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1.  1H NMR metabolomics study of age profiling in children 
NMR in biomedicine  2009;22(8):826-833.
Metabolic profiling of urine provides a fingerprint of personalized endogenous metabolite markers that correlate to a number of factors such as gender, disease, diet, toxicity, medication, and age. It is important to study these factors individually, if possible to unravel their unique contributions. In this study, age-related metabolic changes in children of age 12 years and below were analyzed by 1H NMR spectroscopy of urine. The effect of age on the urinary metabolite profile was observed as a distinct age-dependent clustering even from the unsupervised principal component analysis. Further analysis, using partial least squares with orthogonal signal correction regression with respect to age, resulted in the identification of an age-related metabolic profile. Metabolites that correlated with age included creatinine, creatine, glycine, betaine/TMAO, citrate, succinate, and acetone. Although creatinine increased with age, all the other metabolites decreased. These results may be potentially useful in assessing the biological age (as opposed to chronological) of young humans as well as in providing a deeper understanding of the confounding factors in the application of metabolomics.
PMCID: PMC4009993  PMID: 19441074
age; human urine; metabolite profiling; metabolomics; metabonomics; nuclear magnetic resonance; orthogonal signal correction; principal component analysis
2.  Metabolomics-Based Methods for Early Disease Diagnostics: A Review 
The emerging field of “metabolomics,” in which a large number of small molecule metabolites from body fluids or tissues are detected quantitatively in a single step, promises immense potential for early diagnosis, therapy monitoring and for understanding the pathogenesis of many diseases. Metabolomics methods are mostly focused on the information rich analytical techniques of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Analysis of the data from these high-resolution methods using advanced chemometric approaches provides a powerful platform for translational and clinical research, and diagnostic applications. In this review, the current trends and recent advances in NMR- and MS-based metabolomics are described with a focus on the development of advanced NMR and MS methods, improved multivariate statistical data analysis and recent applications in the area of cancer, diabetes, inborn errors of metabolism, and cardiovascular diseases.
PMCID: PMC3890417  PMID: 18785810
Metabolomics; metabonomics; NMR spectroscopy; mass spectrometry; multivariate statistical analysis; early detection; cancer; diabetes; inborn errors of metabolism; coronary heart disease
3.  Visualization of Bile Homeostasis Using 1H-NMR Spectroscopy as a Route for Assessing Liver Cancer 
Lipids  2008;44(1):10.1007/s11745-008-3254-6.
Changes in bile synthesis by the liver or alterations in the enterohepatic circulation due to a variety of etiological conditions may represent a novel source of liver disease-specific biomarkers. Bile from patients with liver diseases exhibited significant changes in the levels of glycine- and taurine-conjugated bile acids, phospholipids, cholesterol and urea relative to non-liver disease controls. Cholangiocarcinoma and non-malignant liver diseases (NMLD) showed the most significant alterations. Further, hepatocellular carcinoma (HCC) could be differentiated from NMLD (p = 0.02), as well as non-liver disease controls (p = 0.02) based on the amounts of bile acids, phospholipids and/or cholesterol. HCC also differed with cholangiocarcinoma although not significantly. Urea increases somewhat in non-malignant liver disease relative to non-liver disease controls, while the bile acids, phospholipids and cholesterol all decrease significantly. The ratio between some major bile metabolites also distinguished NMLD (p = 0.004–0.01) from non-liver disease controls. This snapshot view of bile homeostasis, is obtainable from a simple nuclear magnetic resonance (NMR) approach and demonstrates the enormous opportunity to assess liver status, explore biomarkers for high risk diseases such as cancers and improve the understanding of normal and abnormal cellular functions.
PMCID: PMC3867446  PMID: 18982376
Bile homeostasis; Liver disease; Hepatocellular carcinoma; Cholangiocarcinoma; Glycine-conjugated bile acids; Taurine-conjugated bile acids; 1H NMR; Metabolomics
4.  Correlative and quantitative 1H NMR-based metabolomics reveals specific metabolic pathway disturbances in diabetic rats 
Analytical biochemistry  2008;383(1):10.1016/j.ab.2008.07.041.
