Analytical protocols based on LC–MS, GC–MS and CE–MS for nontargeted metabolomics of biological tissues

Papers of special note have been highlighted as: • of interest; •• of considerable interest.

References

• 1 Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp. Funct. Genomics 2(3), 155–168 (2001).
  Medline CASGoogle Scholar
• 2 Nicholson JK, Wilson ID. Opinion: understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2(8), 668–677 (2003).
  Medline CASGoogle Scholar
• 3 Nicholson J K, Lindon JC. Systems biology: metabonomics. Nature 455, 1054–1056 (2008).
  Medline CASGoogle Scholar
• 4 Fiehn O. Metabolomics – the link between genotypes and phenotypes. Plant Mol. Biol. 48(1–2), 155–171 (2002).
  Medline CASGoogle Scholar
• 5 Lundström SL, Levänen B, Nording M et al. Asthmatics exhibit altered oxylipin profiles compared to healthy individuals after subway air exposure. PLoS ONE 6(8), e23864 (2011).
  MedlineGoogle Scholar
• 6 Scholz M, Gatzek S, Sterling A, Fiehn O, Selbig J. Metabolite fingerprinting: detecting biological features by independent component analysis. Bioinformatics 20(15), 2447–2454 (2004).
  Medline CASGoogle Scholar
• 7 Kind T, Fiehn O. Metabolomic database annotations via query of elemental compositions: mass accuracy is insufficient even at less than 1 ppm. BMC Bioinformat. 7, 234 (2006).
  MedlineGoogle Scholar
• 8 Kim JW, Ryu SH, Kim S et al. Pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary (1)H NMR-based metabolomics in humans. Anal. Chem. 85(23), 11326–11334 (2013).
  Medline CASGoogle Scholar
• 9 Naz S, Garcia A, Rusak M, Barbas C. Method development and validation for rat serum fingerprinting with CE–MS: application to ventilator-induced-lung-injury study. Anal. Bioanal. Chem. 405(14), 4849–4858 (2013).• Untargeted profiling of rat serum using capillary electrophoresis-mass spectrometry, giving a picture of rat serum metabolites. Also describes the importance of method validation for untargeted metabolomics study.
  Medline CASGoogle Scholar
• 10 Naz S, Garcia A, Barbas C. Multiplatform analytical methodology for metabolic fingerprinting of lung tissue. Anal. Chem. 85(22), 10941–10948 (2013).•• Pronouncing the importance of the multiplatform metabolomics approach along with method validation, emphasizing wider metabolite coverage in lung tissue, which can also be applied to other tissue types.
  Medline CASGoogle Scholar
• 11 Balderas C, Rupérez FJ, Ibañez E et al. Plasma and urine metabolic fingerprinting of Type 1 diabetic children. Electrophoresis 34(19), 2882–2890 (2013).
  Medline CASGoogle Scholar
• 12 Sen Y, Wang K, Chiu L et al. Metabolic phenotype of the healthy rodent model using in-vial extraction of dried serum, urine, and cerebrospinal fluid spots. Anal. Chem. 85(15), 7257–7263 (2013).
  Medline CASGoogle Scholar
• 13 Yonezawa K, Nishiumii S, Kitamoto-Matsuda J et al. Serum and tissue metabolomics of head and neck cancer. Cancer Genom. Proteom. 10(5), 233–238 (2013).
  Medline CASGoogle Scholar
• 14 Huang Q, Yin P, Wang J et al. Method for liver tissue metabolic profiling study and its application in Type 2 diabetic rats based on ultra performance liquid chromatography-mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879(13–14), 961–967 (2011).
  Medline CASGoogle Scholar
• 15 Ganti S, Taylor SL, Abu A et al. Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis. Cancer Res. 72(14), 3471–3479 (2012).
  Medline CASGoogle Scholar
• 16 Hori S, Nishiumi S, Kobayashi K et al. A metabolomic approach to lung cancer. Lung Cancer 74(2), 284–292 (2011).
