.0% (p-value: 8.23×10−8). Discussion: Pleural fluid oleic acid is a novel biomarker for screening MPE.
Yonghai Lu
National University of Singapore, Singapore
Title: Mass spectrometry-based metabolomics reveals that serum lysophospholipids are associated with incident type 2 diabetes
Time : 12:41-13:00
Biography:
Yonghai Lu is a Research Fellow of National University of Singapore. He got his PhD degree from the Chinese University of Hong Kong in 2013. His researches focus on metabolomics studies of diabetes and liver cancer, and has published more than 20 papers in international journals, such as Cancer Research, Environmental Science & Technology, and Metabolomics.
Abstract:
Type 2 diabetes (T2D) usually presents years before becoming clinically apparent, and it is thus crucial to identify more sensitive and specific biomarkers for early diagnosis of this disease. In this study, we applied an integrated mass spectrometry-based untargeted metabolomics approach to characterize serum metabolic profiles in 197 incident T2D cases and 197 healthy controls matched by age and gender, in order to identify metabolic signatures associated with incident T2D. A series of 51 metabolites were found to be altered significantly in cases compared to controls. In addition to widely reported branched-chain amino acids (leucine, isoleucine, and valine) and free fatty acids (palmitic acid, stearic acid, oleic acid, and linoleic acid), we found seven lysophospholipids were significantly associated with the risk of T2D, including lysophosphatidylglycerol (LPG) (12:0) and lysophosphatidylinositol (LPI) species (16:1, 18:1, 18:2, 20:3, 20:4, and 22:6). Odds ratios for the seven lysophospholipids per standard deviation increment ranged from 1.43 to 2.10. Of these, LPI (16:1) showed a good capability for prediction of T2D in both at-risk individuals with high glycated hemoglobin (HbA1c) levels (≥6.5%) and those with normal HbA1c values (<6.5%), with area under the curve (AUC) values of 0.806 and 0.754, respectively. Our study indicates that LPI (16:1) emerges as a potential predictor for diabetes development, although the finding was observed in a single and small cohort, raising the need for further independent validation in well-designed and large-scale studies
Biography:
Yael Porat, PhD, is founder and CEO of BioGenCell Ltd (www.BioGenCell.net), a biotechnology company focusing on stem cell therapy and regenerative medicine.Dr. Porat earned her PhD in immunology from the Sackler School of Medicine, Tel-Aviv University.Prior to founding BioGenCell, she served as head of the Global Biological Development Department at Teva Pharmaceuticals and as CTO at TheraVitae, where she led the translation of innovative research into the production of stem cell-based therapies used to treat patients with severe cardiovascular diseases.BioGenCell is developing groundbreaking technology for automated production of patient-specific, blood-derived stem-cell-based therapies. The company’s proprietary technology utilizes immune-directed stem-cell specific activity to create cell-based products for a wide range of diseases. BioGenCell’s first line of products targets incurable vascular diseases, such as heart failure, stroke and Peripheral Artery Diseases.
Abstract:
Background: Vascular diseases are a major cause of morbidity and mortality, particularly in the elderly and diabetic patient population. Stem/progenitor cell (SPCs) treatments with bone-marrow-derived cells show promising outcomes, albeit not without adverse events related to cell collection and mobilization. We describe a novel technology for generating a therapeutic population (BGC101) of enriched endothelial progenitor cells (EPCs) from peripheral blood, using dendritic cells (DCs) to specifically direct SPC activity in-vitro. This one day culture process utilizes non-mobilized blood as a source for sufficient numbers of potentially therapeutic SPCs. Methods & Results: Plasmacytoid and myeloid DCs from healthy and diabetic donors were activated with anti-inflammatory and pro-angiogenic molecules to induce specific activation signals. Co-culturing of activated DCs with SPCs, from the same patient sample, within one day (12-18hours) generated 83.7±7.4×106 BGC101 cells with 97% viability from 250ml of blood. BGC101, comprising 52.4±2.5% EPCs (expressing Ulex-lectin, AcLDL uptake, Tie2, vascular endothelial growth factor receptor 1 and 2 and CD31) and 16.1±1.9% SPCs (expressing CD34 and CD184). The final product, BGC101 has demonstrated angiogenic and stemness potential and secretion of IL-8, IL-10, VEGF and osteopontin. When administered intramuscularly to nude mice with limb ischemia, BGC101 yielded a high safety profile and improved blood perfusion (x2 p<0.0002), capillary density and limb function within 21 days. Conclusions: These observations indicate that alternatively-activated DCs promote the generation of EPC-enriched SPCs within culture for one day. The resulting unique product, BGC101, has the potential for treatment of vascular conditions, including arteriosclerotic heart disease, stroke and peripheral ischemia.
- Track : 11 Metabolic Syndrome
Track : 12 Metabolomics in Precision Medicine
Chair
Robert Plumb
Imperial College London, UK
Co-Chair
Houkai Li
Shanghai University of Traditional Chinese Medicine, China
Session Introduction
Jose Castro-Perez
Waters Corp, USA
Title: Biomarker Discovery in Cardiovascular Disease and role of LC/MS
Time : 10:01-10:20
Biography:
Jose is the Director of Health Sciences Marketing. Prior to this, Jose spent part of his career as the Team Leader of Biomarkers and Translational Research at Merck, USA. He has published 62 publications and numerous scientific patent applications. He attained his BSc in Chemistry from King's College in London (UK) and subsequently received his MSc in Clinical Biochemistry and Molecular Biology from the University of Surrey (UK). He obtained his Ph.D at the University of Leiden (Netherlands) in Metabolomics and Biomarker discovery. In 2014, Jose was awarded by Thompson Reuters the prestigious Highly Sited Researcher Award.
Abstract:
Metabolomics and Lipidomics play an increasingly important role in the understanding and diagnosis of cardiovascular disease. Lipid profiling in cardiovascular disease drug discovery whether targeted or untargeted is key to provide an insight in the mechanism of action and to prove target engagement. This is particularly important in the early stages of target identification and validation. Furthermore, metabolic tracing of pathways and flux analyses plays a pivotal role because it allows for early indication of lipid target efficacy and aid in the interpretation of phenotypic differences when steady state concentration measurements are insufficient. In this presentation we will present a number of examples using UPLC/high resolution TOF MS which highlights how this technology may be applied to exploratory biomarkers of the metabolic syndrome. The examples will include; perturbation of diet, genetic knockdowns, transcriptome/lipidome relationships, metabolic tracers and metabolic flux of lipids.