Type 1 diabetes was induced in Sprague–Dawley rats using streptozotocin. Rat urine samples (8 diabetic and 10 control) were analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy. The derived metabolites using univariate and multivariate statistical analysis were subjected to correlative analysis. Plasma metabolites were measured by a series of bioassays. A total of 17 urinary metabolites were identified in the 1H NMR spectra and the loadings plots after principal components analysis. Diabetic rats showed significantly increased levels of glucose (P < 0.00001), alanine (P < 0.0002), lactate (P < 0.05), ethanol (P < 0.05), acetate (P < 0.05), and fumarate (P < 0.05) compared with controls. Plasma assays showed higher amounts of glucose, urea, triglycerides, and thiobarbituric acid-reacting substances in diabetic rats. Striking differences in the Pearson's correlation of the 17 NMR-detected metabolites were observed between control and diabetic rats. Detailed analysis of the altered metabolite levels and their correlations indicate a significant disturbance in the glucose metabolism and tricarboxylic acid (TCA) cycle and a contribution from gut microbial metabolism. Specific perturbed metabolic pathways include the glucose–alanine and Cori cycles, the acetate switch, and choline metabolism. Detection of the altered metabolic pathways and bacterial metabolites using this correlative and quantitative NMR-based metabolomics approach should help to further the understanding of diabetes-related mechanisms.
PMCID: PMC3867451  PMID: 18775407
Metabolomics; NMR spectroscopy; Type 1 diabetes; TCA cycle; Gluconeogenesis
5.  Microbiology of Urinary Tract Infections in Gaborone, Botswana 
PLoS ONE  2013;8(3):e57776.
The microbiology and epidemiology of UTI pathogens are largely unknown in Botswana, a high prevalence HIV setting. Using laboratory data from the largest referral hospital and a private hospital, we describe the major pathogens causing UTI and their antimicrobial resistance patterns.
This retrospective study examined antimicrobial susceptibility data for urine samples collected at Princess Marina Hospital (PMH), Bokamoso Private Hospital (BPH), or one of their affiliated outpatient clinics. A urine sample was included in our dataset if it demonstrated pure growth of a single organism and accompanying antimicrobial susceptibility and subject demographic data were available.
A total of 744 samples were included. Greater than 10% resistance was observed for amoxicillin, co-trimoxazole, amoxicillin-clavulanate, and ciprofloxacin. Resistance of E. coli isolates to ampicillin and co-trimoxazole was greater than 60% in all settings. HIV status did not significantly impact the microbiology of UTIs, but did impact antimicrobial resistance to co-trimoxazole.
Data suggests that antimicrobial resistance has already emerged to most oral antibiotics, making empiric management of outpatient UTIs challenging. Ampicillin, co-trimoxazole, and ciprofloxacin should not be used as empiric treatment for UTI in this context. Nitrofurantoin could be used for simple cystitis; aminoglycosides for uncomplicated UTI in inpatients.
PMCID: PMC3587627  PMID: 23469239
6.  Quantitative Analysis of Blood Plasma Metabolites Using Isotope Enhanced NMR Methods 
Analytical chemistry  2010;82(21):10.1021/ac101938w.
NMR spectroscopy is a powerful analytical tool for both qualitative and quantitative analysis. However, accurate quantitative analysis in complex fluids such as human blood plasma is challenging, and analysis using one-dimensional NMR is limited by signal overlap. It is impractical to use heteronuclear experiments involving natural abundance 13C on a routine basis due to low sensitivity, despite their improved resolution. Focusing on circumventing such bottlenecks, this study demonstrates the utility of a combination of isotope tagged NMR experiments to analyze metabolites in human blood plasma. 1H-15N HSQC and 1H-13C HSQC experiments on the isotope tagged samples combined with the conventional 1H one-dimensional and 1H-1H TOCSY experiments provide quantitative information on a large number of metabolites in plasma. The methods were first tested on a mixture of 28 synthetic analogues of metabolites commonly present in human blood; twenty-seven metabolites in a standard NIST (National Institute of Standards and Technology) human blood plasma were then identified and quantified with an average coefficient of variation of 2.4 % for 17 metabolites and 5.6% when all the metabolites were considered. Carboxylic acids and amines represent a majority of the metabolites in body fluids and their analysis by isotope tagging enables a significant enhancement of the metabolic pool for biomarker discovery applications. Improved sensitivity and resolution of NMR experiments imparted by 15N and 13C isotope tagging is attractive for both the enhancement of the detectable metabolic pool and accurate analysis of plasma metabolites. The approach can be easily extended to many additional metabolites in almost any biological mixture.