  MedlineGoogle Scholar
• 17 Sugimoto M, Ikeda S, Niigata K, Tomita M, Sato H, Soga T. MMMDB: mouse multiple tissue metabolome database. Nucleic Acids Res. 40(Database issue), D809–D814 (2012).
  Medline CASGoogle Scholar
• 18 Gang S, Kui Y, Zhongdan Z, Shaoping G, Xianlin H, Richard WG. Shotgun metabolomics approach for the analysis of negatively charged water-soluble cellular metabolites from mouse heart tissue. Anal. Chem. 79(17), 6629–6640 (2007).
  MedlineGoogle Scholar
• 19 Luke CM, Stephen CK, Rong T, Robert ES. Sample preparation methodology for mouse heart metabolomics using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Talanta 108, 123–130 (2013).
  MedlineGoogle Scholar
• 20 Mal M, Koh PK, Cheah PY, Chan EC. Development and validation of a gas chromatography/mass spectrometry method for the metabolic profiling of human colon tissue. Rapid Commun. Mass Spectrom. 23(4), 487–489 (2009).
  Medline CASGoogle Scholar
• 21 Adahchour M, Beens J, Brinkman UA. Recent developments in the application of comprehensive two-dimensional gas chromatography. J. Chromatogr. A 1186(1–2), 67–108 (2008).
  Medline CASGoogle Scholar
• 22 Nikolskiy I, Mahieu NG, Chen YJ, Tautenhahn R, Patti GJ. An untargeted metabolomic workflow to improve structural characterization of metabolites. Anal. Chem. 85, 7713–7719 (2013).
  Medline CASGoogle Scholar
• 23 García-Heredia A, Kensicki E, Mohney RP et al. Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach. J. Proteome Res. 12(4), 1946–1955 (2013).
  Medline CASGoogle Scholar
• 24 McBurney RN, Hines WM, Von Tungeln LS et al. The liver toxicity biomarker study Phase I: markers for the effects of tolcapone or entacapone. Toxicol. Pathol. 40(6), 951–964 (2012).
  Medline CASGoogle Scholar
• 25 Lin S, Liu H, Kanawati B et al. Hippocampal metabolomics using ultrahigh-resolution mass spectrometry reveals neuroinflammation from Alzheimer's disease in CRND8 mice. Anal. Bioanal. Chem. 405, 5105–5117 (2013).
  Medline CASGoogle Scholar
• 26 Yabushita S, Fukamachi K, Tanaka H et al. Metabolomic and transcriptomic profiling of human K-ras oncogene transgenic rats with pancreatic ductal adenocarcenomas. Carcinogenesis 34(6), 1251–1259 (2013).
  Medline CASGoogle Scholar
• 27 Hanzu FA, Vinaixa M, Papageorgiou A et al. Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: an untargeted metabolomics approach. Obesity 22(3), 698–704 (2013).
  MedlineGoogle Scholar
• 28 Shimura D, Nakai G, Jiao Q et al. Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart. Am. J. Physiol. Heart Circ. Physio. 305(4), H494–H505 (2013).
  Medline CASGoogle Scholar
• 29 Boudonck KJ, Mitchell MW, Német L et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol. Pathol. 37(3), 280–292 (2009).
  Medline CASGoogle Scholar
• 30 Baumgarner BL, Cooper BR. Evaluation of a tandem gas chromatography/time-of-flight mass spectrometry metabolomics platform as a single method to investigate the effect of starvation on whole-animal metabolism in rainbow trout (Oncorhynchus mykiss). J. Exp. Biol. 215(Pt 10), 1627–1632 (2012).
  Medline CASGoogle Scholar
• 31 Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29, 1181–1189 (1999).