Houkai Li
Shanghai University of Traditional Chinese Medicine, China
Title: Metabolomic study on the different responses to simvastatin therapy in normal and antibiotic-treated mice
Time : 10:21-10:40
Biography:
Houkai Li has completed his PhD from Shanghai Jiao Tong University and Post-doctoral studies from University of North Carolina (2011.8-2013.5) and Chinese Academy Sciences (2008.11-2011.3) respectively. He is now a Professor at Center for Traditional Chinese Medicine and Systems Biology in Shanghai University of Traditional Chinese Medicine. He has published over 25 papers in reputed journals
Abstract:
Simvastatin is a classical HMG-CoA reductase inhibitor that is widely used for reducing plasma LDL-cholesterol (LDL-c) and risk of cardiovascular disease. There are frequently interindividual variations in therapeutic efficacy of simvastatin among individuals in clinic, while the mechanisms are unclear. Previous study showed that the pre-dose variations of some gut microbial metabolites were correlated with the extent of LDL-c reduction in patients, and lovastatin, an analog of simvastatin could be metabolized by bacteria. Accordingly, we hypothesized that the interindividual variations in therapeutic efficacy of simvastatin might be associated with the variation of gut microbiota. In current study, fifty male C57BL/6J mice were divided into five groups including control (Con), high-fat/cholesterol diet (HFD), antibiotic (AB), simvastatin (ST) and simvastatin plus antibiotic (AB_ST) groups. These mice were fed with correspondingdiet for 12 weeks. Simvastatin was given orally (20 mg/kg) once a day and antibiotic was provided in drinking water during the whole experiment. We performed metabolic profiling on serum samples by using combined GC/MS and UPLC/QTOFMS metabolomic approach. First of all, we found that the disruption of gut microbiota with antibiotic significantly attenuated the hypolipidemic effect of simvastatin in mice. Then, the metabolic profiling showed a distinct separation between ST and AB_ST groups, and the subsequent analysis identified several metabolites that were differently altered between ST and AB_ST groups such as alanine, ribose-5-phosphate, alpha-monooleoylglycerol, cholesterol, PCs and some bile acids. Moreover, we found that the expression of hepatic CYP7A1, CYP7B1 and FXR proteins was differently regulated, while no difference was observed in HMG-CoA reductase between ST and AB_ST groups. These results suggested that the gut microbiota associated alteration in bile acids synthesis processfrom cholesterol might contribute to the different responses tosimvastatin in antibiotic-treated mice.
Robert Plumb
Imperial College London, UK
Title: Understanding human health and disease with LC/MS based metabolic phenotyping
Time : 11:01-11:20
Biography:
Robert Plumb is the Director of Metabolic Phenotyping and Stratified Medicine in the Waters Health Sciences Business Operations Division, based in Milford, Massachusetts. He has published over 100 papers on HPLC/MS and NMR for bioanalysis, metabolomics and metabolite identification. He is a recognized expert in the use of liquid chromatography with mass spectrometry, capillary scale LC, purifications scale LC and metabonomics, giving many invited papers at international meetings around the world. He is currently a visiting Professor in Analytical Chemistry at Kings College London, visiting Professor at Imperial College in the Dept. Surgery and Cancer and a Fellow of the Royal Society of Chemistry. In 2014 he was awarded Highly Cited Researcher by Thompson Reuters.
Abstract:
The MRC-NIHR National Phenome Centre, Imperial College London, is the first of its kind facility. Born out of the UK Olympic Legacy its mandate is to provide “high throughput, forensic quality, metabolic phenotyping to support large scale epidemiological studies as well as basic medical research into disease understanding and patient stratification”. As global life-styles change we are seeing increasing cases of obesity, diabetes, and mental health issues. This not only affects a person’s quality of life but also places increased strain on the health-care systems to provide the right treatment whilst managing costs closely. Metabolic Phenotyping offers a valuable and unique insight into the underlying biochemistry of diseases as well as the patients individual biochemistry “phenotype’, diet, health status, age and stress. To deliver this information, the analytical data generated in processed via a variety of chemometric modelling and analysis methodologies to deliver the relevant biochemical information. These chemometric platforms employed vary from simple multivariant analysis to highly complex model based analysis and is presented in a format ready for interpretation by medics. In this presentation, we will discuss the development of LC/MS analytical platforms as well as a detailed discussion on the workflow, validation, reporting and decision making process. The presentation will cover the development and validation of the “discovery’ screening methods for polar, non polar metabolites and lipid profiling using LC/MS methodology, as well as the quantitative targeted LC/MS assays and the various compounds classes such as bile acids, amino acids, eicosanoids, and acyl cartanines will also be discussed.
Jingxin Zhou
Beijing University of Chinese Medicine, China
Title: Treatment of Natural Plants on Diabetes and Metabolic Syndrome
Time : 11:21-11:40
Biography:
Jingxin Zhou has completed MD from Beijing University of Chinese Medicine in 2014. She is a doctor in Department of Endocrinology, Dongzhimen Hospital Eastern, Beijing University of Chinese Medicine. She does research on Chinese medicine treating diabetes and metabolic sysdrome.
Abstract:
The increasing incidence of diabeties and metabolic syndrome becomes a worldwide threat to global human health. Chinese herbs and natural plants have played an important role in health maintenance for thousand years. Our study have indicated that Chinese medicine including formula, herbal extracts, and compounds mediates the glucose and lipid metabolism. We found Tang-Nai-Kang granules improve the glucose intolerance and insulin resistance by mediating fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats. Meanwhile, Guava leaf extracts significantly enhanced the insulin-related signaling to activate the insulin signaling and promoting glucose metabolism and fatty acid oxidation, lead to the improvement of insulin sensitivity in the SHRSP/ZF rats. In addition, Isoquercitrin appears to regulate AMPK activation, thereby enhancing AdipoR1 expression, suppressing SREBP-1 and FAS expressions, and resulting in the regulation of lipid accumulation in vivo.
Chia-Lin Hsu
National Yang-Ming University, Taiwan
Title: Metabolism and immunity: From a nucleic acid recycling viewpoint
Biography:
Chia-Lin Hsu received her PhD degree in Immunology from Duke University, focusing on cytokine signaling and lineage commitment in hematopoiesis. She was trained as postdoctoral research fellow at Genentech, a San Francisco-based biotechnology company. During this period, she discovered that the nucleoside equilibrium is crucial to the homeostasis of immune system, and when out-of-balance, can lead to lysosomal storage disease-like phenotypes. She then accepted the position as Senior Scientist at the Center of Innovative Therapeutics, Pfizer. She was the biology lead of a multi-centers project that aims to develop immune-modulatory therapeutics with the combined efforts from both pharmaceutical and academic laboratories. She returned to Taiwan in 2013, and now is an Assistant Professor at the Institute of Microbiology and Immunology, National Yang-Ming University.