PMCID: PMC3065653  PMID: 20879716
Metabolites; Quantitation; Plasma; Metabolomics; 1H NMR; Heteronuclear correlation; Isotope tagging; Amines; Carboxylic acids
7.  Early Detection of Recurrent Breast Cancer Using Metabolite Profiling 
Cancer research  2010;70(21):8309-8318.
We report on the development of a monitoring test for recurrent breast cancer using metabolite profiling methods. Using a combination of nuclear magnetic resonance (NMR) and two dimensional gas chromatography-mass spectrometry (GCxGC-MS) methods, we analyzed the metabolite profiles of 257 retrospective serial serum samples from 56 previously diagnosed and surgically treated breast cancer patients. 116 of the serial samples were from 20 patients with recurrent breast cancer and 141 samples were from 36 patients with no clinical evidence of the disease during the approximately 6-year sample collection period. NMR and GCxGC-MS data were analyzed by multivariate statistical methods to compare identified metabolite signals between the recurrence and no evidence of disease samples. Eleven metabolite markers (7 from NMR and 4 from GCxGC-MS) were shortlisted from an analysis of all patient samples using logistic regression and 5-fold cross validation. A PLS-DA model built using these markers with leave one out cross validation provided a sensitivity of 86% and a specificity of 84% (AUROC =0.88). Strikingly, 55% of the patients could be correctly predicted to have recurrence 13 months (on average) before the recurrence was diagnosed clinically, representing a large improvement over the current breast cancer monitoring assay CA 27.29. To the best of our knowledge, this is the first study to develop and pre-validate a prediction model for early detection of recurrent breast cancer based on a metabolic profile. In particular, the combination of two advanced analytical methods, NMR and MS, provides a powerful approach for the early detection of recurrent breast cancer.
PMCID: PMC2995269  PMID: 20959483
Breast Cancer; Recurrence; Metabolomics; Metabolite Profiling; NMR; Gas Chromatography; CA 27.29
8.  4-(4-Chloro­phen­yl)-N-[(E)-4-(dimethyl­amino)­benzyl­idene]-1,3-thia­zol-2-amine 
The title compound, C18H16ClN3S, adopts an extended mol­ecular structure. The thia­zole ring is inclined by 9.2 (1) and 15.3 (1)° with respect to the chloro­phenyl and 4-(dimethyl­amino)­phenyl rings, respectively, while the benzene ring planes make an angle of 19.0 (1)°. A weak inter­molecular C—H⋯π contact is observed in the crystal structure.
PMCID: PMC3213556  PMID: 22091133
9.  3-Ethyl-4-methyl-1H-pyrazol-2-ium-5-olate 
The title compound, C6H10N2O, is a zwitterionic pyrazole derivative. The crystal packing is predominantly governed by a three-center iminium–amine N+—H⋯O−⋯H—N inter­action, leading to an undulating sheet-like structure lying parallel to (100).
PMCID: PMC3213569  PMID: 22091146
10.  Bis(acetyl­acetonato-κ2 O,O′)(pyridine-κN)zinc(II) 
In the title compound, [Zn(C5H7O2)2(C5H5N)], the metal atom has square-pyramidal coordination geometry with the basal plane defined by the four O atoms of the chelating acetyl­acetonate ligands and with the axial position occupied by the pyridine N atom. The crystal packing is characterized by a C—H⋯O hydrogen-bonded ribbon structure approximately parallel to [10].