  Medline CASGoogle Scholar
• 32 Nicholson JK, Connelly J, Lindon JC, Holmes E. Metabonomics: a platform for studying drug toxicity and gene function. Nat. Rev. Drug Discov. 1, 153–161 (2002).
  Medline CASGoogle Scholar
• 33 Gray H, Lewis WH. Gray's Anatomy of the Human Body (20th Edition). Bartleby, New York, NY, USA (2000).
  Google Scholar
• 34 Brauer HA, Makowski L, Hoadley KA et al. Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer. Clin. Cancer Res. 19(3), 571–585 (2013).
  Medline CASGoogle Scholar
• 35 Laws ER, Parney IF, Huang W et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J. Neurosurg. 99(3), 467–473 (2003).
  MedlineGoogle Scholar
• 36 Zhang WY, Liu S, Li HD, Cai HL. Chronic unpredictable mild stress affects myocardial metabolic profiling of SD rats. J. Pharm. Biomed. Anal. 70, 534–438 (2012).
  Medline CASGoogle Scholar
• 37 Ly-Verdú S, Schaefer A, Kahle M et al. The impact of blood on liver metabolite profiling– a combined metabolomic and proteomic approach. Biomed. Chromatogr. 28(2), 231–240 (2013). 
  MedlineGoogle Scholar
• 38 Zhang G, He P, Tan H, Budhu A et al. Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer. Clin. Cancer Res. 19(18), 4983–4993 (2013).
  Medline CASGoogle Scholar
• 39 Figueroa JD, Cordero K, Serrano-Illan M et al. Metabolomics uncovers dietary omega-3 fatty acid-derived metabolites implicated in anti-nociceptive responses after experimental spinal cord injury. Neuroscience 255C, 1–18 (2013).
  Google Scholar
• 40 Zhao T, Zhang H, Zhao T et al. Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease. J. Pharm. Biomed. Anal. 60, 32–43 (2012).
  Medline CASGoogle Scholar
• 41 Chintapalli VR, Al Bratty M, Korzekwa D et al. Mapping an atlas of tissue-specific Drosophila melanogaster metabolomes by high resolution mass spectrometry. PLoS ONE 8(10), e78066 (2013).
  Medline CASGoogle Scholar
• 42 Masson P, Alves AC, Ebbels TM, Nicholson JK, Want EJ. Optimization and evaluation of metabolite extraction protocols for untargeted metabolic profiling of liver samples by UPLC–MS. Anal. Chem. 82, 7779–7786 (2010).•• Proposing a robust metabolites extraction protocol for untargeted liver profiling, which can be applied to other tissues.
  Medline CASGoogle Scholar
• 43 Masson P, Spagou K, Nicholson JK, Want EJ. Technical and biological variation in UPLC–MS-based untargeted metabolic profiling of liver extracts: application in an experimental toxicity study on galactosamine. Anal. Chem. 83, 1116–1123 (2011).
  Medline CASGoogle Scholar
• 44 Liang X, Ubhayakar S, Liederer BM et al. Evaluation of homogenization techniques for the preparation of mouse tissue samples to support drug discovery. Bioanalysis 3, 1923–1933 (2011).• Comparing available homogenization conditions on different types of mouse tissue and optimizing the homogenization solvent and other conditions for each tissue type.
  CASGoogle Scholar
• 45 Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).
  Medline CASGoogle Scholar
• 46 Le Belle JE, Harris NG, Williams SR, Bhakoo KK. A comparison of cell and tissue extraction techniques using high resolution 1H-NMR spectroscopy. NMR Biomed. 15, 37–44 (2002).
  Medline CASGoogle Scholar
• 47 Matyash V, Liebisch G, Kurzchalia TV, Schevchenko A, Schwudke D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J. Lipid Res. 49(5), 1137–1146 (2008).
  Medline CASGoogle Scholar
• 48 Wu H, Southam AD, Hines A, Viant MR. High-throughput tissue extraction protocol for NMR- and MS-based metabolomics. Anal. Biochem. 372(2), 204–212 (2008).