Abstract:
Immunometabolism is a new term describing the interactions between metabolism and immunity, the biological functions that have long considered as two distinct entities. However, despite the substrate to be pathogens or nutrients, both processes work to restoring the homeostasis of the body. With modern diet, the correlation between overnutrition and chronic inflammation brings the attention to how metabolic homeostasis contribute to properly controlled immune system. It is becoming clear that immune activation can affect metabolism while metabolic changes also have profound influence on immunological functions. Nevertheless, the molecular mechanisms that connect these two systems are still unclear. For example, lysosomal storage diseases (LSDs) are a group of heterogeneous disorders caused by defects in lysosomal enzymes or transporters, resulting in accumulation of un-degraded macromolecules or metabolites. This accumulation disrupts the cell's normal functioning and gives rise to the clinical manifestations of LSDs. We found that equilibrative nucleoside transporter 3 (ENT3) is a lysosomal specific nucleoside transporter that highly expresses in macrophages. Mice lacking ENT3 developed a spontaneous and progressive macrophage-dominated histiocytosis. In the absence of ENT3, defective apoptotic cell clearance led to lysosomal nucleoside buildup, elevated intralysosomal pH, and altered macrophage function. These studies suggest a cellular and molecular basis for the development of histiocytosis in several human syndromes associated with ENT3 mutations and potentially other LSDs. Furthermore, we will discuss potential roles of ENT3 in other aspects of immune response.
- Special Session
Session Introduction
Yoshiro Fujii
Shin Kobe Dental Clinic, Kobe City, Japan
Title: Two cases of the serious dementia improved dramatically by placing denture
Time : 13:46-14:45
Biography:
Dr. Yoshiro Fujii is a director and chief dentist of Shin Kobe Dental Clinic. 1985:D.D.S. (Certified by Japanese Health Ministry).1989: He received Koide prize. Finished graduate school, Nagoya, Japan. and Ph.D (Aich Gakuin University Graduate school, Nagoya). 2000: Dr. Fujii began to run Shin Kobe Dental Clinic (Kobe, Japan). 2009: Fellow of the international college of acupuncture and electro-therapeutics (F.I.C.A.E). 2013,2014: 100 next era CEOs in Asia (Japan times). 2014: Editioriall board member of Savvy Science Publisher. 2015: Editorial board member of British Journal of Medical Research.. 2015: 100 Next-era Leaders in Asia (Japan times). He has written five published works in Japanese and two in English. He is an Authorization doctor of the Japan Bi-Digital O-Ring Test. Association and a director of the Japan Society of Dental Equipment. He published eleven international academic articles in English. 2014-15: He was a chair or co-chair three times in various international congresses.
Abstract:
Serious dementia, including Alzheimer’s disease seems intractable and progressive. The purpose of this study was to demonstrate the improvement of two cases of serious dementia by placing denture(s). The two subjects were women in their 70s. They had serious dementia and were diagnosed as having Alzheimer’s disease by a medical doctor in charge of their cases. In the first case, the subject’s symptoms included severe disorientation, impaired communication and a tendency to wander. Two weeks after a lower full denture placing, she was able to greet others. Five weeks later she was able to communicate and to read an analog clock precisely. Her improved condition continued for least three months. In the second case, the subject constantly kept her mouth open. She was in a vegetable stage; she was bedridden, hardly moved, talked or laughed. It was impossible to communicate with her. Only a few seconds after an upper full denture placement, she started to talk but it was unintelligible. Two weeks after a lower full denture placement, she could communicate smoothly, laugh and walk without help. The underlining mechanism has not yet been clarified, however, the author hypothesizes that positive signals from the oral area transferred to the brain as the positive stimulation, via the trigeminal nerve, which is the biggest of the cranial nerves.
- Special Session
Session Introduction
Andrea Armirotti
Istituto Italiano di Tecnologia, Italy
Title: Metabolomics in neuroscience: Old tools for new models and new tools for old models
Time : 13:46-14:45
Biography:
Andrea Armirotti joined the Istituto Italiano di Tecnologia (Genova, Italy) in 2010, where he leads the Analytical Chemistry laboratory of the Drug Discovery and Development Department (D3). He is involved in several research projects requiring MS-based metabolomics and proteomics characterization of biological and pharmacological models. He also works in the biomarker discovery field, with the aim to translate the findings from the animal models to clinical research. He has published more than 50 papers in the analytical chemistry field, spanning over a broad range of topics.
Abstract:
Over the last years, mass spectrometry-based untargeted metabolomics, in combination with advanced data analysis techniques, has reached outstanding levels of analytical performance and it now represents a valuable tool for the efficient exploration of the biochemical pathways of the brain. Using this technology, key advancements have been made in almost any field of neuroscience, with several important breakthrough discoveries. On the other hand, new technologies for data acquisition and analysis are always coming up. We recently successfully applied some of the most well-established techniques to a new model: long-term exposure of primary neurons to graphene-related materials (GRM). We deeply investigated the molecular changes occurring in the cell as natural response to GRM. Our findings clearly outline that important alterations occur in the neuron metabolome and are associated to phenotypic and functional changes. On the other hand, these well-established tools for untargeted analysis sometimes fail in detecting significant shifts in the metabolome, particularly when they occur to low abundance species. We then applied a totally new data analysis technique to the very early stages of a well-known mouse model of Parkinson’s disease (6-hydroxy-DOPA in the brain), when no phenotypic of functional changes are observed in animals. We discovered that the regulation of a particular class of large phospholipids, naturally present at ppb levels in the brain, is significantly increased immediately after the insult to dopaminergic neurons.
- Track : 10 Plant & Environmental Metabolomics
Track : 13 Food & Nutritional Metabolomics
Session Introduction
Min Guan
Chinese Academy of Sciences, China
Title: ERRα induces mitochondrial glutaminase expression guiding anaplerosis upon osteogenic differentiation of mesenchymal stem cells
Time : 14:46-15:05
Biography:
Min Guan received her Ph.D. degree from Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences in 2009. She performed postdoctoral studies at University of California and Johns Hopkins Medical School, USA. She was appointed as Associate Professor at Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences in 2013. She focuses on studying mechanisms of metabolic diseases, and has published in reputed journals including Nature medicine, Hepatology and Stem cells.