PMCID: PMC3120430  PMID: 21754690
11.  (2E)-3-(4-Eth­oxy­phen­yl)-1-(2-methyl-4-phenyl­quinolin-3-yl)prop-2-en-1-one monohydrate 
The title hydrate, C27H23NO2·H2O, features an almost planar quinoline residue (r.m.s. deviation = 0.015 Å) with the benzene [dihedral angle = 63.80 (7) °] and chalcone [C—C—C—O torsion angle = −103.38 (18)°] substituents twisted significantly out of its plane. The configuration about the C=C bond [1.340 (2) Å] is E. In the crystal, mol­ecules related by the 21 symmetry operation are linked along the b axis via water mol­ecules that form O—H⋯Oc and O—H⋯Nq hydrogen bonds (c = carbonyl and q = quinoline). A C—H⋯O inter­action also occurs.
PMCID: PMC3011764  PMID: 21589564
12.  1-{3-[(4-Oxopiperidin-1-yl)carbon­yl]benzoyl}piperidin-4-one 
Two independent mol­ecules comprise the asymmetric unit in the title compound, C18H20N2O4. One of the mol­ecules exhibits disorder in one of its 4-piperidone rings, which is disposed over two orientations [site occupancy of the major component = 0.651 (5)]. The first independent mol­ecule and the minor component of the second disordered mol­ecule are virtually superimposable. The central four C atoms in the major component of the disordered mol­ecule have an opposite orientation. All the 4-piperidone rings have a chair conformation. The carbonyl groups in each mol­ecule have approximate anti conformations [O=C⋯C=O = 146.2 (2) and −159.9 (2)°]. The 4-piperidone rings lie to opposite sides of the central benzene ring in both mol­ecules. In the crystal, mol­ecules are linked by C—H⋯O inter­actions. The crystal studied was found to be a non-merohedral twin (twin law −1 0 0, 0 1 0, 0 − 1/2 − 1), the fractional contribution of the minor component being approximately 11%.
PMCID: PMC3007266  PMID: 21588303
13.  Synchronous Adenocarcinoma and Gastrointestinal Stromal Tumor in the Stomach 
In recent years, the synchronous occurrence of tumors of different histotypes arising in the same organ has been reported more frequently in the literature. In the stomach, adenocarcinoma has been described with coexisting primary rhabdomyosarcoma, carcinoid, and low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. The simultaneous development of adenocarcinoma and gastric mesenchymal tumor has been documented rarely. We report one such case. A 65-year-old male was diagnosed with a proximal gastric adenocarcinoma and underwent subtotal gastrectomy. Subsequent histopathological examination revealed the presence of another tumor at the gastric antrum. This was a gastrointestinal stromal tumor of low risk category (GIST). The literature has only a few previous reports of this very rare association. It is not known whether this synchronicity is incidental or there is a causative factor inducing the development of tumors of different histotypes in the same organ. Pathologists, oncologists and surgeons should be aware of this interesting condition.
PMCID: PMC3003220  PMID: 20616420
Adenocarcinoma; stromal tumor; synchronus
14.  A Chemoselective 15N Tag for Sensitive and High Resolution NMR Profiling of the Carboxyl-Containing Metabolome 
Analytical chemistry  2009;81(12):4882-4888.
Metabolic profiling has received increasing recognition as an indispensable complement to genomics and proteomics for probing biological systems and for clinical applications. 1H nuclear magnetic resonance (NMR) is widely used in the field but is challenged by spectral complexity and overlap. Improved and simple methods that quantitatively profile a large number of metabolites are sought to make further progress. Here, we demonstrate a simple isotope tagging strategy, in which metabolites with carboxyl groups are chemically tagged with 15N-ethanolamine and detected using a 2D heteronuclear correlation NMR experiment. This method is capable of detecting over one hundred metabolites at concentrations as low as a few micromolar in biological samples, both quantitatively and reproducibly. Carboxyl-containing compounds are found in almost all metabolic pathways, and thus this new approach should find a variety of applications.