  Medline CASGoogle Scholar
• 49 Want EJ, Masson P, Michopoulos F et al. Global metabolic profiling of animal and human tissues via UPLC–MS. Nat. Protoc. 8, 17–32 (2013).•• Explaining the protocol for biphasic sample treatment, analytical conditions for ultra-performance liquid chromatography–mass spectrometry, data treatment and metabolite identification of animal and human tissues.
  Medline CASGoogle Scholar
• 50 Kirwan JA, Broadhurst DI, Davidson RL, Viant MR. Characterising and correcting batch variation in an automated direct infusion mass spectrometry (DIMS) metabolomics workflow. Anal. Bioanal. Chem. 405(15), 5147–5157 (2013).• Developing a robust workflow that will help in minimizing batch-to-batch variation in large-scale studies.
  Medline CASGoogle Scholar
• 51 Yamatani H, Takahashi K, Yoshida T, Soga T, Kurachi H. Differences in the fatty acid metabolism of visceral adipose tissue in postmenopausal women. Menopause 21(2), 170–176 (2014).
  MedlineGoogle Scholar
• 52 Ji B, Ernest B, Gooding JR, Das S et al. Transcriptomic and metabolomic profiling of chicken adipose tissue in response to insulin neutralization and fasting. BMC Genomics 13, 41 (2012).
  MedlineGoogle Scholar
• 53 Putluri N, Shojaie A, Vasu VT et al. Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression. Cancer Res. 71(24), 7376–7386 (2011).
  Medline CASGoogle Scholar
• 54 Thysell E, Surowiec I, Hörnberg E et al. Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol. PLoS ONE 5(12), e14175 (2010).
  Medline CASGoogle Scholar
• 55 Wang X, Zeng C, Lin J et al. Metabonomics approach to assessing the modulatory effects of St John's Wort, ginsenosides, and clomipramine in experimental depression. J. Proteome Res. 11(12), 6223–6230 (2012).
  Medline CASGoogle Scholar
• 56 Graham SF, Chevallier OP, Roberts D, Hölscher C, Elliott CT, Green BD. Investigation of the human brain metabolome to identify potential markers for early diagnosis and therapeutic targets of Alzheimer's disease. Anal. Chem. 85(3), 1803–1811 (2013).
  Medline CASGoogle Scholar
• 57 Epstein AA, Narayanasamy P, Dash PK et al. Combinatorial assessments of brain tissue metabolomics and histopathology in rodent models of human immunodeficiency virus infection. J. Neuroimmune Pharmacol. 8(5), 1224–1238 (2013).
  MedlineGoogle Scholar
• 58 van Vliet E, Eixarch E, Illa M et al. Metabolomics reveals metabolic alterations by intrauterine growth restriction in the fetal rabbit brain. PLoS ONE 8(5), e64545 (2013).
  Medline CASGoogle Scholar
• 59 Kopp F, Komatsu T, Nomura DK et al. The glycerophospho metabolome and its influence on amino acid homeostasis revealed by brain metabolomics of GDE1(-/-) mice. Chem. Biol. 17(8), 831–840 (2010).
  Medline CASGoogle Scholar
• 60 García-Cañaveras JC, Donato MT, Castell JV, Lahoz A. A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations. J. Proteome Res. 10(10), 4825–4834 (2011).
  Medline CASGoogle Scholar
• 61 Lv H, Palacios G, Hartil K, Kurland IJ. Advantages of tandem LC–MS for the rapid assessment of tissue-specific metabolic complexity using a pentafluorophenylpropyl stationary phase. J. Proteome Res. 10(4), 2104–2112 (2011).
  Medline CASGoogle Scholar
• 62 Fenli S, Feng W, Ronghua Z, Huande L. Biochemical mechanism studies of venlafaxine by metabonomic method in rat model of depression. Eur. Rev. Med. Pharmacol. Sci. 17(1), 41–48 (2013).