Abstract:
Aging deteriorates osteogenic capacity of mesenchymal stem/stromal cells (MSCs), contributing to imbalanced bone remodeling and osteoporosis. Glutaminase (Gls) catabolizes glutamine into glutamate at the first step of mitochondrial glutamine-dependent anaplerosis which is essential for MSCs upon osteogenic differentiation. Estrogen-related receptor α (ERRα) regulates genes required for mitochondrial function. Here, we found that ERRα and Gls are up-regulated by osteogenic induction in human MSCs (hMSCs). In contrast, bone mass, osteogenic differentiation capacity of MSCs, ERRα, Gls and osteogenic marker genes are significantly reduced with age. We demonstrated that ERRα binds to response elements on Gls promoter and affects glutamine anaplerosis through transcriptional induction of Gls. Conversely, ERRα inverse agonist compound 29 or mTOR inhibitor rapamycin significantly decreased expression levels of ERRα and Gls, leading to deteriorated osteogenic differentiation of hMSCs. Importantly, overexpression of ERRα in hMSCs promoted osteogenic differentiation and partially restored impairment by rapamycin. Finally, we proved that compensated ERRα expression indeed potentiated osteogenesis capability of elderly mice MSCs in vitro. Together, we establish that Gls is a novel ERRα target gene and ERRα/Gls signaling pathway plays an important role in osteogenic differentiation of MSCs. Our findings suggest that restoring age-related mitochondrial glutamine-dependent anaplerosis may be beneficial for osteoporosis.
Yongyu Zhang
Shanghai University of Traditional Chinese Medicine, China
Title: Urine metabolomics study on unilateral ureteral obstruction induced renal fibrosis in rats and intervention effects of total aglycone extracts of Scutellaria baicalensis
Time : 15:06-15:25
Biography:
Yongyu Zhang got the degree of Ph.D. of Pharmacy in Meiji Pharmaceutical University, Tokyo, Japan in 2000, and now works as a doctoral supervisor in Shanghai University of Traditional Chinese Medicine,Shanghai, China. In addition, he works as the adjunct research fellow of research center for drug metabolism, Shanghai institutes of pharmacology, Chinese Academy of Sciences and the jury of the National Natural Science Funds of China. What' s more, he have been authorized two US patents and have publicated more than 40 SCI papers.
Abstract:
Renal fibrosis (RF) is the final common pathological process to chronic renal failure caused by various kidney diseases. In the present study, we investigated effects of Total Aglycone Extracts of Scutellaria Baicalensis (TAES) on some RF closely related parameters in unilateral ureteral obstruction (UUO) rats, and a urine metabolomics method, based on gas chromatography-mass spectrometry (GC/MS), was developed to monitor metabolic alterations. In the metabolomics study, the metabolic perturbations induced by UUO were reversed based on pattern recognition analysis and different metabolites associated with RF were identified. Ontology-based enrichment analysis by BiNChE aids in the interpretation of difference metabolites and relevant disturbed pathways were extracted by MetPA analysis. Our findings indicate that TAES have positive effects on UUO-induced RF in rats, meanwhile, metabolomics method coupled with metabolites enrichment analysis is useful to reveal the pathogenesis of diseases and action mechanism of medicine on the whole body.
Ewelina P Dutkiewicz
National Chiao Tung University, Taiwan
Title: Skin metabolomics approach for the development of biomarkers in psoriatic disease
Time : 16:41-17:00
Biography:
Ewelina P Dutkiewcz has obtained her MSc degree at the Department of Chemistry at Warsaw University, Poland. Currently, she is a PhD candidate at the Department of Applid Chemistry at National Chiao Tung University (NCTU), Taiwan. Her research interests include analysis of unconventional biological specimens for clinical applications by means of mass spectrometry. She works in the group of Prof. Pawel L. Urban (NCTU) and collaborates with Dr. Hsin-Yi Chiu (NTUH). She is an author of articles (Anal. Chem., 2014, 86, 2337; J. Mass Spectrom., 2015, 50, 1321) related to a novel method for profilng of skin metabolites.
Abstract:
Human skin is covered with numerous low-molecular-weight metabolites excreted by specialized glands of skin or produced during the breakdown of proteins. Those metabolites have a huge potential as disease biomarkers. However, due to the lack of convienient analytical methodology, the analysis of skin excretions has not become popular. Recently, we have introduced a facile method – hydrogel micropatch probe – for collection and mass spectrometric profiling of skin metabolites. We have applied this method to investigate the skin metabolome of patients suffering from one of the skin diseases – psoriasis. Psoriasis is an inflammatory immune-mediated disease that affects 2-3% of the world population. We have examined over 200 subjects. With aid of customized informatic tools based on C language programming and chemometric methods, the study unraveled the differences in skin metabolomes of psoriatic patients and healthy individuals. We proposed several biomarkers of disease progression, which correlate positively or negatively with plaque severity scores of examined psoriatic lesions. Currently, we work on evaluation of the relationship between skin metabolic profiles and treatment outcomes in psoriasis. In future work, we would also like to find a relation between skin and plasma metabolomes. We target patients treated with the newest type of therapy – biologic agents – which are very effective in the case of some patients. Moreover, the cost of biologic therapy is very expensive. We believe this metabolomic study will bring new insights on the psoriasis disease pathophysiology and will help to predict the treatment response.
Tao Wu
Shanghai University of Traditional Chinese Medicine, China
Title: Serum Lipid Alterations Identified in Chronic Hepatitis B, Hepatitis B Virus-Related Cirrhosis and Carcinoma Patients
Biography:
Dr.Wu has completed her PhD at the age of 35 years from Shanghai University of Traditional Chinese Medicine. She is mainly engaged in the field of the prevention and treatment of metabolic disease and application of metabonomics in clinical metabolic disease. She has published more than 20 papers in reputed journals.
Abstract:
Backgrounds&Aims: Hepatitis B virus (HBV) is a major pathogenic factor of liver diseases. The incidences of chronic hepatitis B (CHB), HBV-induced cirrhosis and carcinoma are high and increasing. This study aimed to evaluate lipid metabolite changes in the serum that are associated with disease progression from CHB to HBV-induced cirrhosis and to HBV-induced carcinoma. Methods: A targeted metabolomic assay was performed in fasting sera from 136 patients with CHB, 104 patients with HBV-Cirrhosis, and 95 patients with HBV-carcinoma using ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-TQMS). Results: Totally 140 metabolites were identified. A clear separation between HBV-cirrhosis and HBV-carcinoma was obtained using the PLS-DA (partial least squares discriminant analysis) scores of 9 lipid metabolites. Among the 9 metabolites, progressively lower levels of long-chain lysophosphatidylcholines (lysoPC a C18:2, lysoPC a C20:3, lysoPC a C20:4) were observed from CHB to cirrhosis to carcinoma; lower levels of lysoPC a C20:4 were also found in patients with higher Model For End-Stage Liver Disease (MELD Score) in the same disease group; and lysoPC a C20:3 levels were lower in Child-pugh Class C than in Class A and Class B in HBV-Cirrhosis and HBV-Carcinoma patients. Octadecadienylcarnitine(AC C18:2) level was higher in HBV-Cirrhosis patients than in the other two groups. Conclusions: Serum levels of selected long-chain lysoPCs are promising markers for the progression of HBV-induced liver diseases.