PMCID: PMC2861042  PMID: 19518144
Metabolic Profiling; Metabolomics; Metabonomics; NMR; Heteronuclear correlation; 15N Isotope Tagging; Carboxylic Acid
15.  1-[2,4,6-Trimethyl-3,5-bis­(4-oxopiperidin-1-ylmeth­yl)benz­yl]piperidin-4-one 
In the structure of the title compound, C27H39N3O3, each of the (4-oxopiperidin-1-yl)methyl residues adopts a flattened chair conformation (with the N and carbonyl groups being oriented to either side of the central C4 plane) and they occupy positions approximately orthogonal to the central benzene ring [Cbenzene—C—Cmethyl­ene—N torsion angles 103.4 (2), −104.4 (3) and 71.9 (3)°]; further, two of these residues are oriented to one side of the central benzene ring with the third to the other side. In the crystal packing, supra­molecular layers in the ab plane are sustained by C—H⋯O inter­actions.
PMCID: PMC2979355  PMID: 21579402
16.  Identification of 4-deoxythreonic acid present in human urine by combining HPLC and NMR techniques 
The 1H NMR spectrum of urine exhibits a large number of detectable and quantifiable metabolites and hence urine metabolite profiling is potentially useful for the study of systems biology and the discovery of biomarkers for drug development or clinical applications. While a number of metabolites (50–100) are readily detectable in urine by NMR, a much larger number is potentially available if lower concentration species can be detected unambiguously. Lower concentration metabolites are thought to be more specific to certain disease states and thus it is important to detect these metabolites with certainty. We report the identification of 4-deoxythreonic acid, a relatively low concentration endogenous metabolite that has not been previously identified in the 1H NMR spectrum of human urine. The complimentary use of HPLC and NMR spectroscopy facilitated the unequivocal and non-invasive identification of the molecule in urine which is complicated by extensive peak overlap and multiple, similar resonances from other metabolites such as 3-hydroxybutanoic acid. High-resolution detection and good sensitivity were achieved by the combination of multiple chromatographic fraction collection, sample pre-concentration, and the use of a cryogenically cooled NMR probe.
PMCID: PMC2861046  PMID: 19615840
Metabolite; Metabolomics; HPLC-NMR; Urine; TOCSY; 4-deoxythreonic acid
17.  Application of 31P NMR Spectroscopy and Chemical Derivatization for Metabolite Profiling of Lipophilic Compounds in Human Serum 
Magnetic resonance in chemistry : MRC  2009;47(Suppl 1):S74-S80.
New methods for obtaining metabolic fingerprints of biological samples with improved resolution and sensitivity are highly sought for early disease detection, studies of human health and pathophysiology, and for better understanding systems biology. Considering the complexity of biological samples, interest in biochemical class selection through the use of chemoselective probes for improved resolution and quantitation is increasing. Considering the role of lipids in the pathogenesis of a number of diseases, in this study fingerprinting of lipid metabolites was achieved by 31P labeling using the derivatizing agent 2-chloro-4,4,5,5-tetramethyldioxaphospholane. Lipids containing hydroxyl, aldehyde and carboxyl groups were selectively tagged with 31P and then detected with good resolution using 31P NMR by exploiting the 100% natural abundance and wide chemical shift range of 31P. After standardizing the reaction conditions using representative compounds, the derivatization approach was used to profile lipids in human serum. The results show that the 31P derivatization approach is simple, reproducible and highly quantitative, and has the potential to profile a number of important lipids in complex biological samples.
PMCID: PMC2861047  PMID: 19610016
NMR; 31P; metabolite profiling; metabolomics; chemical derivatization; lipids
18.  (2E)-3-(4-Bromo­phen­yl)-1-(2-methyl-4-phenyl-3-quinol­yl)prop-2-en-1-one 
The conformation about the ethene bond [1.316 (3) Å] in the title compound, C25H18BrNO, is E. The quinoline ring forms dihedral angles of 67.21 (10) and 71.68 (10)° with the benzene and bromo-substituted benzene rings, respectively. Highlighting the non-planar arrangement of aromatic rings, the dihedral angle formed between the benzene rings is 58.57 (12)°.