  Medline CASGoogle Scholar
• 63 Baur P, Martin FP, Gruber L et al. Metabolic phenotyping of the Crohn's disease-like IBD etiopathology in the TNF(ΔARE/WT) mouse model. J. Proteome Res. 10(12), 5523–5535 (2011).
  Medline CASGoogle Scholar
• 64 Maekawa K, Hirayama A, Iwata Y et al. Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy. J. Mol. Cell Cardiol. 59, 76–85 (2013).
  Medline CASGoogle Scholar
• 65 Montrose DC, Zhou XK, Kopelovich L et al. Metabolic profiling, a noninvasive approach for the detection of experimental colorectal neoplasia. Cancer Prev. Res. (Phila). 5(12), 1358–1367 (2012).
  Medline CASGoogle Scholar
• 66 Liu Y, Yan S, Ji C et al. Metabolomic changes and protective effect of (L)-carnitine in rat kidney ischemia/reperfusion injury. Kidney Blood Press Res. 35(5), 373–381 (2012).
  Medline CASGoogle Scholar
• 67 Mains J, Tan LE, Zhang T, Young L, Shi R, Wilson C. Species variation in small molecule components of animal vitreous. Invest. Ophthalmol. Vis. Sci. 53(8), 4778–4786 (2012).
  Medline CASGoogle Scholar
• 68 Brauer HA, Makowski L, Hoadley KA et al. Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer. Clin. Cancer. Res. 19(3), 571–585 (2013).
  Medline CASGoogle Scholar
• 69 Chen S, Hoene M, Li J et al. Simultaneous extraction of metabolome and lipidome with methyl tert-butyl ether from a single small tissue sample for ultra-high performance liquid chromatography/mass spectrometry. J. Chromatogr. A. 1298, 9–16 (2013).
  Medline CASGoogle Scholar
• 70 Holst S, Stavenhagen K, Balog CI et al. Investigations on aberrant glycosylation of glycosphingolipids in colorectal cancer tissues using liquid chromatography and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). Mol. Cell Proteomics 12(11), 3081–3093 (2013).
  Medline CASGoogle Scholar
• 71 Huang Q, Tan Y, Yin P et al. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res. 73(16), 4992–5002 (2013).
  Medline CASGoogle Scholar
• 72 Budczies J, Brockmöller SF, Müller BM et al. Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism. J. Proteomics 94, 279–288 (2013).
  Medline CASGoogle Scholar
• 73 McDunn JE, Li Z, Adam KP et al. Metabolomic signatures of aggressive prostate cancer. Prostate 73(14), 1547–1560 (2013).
  Medline CASGoogle Scholar
• 74 Denkert C, Budczies J, Weichert W et al. Metabolite profiling of human colon carcinoma – deregulation of TCA cycle and amino acid turnover. Mol. Cancer 7, 72 (2008).
  MedlineGoogle Scholar
• 75 Kami K, Fujimori T, Sato H et al. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry. Metabolomics 9(2), 444–453 (2013).
  Medline CASGoogle Scholar
• 76 Mal M, Koh PK, Cheah PY, Chan EC. Metabotyping of human colorectal cancer using two-dimensional gas chromatography mass spectrometry. Anal. Bioanal. Chem. 403(2), 483–493 (2012).
  Medline CASGoogle Scholar
• 77 Koek MM, van der Kloet FM, Kleemann R, Kooistra T, Verheij ER, Hankemeier T. Semi-automated non-target processing in GC × GC–MS metabolomics analysis: applicability for biomedicalstudies. Metabolomics 7(1), 1–14 (2011).
  Medline CASGoogle Scholar
• 78 Chan EC, Koh PK, Mal M et al. Metabolic profiling of human colorectal cancer using high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and gas chromatography mass spectrometry (GC/MS). J. Proteome Res. 8(1), 352–361 (2009).