Pier Paolo Piccaluga
Bologna University School of Medicine, Italy
Title: Metabolism alterations in aggressive lymphomas
Biography:
Pier Paolo Piccaluga has done MD with honors from Bologna University (1997). He did Specialty in Hematology with honors (2001), PhD in Clinical and Experimental Hematology at Bologna University (2005), Specialty in Pathology with honors at Siena University (2014) and Post-doctoral fellowship at Columbia University, New York (USA). He is a Visiting fellow at Columbia University (USA, 2008) and Kiel University (Germany, 2009), Lecturer in Pathology at Bologna University: 2006-2012. Currently he is appointed as Associate Professor at the Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Italy.
Abstract:
Lipid metabolism alteration have been recently described in human cancer with relevant pathogenetic and possibly therapeutic implications. Our group described specific lipid metabolism patterns in Burkitt lymphomas. We have now extended our analysis to the spectrum of aggressive non Hodgkin lymphomas (NHL) including BL, diffuse large B-cell lymphoma (DLBCL), post-transplant lymphoproliferative diseases (PTLD), and nodal peripheral T-cell lymphomas (PTCLs). Particularly, we performed a gene expression profile-based analysis of 250 NHL cases and 25 samples representative of normal B-cell subsets (naïve, memory, germinal center, and plasmacells). Immunohistochemistry and quantitative real time PCR (RTQ-PCR) were used for validation. We found that BL, DLBCL and PTLD presented with consistent abnormalities if compared to normal B-cell subsets. The specific patterns were associated with clinico-pathological features including proliferation rate and genetic imbalances. Concerning DLBCL, specific analyses were carried out in ABC vs GCB cases as well as based on the genetic profile (double hit lymphomas vs. others). Further, specific attention was payed to EBV-associated tumors since virus can alter the metabolic profile. In conclusion, we identified specific metabolic patterns associated with B-cell lymphomagenesis and particularly those associated with peculiar features such as genetics and EBV infection.
Song Xue
Dalian Institute of Chemical Physics-CAS, China
Title: The correlation of polar lipids changes with TAG accumulation under nitrogen deprivation in Nannochloropsis oceanica based on lipidomics
Biography:
Song Xue PhD, is Professor, Marine Bioengineering Group Leader, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. She completed PhD in Biochemical Engineering in 2003 and was funded by “100 talents plan” of Chinese Academy of Sciences. From 2007 to 2009, she worked at Florida State University as research faculty. She has published papers in Science, Nature Structural & Molecular Biology, Molecular Cell, Bioresource technology and so on.
Abstract:
Nannochloropsis as one of the ocean microalgal species, has been considered as a promising resource of biodiesel feedstocks because of its capacity of TAG accumulation. TAG biosynthesis has been classified in different pathways. Polar lipids have big contribution for TAG accumulation by providing acyl group or DAG. The quantification and characterization of the contribution in microalgae are still veiled. In this study, there are total 117 polar lipid species covering eight classes (i.e. MGDG, DGDG, SQDG, DGTS, PC, PE, PG, PI) identified by UPLC/Orbitrap and quantified by UPLC/Q-TOF to study the correlation of polar lipids changes with TAG synthesis under nitrogen deprivation condition of Nannochloropsis oceanica IMET1. Through comparision of the lipids profiling of polar lipids, we proposed that C18 acyl groups are desaturated while attached to PC. PE and DGTS acts as the carrier of EPA synthesis and the donors of imported DAG to the chloroplast for major MGDG which is eukaryotic-like molecule species. Under nitrogen limitation, the 16:0 acyl chain-containing lipid species in PC and DGTS were increased while 16:1 acyl chain-containing lipid species decreased. Similarly, in PE and DGTS, 18:0, 18:1 acyl chain-containing lipid species in PC and DGTS increased while 18:2 acyl chain-containing lipid species decreased. The changes of lipid species in DGTS, PC and PE further affected photosynthetic membrane lipids profiling. Thus we suggest under nitrogen limitation, the changes in polar lipid are mainly caused by the reduction of palmitic ∆7 desaturase and oleic ∆12 desaturase activity.
Brijesh Pandey
Amity University Lucknow, India
Title: Does Zn2+ regulate structure and function of cinnamyl alcohol dehydrogenase isolated from Leucaena leucocephala?
Biography:
Brijesh Pandey has completed his PhD in Biochemistry from Univesity of Lucknow in 2010. He is the Programme Leader of BTech Biotechnology in Amity University Uttar Pradesh, Lucknow Campus from 2008 and Assistant Professor dealing with Recombinant DNA Technology. He has contributed significantly to understanding and designing strategy for Genetic improvement of Leucaena leucocephala.
Abstract:
Cinnamyl alcohol dehydrogenase (CAD) is a key enzyme of lignin biosynthetic pathway. The effect of Zn2+ on structure and function of native CAD enzyme, isolated from stem xylem of Leucaena leucocephala, was studied. The enzyme exhibited in vitro regulation by Zn2+ concentration. Inactive oligomerization was exhibited by this homodimeric enzyme of 76 kDa, at more than 2 mM Zn2+. Effect of Zn2+ was also studied on recombinant protein. At 2 mM Zn2+, the active enzyme was maximally expressed in soluble fraction and partitioned to inclusion bodies at higher concentrations. The in silico predicted structure revealed presence of two Zn2+ binding domains, one structural and other catalytic. The structural Zn2+ binding (C100,C103,C106,C114) domain was found projected out (as lobe) from main body of enzyme and speculated to cause inactive oligomerization of enzyme at higher Zn2+ concentration. Inactive oligomerization was validated by native PAGE. The structural Zn2+ may thus, be crucial, but the actual role assignment needs further experimental validation by mutagenesis of the structural Zn2+ binding domain. The role validation of structural Zn2+ would enable us to understand the mechanism by which the Zn2+ homoeostasis regulates the enzyme.
Sayyid Nooreddin Faraji
Shiraz University of Medical Science, Iran
Title: Correlation between tempers and metabolomics: A study protocol
Biography:
Sayyid Nooreddin Faraji has completed his MSc degree from Shiraz University of Medical Science and he is currently pursuing his PhD in Medical Biotechnology, Shiraz University of Medical Science, School of Medicine, Immunology departments, Recombinant Antibodies Lab.