PMCID: PMC2979249  PMID: 21579162
19.  Dimethyl 4-(3-hydroxy­phen­yl)-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate 
The 1,4-dihydro­pyridine ring in the title compound, C17H19NO5, has a flattened-boat conformation, and the benzene ring is almost orthogonal to it [dihedral angle = 82.98 (12)°]. The hydr­oxy group is disordered over two positions in a 0.780 (4):0.220 (4) ratio. In the crystal, hydrogen-bonding inter­actions of the type Na—H⋯Oc and Oh—H⋯Oc (a = amine, c = carbonyl and h = hydr­oxy) link the mol­ecules into a three-dimensional network.
PMCID: PMC2983893  PMID: 21580781
20.  1-[5-Acetyl-4-(4-bromo­phen­yl)-2,6-dimethyl-1,4-dihydro­pyridin-3-yl]ethanone monohydrate 
The 1,4-dihydro­pyridine ring in the title hydrate, C17H18BrNO2·H2O, has a flattened-boat conformation, and the benzene ring is occupies a position orthogonal to this [dihedral angle: 82.19 (16)°]. In the crystal packing, supra­molecular arrays mediated by N—H⋯Owater and Owater—H⋯Ocarbon­yl hydrogen bonding are formed in the bc plane. A highly disordered solvent mol­ecule is present within a mol­ecular cavity defined by the organic and water mol­ecules. Its contribution to the electron density was removed from the observed data in the final cycles of refinement and the formula, mol­ecular weight and density are given without taking into account the contribution of the solvent mol­ecule.
PMCID: PMC2983612  PMID: 21580408
21.  Diethyl 4-(2,4-dichloro­phen­yl)-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate 
In the title compound, C19H21Cl2NO4, the dihydro­pyridine ring adopts a flattened boat conformation. The dichloro­phenyl ring is oriented almost perpendicular to the planar part of the dihydro­pyridine ring [dihedral angle = 89.1 (1)°]. An intra­molecular C—H⋯O hydrogen bond is observed. In the crystal structure, mol­ecules are linked into chains along the b axis by N—H⋯O hydrogen bonds
PMCID: PMC2979797  PMID: 21579787
22.  Ethyl 2-acetyl-3-(4-bromo­anilino)butanoate 
The title compound, C14H18BrNO3, adopts an extended conformation, with all of the main-chain torsion angles associated with the ester and amino groups close to trans. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds are observed.
PMCID: PMC2979926  PMID: 21579730
23.  1,1′-(p-Phenyl­enedimethyl­ene)dipiperidin-4-one 
In the mol­ecule of the title compound, C18H24N2O2, the piperidine rings are in chair conformations. The crystal structure is stabilized by inter­molecular C—H⋯O hydrogen bonding. There are neither C—H⋯π nor π–π inter­actions in the structure.
PMCID: PMC2980215  PMID: 21580057
24.  Tris(methyl 3-oxobutanoato-κ2 O,O′)aluminium(III) 
In the title compound, [Al(C5H7O3)3], three acac-type ligands (methyl 3-oxobutanoate anions) chelate to the aluminium(III) cation in a slightly distorted AlO6 octa­hedral coordination geometry. Electron delocalization occurs within the chelating rings.
PMCID: PMC2972076  PMID: 21578687
25.  1,1′-[4-(2-Methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]diethanone 
In the title compound, C18H21NO3, the 1,4-dihydro­pyridine ring exhibits a flattened boat conformation. The methoxy­phenyl ring is nearly planar [r.m.s. deviation = 0.0723 (1) Å] and is perpendicular to the base of the boat [dihedral angle = 88.98 (4)°]. Inter­molecular N—H⋯O and C—H⋯O hydrogen bonds exist in the crystal structure.
PMCID: PMC2971406  PMID: 21578463

Results 1-25 (28)