  Medline CASGoogle Scholar
• 79 Song H, Wang L, Liu HL et al. Tissue metabolomics fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity. Oncol. Rep. 26(2), 431–438 (2011).
  Medline CASGoogle Scholar
• 80 Beyoğlu D, Imbeaud S, Maurhofer O. Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. Hepatology 58(1), 229–238 (2013).
  Medline CASGoogle Scholar
• 81 Chuang HL, Huang YT, Chiu CC et al. Metabolomics characterization of energy metabolism reveals glycogen accumulation in gut-microbiota-lacking mice. J. Nutr. Biochem. 23(7), 752–758 (2012).
  Medline CASGoogle Scholar
• 82 Gu S, A J, Wang G et al. Metabonomic profiling of liver metabolites by gas chromatography-mass spectrometry and its application to characterizing hyperlipidemia. Biomed. Chromatogr. 24(3), 245–252 (2010).
  MedlineGoogle Scholar
• 83 Sakai A, Nishiumi S, Shiomi Y et al. Metabolomic analysis to discover candidate therapeutic agents against acute pancreatitis. Arch. Biochem. Biophys. 522(2), 107–120 (2012).
  Medline CASGoogle Scholar
• 84 Heazell AE, Brown M, Dunn WB et al. Analysis of the metabolic footprint and tissue metabolome of placental villous explants cultured at different oxygen tensions reveals novel redox biomarkers. Placenta 29(8), 691–698 (2008).
  Medline CASGoogle Scholar
• 85 Catchpole G, Platzer A, Weikert C et al. Metabolic profiling reveals key metabolic features of renal cell carcinoma. J. Cell Mol. Med. 15(1), 109–118 (2011).
  Medline CASGoogle Scholar
• 86 Hu ZP, Kim YM, Sowa MB et al. Metabolomic response of human skin tissue to low dose ionizing radiation. Mol. Biosyst. 8(7), 1979–1986 (2012).
  Medline CASGoogle Scholar
• 87 Abaffy T, Möller M, Riemer DD, Milikowski C, Defazio RA. A case report – volatile metabolomic signature of malignant melanoma using matching skin as a control. J. Cancer Sci. Ther. 3(6), 140–144 (2011).
  MedlineGoogle Scholar
• 88 Huang CC, Lin WT, Hsu FL, Tsai PW, Hou CC. Metabolomics investigation of exercise-modulated changes in metabolism in rat liver after exhaustive and endurance exercises. Eur. J. Appl. Physiol. 108(3), 557–566 (2010).
  Medline CASGoogle Scholar
• 89 Wang Y, Tao Y, Lin Y et al. Integrated analysis of serum and liver metabonome in liver transplanted rats by gas chromatography coupled with mass spectrometry. Anal. Chim. Acta 633(1), 65–70 (2009).
  Medline CASGoogle Scholar
• 90 Wone B, Donovan ER, Hayes JP. Metabolomics of aerobic metabolism in mice selected for increased maximal metabolic rate. Comp. Biochem. Physiol. Part D Genomics Proteomics 6(4), 399–405 (2011).
  Medline CASGoogle Scholar
• 91 Houtkooper RH, Argmann C, Houten SM et al. The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011).
  MedlineGoogle Scholar
• 92 Brown M, Dunn WB, Dobson P et al. Mass spectrometry tools and metabolite-specific databases for molecular identification in metabolomics. Analyst 134(7), 1322–1332 (2009).
  Medline CASGoogle Scholar
• 93 Shimura D, Nakai G, Jiao Q et al. Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart. Am. J. Physiol. Heart Circ. Physiol. 305(4), H494–H505 (2013).
  Medline CASGoogle Scholar
• 94 Ooga T, Sato H, Nagashima A et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol. Biosyst. 7(4), 1217–1223 (2011).