Abstract:
According to traditional medicine, several single or combined tempers have been narrated. There are several approaches regarding to temper classifications in traditional medicine. While previous studies showed the effects of genetic and environmental factors on human metabolomics, however there is no study to evaluate how different tempers affect the human metabolomics. The first step of the study was done based on reviewing the literature for different temper approaches and their classification weather in Iran or China. Finally the details of the hypothesis into which how to make a proper statistical society for checking the molecular tests on them is offered. The genome of all humans is almost similar but there are differences in their healthy conditions. Investigating the metabolomics profiles of peoples who have different tempers and different healthy conditions and then compare them with other peoples of the statistical groups could be helpful to establish novel and molecular based classification of tempers. In these such investigations, we can make four groups to the study including: Classification of individuals based on Ibn Sina temper classification, based on other classification, a group that obey a proper diet according to their temper at least 40 days and other individuals and patients. This study will help to make molecular basis of different types of temper more clear. Also it could help people to know their body better and make proper decision for a choosing healthier diet and life style.
- Track : 14 Frontiers of Metabolomics Research
Track : 16 Therapeutic Metabolomics
Track : 18 Transcriptomics & Metabolic pathways
Chair
Andrea Armirotti
Istituto Italiano di Tecnologia, Italy
Co-Chair
Horng-Mo Lee
Taipei Medical University, Taiwan
Session Introduction
Loeffler Jean Philippe
Université de Strasbourg, France
Title: Metabolomic biomarkers for amyotrophic lateral sclerosis (ALS) in patients and animal models of ALS
Time : 14:46-15:05
Biography:
Dr. Jean-Philippe Loeffler is head of the Central and Peripheral Mechanisms of Neurodegeneration Laboratory (UMRs-INSERM U1118)in Strabourg (France). He got his B Sc in Biochemistry and Physiology, M Sc in physiology and his PhD in Neurobiology at University of Strasbourg (France). After a post doctoral fellow at Dept. of Neuropharmacology, Max Plank Institute of Psychiatry, Munich, he obtained a tenure position at INSERM from 1987 to 1996 as researcher and from 1996 to present as Research Director (H index: 46).From 1994 to 2000 he was Visiting Associate professor of Molecular Neurobiology (faculty member) at the Mount Sinaï Hospital, New York, USA. Since 2001, he heads a laboratory working at the interface between fundamental and clinical research, specifically striving to understand the mechanisms underlying the processes of neuronal death in neurodegenerative diseases.
Abstract:
Amyotrophic lateral sclerosis (ALS) is the most common motor-neuron (MN) disease in adults. ALS is characterized by the degeneration of upper and lower MN and is fatal within a time frame of 2 to 5 years following diagnosis. This diagnostic rests on differential clinical diagnosis that can take a year and thus the urgent medical need for this disease is to develop a rapid and simple diagnostic test based on the use of validated biomarkers. To address this issue, we focused over the last years on the metabolic aspects of ALS. We analysed the role of hypermetabolism associated with ALS and the role of lipids, both as a source of energy supply but also as a source of biochemical signalling molecules. We recently showed that in ALS models and in ALS patients, beta oxidation is favored compared with glycolysis. This results from a loss of metabolic flexibility and could be traced down at the genetic level to the induction of pyruvate dehydrogenase (PDH) kinase (PDK)4, the main regulator of PDH in the striated muscle tissue. This effect appears to be highly specific to ALS and is found in various ALS mice models (e.g., Tg for SOD1, FUS, TDP43……) and in ALS patient biopsies. Further, using global methods (e.g., transcriptomics and metabonomics) we show that: 1) Stearoyl coenzyme desaturase 1 (SCD1), the enzyme that drives lipids (mainly C 16 and C 18) towards beta oxidation is increased in patients and could thus be responsible for the ALS associated hypermetabolism. Further, we show that SCD1 activity, estimated by ratio of unsaturated on saturated C16 is a good predictor of ALS outcome. 2) The use of UPCL/TOF-MS reveals a crucial of glucosylceramides (GlcCer) in the course of the disease. HPLC analyses showed increased amounts of GlcCer and the downstream glycosphingolipids (GSLs) in ALS mice models (SOD1 G86R) and ALS patients. These findings suggest a crucial role of GSLs in ALS. Taken together, this set of data indicates a fundamental role of lipid metabolism in ALS. This approach should help to develop reliable biomarkers that will help to validate diagnostic tools that are currently required urgently.
Woo Duck Seo
National Institute of Crop Science, Republic of Korea
Title: Comparative assessment of phenolic compounds and antioxidant properties related to the harvest times from the leaves of Korean barley (Hordeum vulgare L.) cultivars
Time : 15:06-15:25
Biography:
Woo Duck Seo has completed his PhD from Gyeongsang National University and Post-doctoral studies from Korea Institute of Radiological & Medical Sciences. His researches focus on the analyses of natural product from crop source and test of biological assay such as metabolic syndrome.
Abstract:
This research was the first to investigate changes in phenolic profiles and antioxidant capacities from the leaves of various barley cultivars through four different harvest times. Ten phenolics were characterised as hydroxycinnamic acid, orientin, isoorientin, and isovitexin derivatives using UPLC-PDA-ESI/MS and nuclear magnetic resonance (NMR), especially, lutonarin (2) and saponarin (3) were the predominant constituents (71–75%) with significant differences in cultivars and harvest times. The highest average phenolic content was found with 2671.8 mg/100g on 23 days after sowing, whereas the lowest was 1400.8 mg/100g on 56 days. The radical scavenging abilities also exhibited considerable differences in the 80% methanol extracts (40 μg/ml), depending upon the phenolic contents. Interestingly, isoorientin (5) and orientin (6) possessed potent antioxidant effects with IC50 values of 20.7±1.1 and 27.5±7.3 μM (DPPH) as well as 5.7±0.3 and 8.2±0.3 μM (ABTS), respectively. Our results may be useful information to determine the optimal harvest time (mid-April) of barley leaves.
Benedetto Grimaldi
Istituto Italiano di Tecnologia, Italy
Title: Crosstalk between the circadian clock and cancer metabolism reveals novel anticancer strategies
Biography:
Benedetto Grimaldi, after completing his PhD in Genetics and Molecular Biology from University of Rome, La Sapienza (Italy), transitioned into a Post-doctoral fellowship under the mentorship of Prof. Sassone-Corsi (University of California, Irvine, USA), a leader in the field of circadian clock, metabolism and epigenetics. He is Senior Researcher at the “Istituto Italiano di Tecnologia (IIT)”, Italy, where he directs a laboratory of Molecular Medicine pursuing a line of research focused on the study of “clock-related pathologies”, and on the identification and evaluation of novel molecules with “clock modulator” activity for therapeutic applications
Abstract:
Despite epidemiological data indicate a close relation between circadian disruption and cancer, the suitability of a pharmacological modulation of the clock machinery as a viable approach to cancer therapy remains to be determined. We recently obtained the first evidence that the pharmacological targeting of a circadian regulator may be a suitable anticancer strategy: we revealed that the beta-variant of circadian nuclear receptor REV-ERB, REV-ERBβ, functions as an unpredicted major regulator of clock gene expression in different human tumor tissues cells, where it plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. These studies also identified a novel class of compounds with a dual inhibitory activity against both REV-ERBβ and autophagy, which decreased the viability of different tumor tissue cells at concentrations from 5 to 50 times lower than the singular clinically relevant autophagy inhibitor, chloroquine. The crucial position of REV-ERB proteins in the regulation of cellular metabolism suggests the provocative hypothesis in which the inhibition of both REV-ERBβ and autophagy cooperate to induce a metabolic dysfunction that is incompatible with cancer cell viability. Consistent with this view, we obtained data indicating a REV-ERBβ-mediated transcriptional regulation of cancer metabolism. Implicit in this hypothesis is the concept that the altered circadian regulation found in several tumors may be triggered by the special metabolic needs of the cancer cell. In addition, this scenario opens the possibility that REV-ERBβ inhibition may be suitable not only for combinatorial therapy with autophagy inhibitors, but also with a number of metabolic-related anticancer drugs, which identification and optimization is source of increasing effort in cancer research.
Horng-Mo Lee
Taipei Medical University, Taiwan
Title: Ferrous glycinate reverses Warburg effect and regulates cell energy metabolism via suppression of hypoxia-induced factor in human lung adenocarcinoma A549 cells
Time : 15:46-16:05
Biography:
Horng-Mo Lee graduated from School of Pharmacy in Taipei Medical University, Taipei, Taiwan. Upon graduation, he went to the U.S.A. and completed his PhD in Biochemistry at the University of Tennessee, Memphis, and postdoctoral training in St. Jude Children’s research hospital in Memphis, Tennessee. He is currently working on exploring the cancer therapeutic approaches targeting energy metabolism. He has published more than 75 articles in peer-reviewed journals. He served as the president of Central Taiwan University of Science and Technology from 2009-2015. He is now a professor in Department of Medical Technology and Biotechnology in Taipei Medical University.
Abstract:
Cancer cells are characterized with aerobic glycolysis and suppressing of mitochondrial energy metabolism (Warburg effect). In the present study, we demonstrated that treatment with ferrous glycinate reversed aerobic glycolysis, reactivated mitochondrial energy metabolism in lung adenocarcinoma A549 cells. Incubation of A549 cells with ferrous glycinate for 24h decreased expression levels of glucose transporter, Glut-1, and glycolytic enzymes including hexokinase-2, and lactate dehydrogenase A. On the other hand, treatment with ferrous glycinate reactivated oxidative phosphorylation by suppressing the expression of pyruvate dehydrogenase kinase-1 and thereby pyruvate dehydrogenase phosphorylation which subsequently increased mitochondrial membrane potential and ATP production. Treatment of A549 cells with ferrous glycinate decreased the protein levels of HIF-1 alfaunder nomoxia and hypoxia conditions. The reduction of HIF-1 alfa was reversed by pretreatment with proteosome inhibitor, or prolyl hydroxylase inhibitor. Given HIF-1 alfaplays a pivotal role in regulating cancer cell metabolism, these data suggest that ferrous glycinate may regulate energy metabolism, glycolysis in lung adenocarcinoma cells via suppression of HIF-1 alfa
Björn Riefke
Bayer Pharma AG, Germany
Title: NMR-based metabolomics analysis of 2D with 3D (Spheroids) of breast cancer cells
Time : 16:26-16:45
Biography:
Dr. Björn Riefke completed his PhD in Biology in 1994 from Heinrich-Heine-University in Duesseldorf, Germany. Since 1994 he have worked in various positions in research and development of former Schering AG and since 2006 of Bayer Pharma AG. He is head of Metabolic Profiling and Clinical Pathology Group in Toxicology and since then involved in the establishment of metabolic profiling platform supporting projects in toxicology, biomarker research and pharmacology.
Abstract:
Findings in 2D tumor cell models only partly translate to experimental outcome in vivo. Chemotherapy strategies target proliferating cells adjacent to blood vessels with sufficient supply of oxygen and nutrients. In poorly vascularized regions of the tumor cells adapt to survive and are resistant to chemotherapy. 3D Spheroids of tumor cells resemble characteristics of invasive tumors and are an intersting model to target the inner core of tumors. We used NMR-based metabolomics to study the metabolic differences of T47D breast cancer cells cultivated in 2D and 3D conditions. Additionally tumor spheroids were treated with compounds targeting the inner core of the spheroids. After 48 h incubation cells were quenched and harvested with a ice-cold MeOH/Chloroform/H2O mixture. The freeze dryed sample extracts were reconstituted in phophate-buffered saline and high-resolution 1H-NMR spectra were measured with a 600 MHz Bruker Biospin equipped with a cryo-probe and sample jet system. Baseline and peak shift corrected spectra were divided into 0.04 ppm buckets and integrated. Multivariate data analysis was performed on bucketed spectra to identify difference between 2D and 3 D control conditions. Afterwards metabolites were annotated using the Chenomx Profiler software. Metabolite differences showed signatures indicative for glucose deprivation in spheroids accompanied with limited capacity to perfom synthesis and cell division to maintain cell hemostasis and resulting in tumor dormancy. Studied compounds targeting the specific inner core region of tumor spheroids resemble metabolic profiles similar to inhibitors of mitochondrial respiration like Antimycin A or Oligomycin.
Dilson Ferreira da Luz
Plastic Clinic Dilson Luz, Brazil
Title: Progressive tunnelizations in neck face lift detachment: Fat grafts as complement
Biography:
Graduated in medicine in 1969, performing plastic surgery since 1975. Presents this original technique for cutaneous detachment in Face Lift for 16 years. Having held dozens of lectures at conferences in Brazil and abroad. Publications in various journals. In 2009 he published the book Technical Dilson Luz, Tunelizações Progressive in the Face Lift. In 2013 published Technical Dilson Luz, Tunelizaciones Progresivas. In 2014, he published the chapter Progressive Tunnelizations in Neck Face Lift Detachment in necklift book, author Malcolm Paul. Member and Specialist of the Brazilian Society of Plastic Surgery and a member of the International Society Aesthetic Plastic Surgery.