  Medline CASGoogle Scholar
• 95 Hrydziuszko O, Silva MA, Perera MT et al. Application of metabolomics to investigate the process of human orthotopic liver transplantation: a proof-of-principle study. OMICS 14(2), 143–150 (2010).
  Medline CASGoogle Scholar
• 96 Ly-Verdú S, Schaefer A, Kahle M et al. An untargeted metabolomic workflow to improve profiling – a combined metabolomic and proteomic approach. Anal. Chem. 85(16), 7713–7719 (2013).
  MedlineGoogle Scholar
• 97 Beyoğlu D, Imbeaud S, Maurhofer O et al. Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. Hepatology 58(1), 229–238 (2013).
  Medline CASGoogle Scholar
• 98 Budczies J, Denkert C, Müller BM et al. Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue-a GC-TOFMS based metabolomics study. BMC Genomics 13, 334 (2012).
  Medline CASGoogle Scholar
• 99 Wu H, Xue R, Lu C et al. Metabolomic study for diagnostic model of oesophageal cancer using gas chromatography/mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877(27), 3111–3117 (2009).
  Medline CASGoogle Scholar
• 100 Wu H, Xue R, Tang Z et al. Metabolomic investigation of gastric cancer tissue using gas chromatography/mass spectrometry. Anal. Bioanal. Chem. 396(4), 1385–1395 (2010).
  Medline CASGoogle Scholar
• 101 Lin S, Yang Z, Zhang X, Bian Z, Cai Z. Hippocampal metabolomics reveals 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity associated with ageing in Sprague-Dawley rats. Talanta 85(2), 1007–1012 (2011).
  Medline CASGoogle Scholar
• 102 Cubero-Leon E, Minier C, Rotchell JM, Hill EM. Metabolomic analysis of sex specific metabolites in gonads of the mussel, Mytilus edulis. Comp. Biochem. Physiol. Part D Genomics Proteomics 7(2), 212–219 (2012).
  Medline CASGoogle Scholar
• 103 Liu SY, Zhang RL, Kang H, Fan ZJ, Du Z. Human liver tissue metabolic profiling research on hepatitis B virus-related hepatocellular carcinoma. World J. Gastroenterol. 19(22), 3423–3432 (2013).
  Medline CASGoogle Scholar
• 104 Clarke J D, Novak P, Lake AD et al. Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. Dig. Dis. Sci. 59(2), 365–374 (2014).
  Medline CASGoogle Scholar
• 105 Parab GS, Rao R, Lakshminarayanan S, Bing YV, Moochhala SM, Swarup S. Data-driven optimization of metabolomics methods using rat liver samples. Anal. Chem. 81(4), 1315–1323 (2009).
  Medline CASGoogle Scholar
• 106 Bojko B, Gorynski K, Gomez-Rios GA et al. Solid phase microextraction fills the gap in tissue sampling protocols. Anal. Chim. Acta 803, 75–81 (2013).
  Medline CASGoogle Scholar
• 107 Pekkinen J, Olli K, Huotari A et al. Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high-fat diet as studied by nontargeted LC–MS metabolomics approach. Mol. Nutr. Food Res. 57(11), 1959–1968 (2013).
  Medline CASGoogle Scholar
• 108 Sreekumar A, Poisson LM, Rajendiran TM et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457(7231), 910–914 (2009).
  Medline CASGoogle Scholar
• 109 Kelly AD, Breitkopf SB, Yuan M, Goldsmith J, Spentzos D, Asara JM. Metabolomic profiling from formalin-fixed, paraffin-embedded tumor tissue using targeted LC/MS/MS: application in sarcoma. PLoS ONE 6(10), e25357 (2011).
  Medline CASGoogle Scholar
• 110 de Bekker C, Smith PB, Patterson AD, Hughes DP. Metabolomics reveals the heterogeneous secretome of two entomopathogenic fungi to ex vivo cultured insect tissues. PLoS ONE 8(8), e70609 (2013).
  Medline CASGoogle Scholar