Abstract:
The author describe 12 years experienced in the application of a new and simple method of facial cutaneous detachment using specially designed bi-faceted rigid steel wands called “Dilson Luz Vascular Dilation Wands®”. These wands considerably reduce the bleeding during face-lift surgery, reducing both postoperative hematomas as well as the risk of facial nerve injury. This technique "PROGRESSIVES TUNNELIZATIONS" involves stretching the blood vessels to the point of rupture by inserting progressively larger “wands.” At the point of rupture, a spontaneous coagulation within the vascular extremities occurs. This is due to a significant blood platelet migration induced by the stimulation from the rupture of the vascular intima. The wands vary in dimension from 1.5 to 20 mm and the larger were used for cutaneous facial complete detachment, and the more fine to perform tunnels. A method which we found to result in minimal bleeding across the detached surface as well as an excellent perfusion of the over lying skin. With this new technique, we have obtained improved cutaneous detachment, reduced postoperative swelling, edema and ecchymosis; prophylaxis of facial nerve damage and/or late postoperative hematoma formation. The fat grafts with active platelets always perform the face lift.
Biography:
Simon D Lytton has completed his PhD at the age of 34 years from Hebrew University-Jerusalem and postdoctoral studies from Karolinska Institute Sweden and NIH Bethedsda Maryland USA. He is private consultant of SeraDiaLogistics, focused on immunology medical research and diagnostics. He has published more than 30 papers in reputed journals and has been serving as a consultant for the VG Test device 3QBD CEO Mr. Moshe Golan
Abstract:
Purpose A new CE-marked portable desktop ion mobility spectrometer (VGTest) was used for detection of malodorous biogenic amines indicative of bacterial vaginosis (BV). This study aimed to assess the performance of this testing method for the first time in a routine ambulatory care clinic and to determine the relative levels of biogenic amines in vaginal fluid of BV. Methods Vaginal and cervical swabs (n = 57) were surveyed for infections. Cases of BV (n = 18) confirmed positive according to ‘‘Amsel’’ criteria and normal controls (n = 39) showing no infection under clinical examination and testing negative in wet mount microscopy were included in the IMS analysis. Results The trimethylamine (TMA) content in vaginal fluid of the BV-positive cases, AUCTMA/AUCTotal [mean 0.215 (range 0.15–0.35)] was significantly higher than normal controls [mean 0.06 (range 0.048–0.07)] p .0001. The putrescine (1,4-diaminobutane, PUT) and cadaverine (1,5-diaminopentane, CAD) of BV-positive cases were above controls at borderline significance. The AUCTMA/AUCTotal ratios correlated neither with AUCPUT/ AUCTotal nor AUCCAD/AUCTotal among BV-positive patients. In contrast, among normal controls all the biogenic amines were at a low level and the linear regression analysis revealed striking positive correlations of AUCTMA/AUCTotal with AUCPUT/AUCTotal (p .05) and AUCCAD/AUCTotal (p .001). The test shows 83 % sensitivity and 92 % specificity at a cut-off of AUCTMA/ AUCTotal = 0.112 and AUC of receiver operator characteristic = 0.915 (0.81–0.97, 95 % CI). Conclusions VGTest-IMS is accurate and feasible for point-of-care testing of BV in the ambulatory care setting. Further evaluations are in progress to assess the utility of VGTest-IMS for differential diagnosis of candidosis, non-BV infection and common inflammatory conditions.
- Special Session 2
Session Introduction
Ashkan Emadi
University of Maryland School of Medicine, USA
Title: Translational Research in Targeting Glucose or Glutamine Dependency in Solid and Hematologic Neoplasms
Biography:
Dr. Emadi received his M.D. at Tehran University of Medical Sciences and his Ph.D. in Organic Chemistry at the Illinois Institute of Technology. He developed novel methodologies for the regiospecific synthesis of multiple naphthoquinone derivatives related to the natural product conocurvone, and was granted “Highest Standards of Academic Achievement Award”. Following completion of his Ph.D., he completed his internship and residency in Internal Medicine at the University of Kentucky and the University of Cincinnati, respectively. Subsequently, Dr. Emadi was trained in Hematology and Medical Oncology Fellowship Program at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center. Dr. Emadi joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center as an Associate Professor of Medicine, Pharmacology and Experimental Therapeutics at the University of Maryland School Of Medicine and serves as Director of the ACGME-accredited Hematology and Oncology Fellowship Program. He previously served as medical officer at the Division of Hematology Products (DHP), United States Food and Drug Administration (FDA), and as visiting scientist at Division of Adult Hematology, Department of Internal Medicine, School of Medicine, Johns Hopkins University. Dr. Emadi has experience and in-depth understanding of the multiple aspects of cancer drug development including basic organic chemistry and molecular synthesis, in vitro and in vivo studies, and all phases of clinical trials as well as regulatory science.
Abstract:
Before the recruitment of new blood vessels, proliferation of cancer cells in a three dimensional multi-cellular cluster is limited by diffusion of oxygen and nutrients, such that a phase of metabolic adaptation must be endured. Transcription factors such as hypoxia inducible factors (HIFs) are overexpressed in many neoplastic cells and induce genes, such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), which permit hypoxic metabolic adaptation. Glucose, which is the main energy source for normal and tumor cells, is taken up and converted by glycolysis to two molecules of pyruvate. The dramatic increase in glucose uptake by tumors provides a means to detect cancers and follow response to therapy by PET scanning. When oxygen is available, pyruvate converted to acetyl-CoA by pyruvate dehydrogenase in the mitochondrion and further metabolized through tricarboxylic acid cycle. When oxygen is limited, HIF-1 induces virtually all glycolytic enzyme genes and PDK1, which inhibits PDH and diminishes mitochondrial acetyl-CoA production and respiration. Through this adaptation, hypoxic cells switch initially to anaerobic glycolysis that catalyzes the final conversion of pyruvate to lactate via LDHA. Later on, due to genetic alterations, even under non-hypoxic conditions, neoplastic cells utilize aerobic glycolysis phenomenon. Small molecule inhibitors against different enzymes in the glucose metabolism are already available making the potential for clinical translation the more likely. Glutamine is the most abundant amino acid in the intracellular compartment as well as human plasma. Glutamine is involved in the generation of non-essential amino acids for protein synthesis as well as nitrogen supply for purine and pyrimidine synthesis. Glutamine also stimulates the mammalian target of rapamycin complex 1 (mTORC1) and its deprivation inhibits mTORC1 and causes apoptosis of many neoplastic cells. After entering the cell through a special transporter, glutamine can be converted to glutamic acid by removal of its amide group, a reaction catalyzed by glutaminase enzymes. Subsequently, glutamic acid can be converted to α-ketoglutarate (αKG), either by transamination or by oxidation processes. Perturbation of different aspects of glutamine metabolism for treatment of solid and neoplastic malignancies is currently being tested in clinical trials. These fundamental metabolic differences between the cancers and normal tissues will be discussed for therapeutic applications.