Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Molecular biomarkers could detect biochemical changes associated with disease processes. The key metabolites have become an important part for improving the diagnosis, prognosis, and therapy of diseases. Because of the chemical diversity and dynamic concentration range, the analysis of metabolites remains a challenge. Assessment of fluctuations on the levels of endogenous metabolites by advanced NMR spectroscopy technique combined with multivariate statistics, the so-called metabolomics approach, has proved to be exquisitely valuable in human disease diagnosis. Because of its ability to detect a large number of metabolites in intact biological samples with isotope labeling of metabolites using nuclei such as H, C, N, and P, NMR has emerged as one of the most powerful analytical techniques in metabolomics and has dramatically improved the ability to identify low concentration metabolites and trace important metabolic pathways. Multivariate statistical methods or pattern recognition programs have been developed to handle the acquired data and to search for the discriminating features from biosample sets. Furthermore, the combination of NMR with pattern recognition methods has proven highly effective at identifying unknown metabolites that correlate with changes in genotype or phenotype. The research and clinical results achieved through NMR investigations during the first 13 years of the 21st century illustrate areas where this technology can be best translated into clinical practice.

In the last decade, proteomics and metabolomics have contributed substantially to our understanding of cardiovascular diseases. The unbiased assessment of pathophysiological processes without a priori assumptions complements other molecular biology techniques that are currently used in a reductionist approach. A discrete biological function is very rarely attributed to a single molecule; more often it is the combined input of many proteins. In contrast to the reductionist approach, in which molecules are studied individually, “omics” platforms allow the study of more complex interactions in biological systems. Combining proteomics and metabolomics to quantify changes in metabolites and their corresponding enzymes will advance our understanding of pathophysiological mechanisms and aid the identification of novel biomarkers for cardiovascular disease.

Marginal deficiency of vitamin B-6 is common among segments of the population worldwide. Because pyridoxal 5′-phosphate serves as a coenzyme in the metabolism of amino acids, carbohydrates, organic acids, and neurotransmitters, as well as in aspects of one-carbon metabolism, vitamin B-6 deficiency could have many effects. NMR spectral features of selected metabolites indicated that vitamin B-6 restriction significantly increased the ratios of glutamine/glutamate and 2-oxoglutarate/glutamate and tended to increase concentrations of acetate, pyruvate, and trimethylamine-N-oxide. Tandem MS showed significantly greater plasma proline after vitamin B-6 restriction, but there were no effects on the profile of 14 other amino acids and 45 acylcarnitines. These findings demonstrate that marginal vitamin B-6 deficiency has widespread metabolic perturbations and illustrate the utility of metabolomics in evaluating complex effects of altered vitamin B-6 intake.

Hepatocellular carcinoma is one of the most common malignancies worldwide, and it has a poor prognosis due to its rapid development and early metastasis. An understanding of tumor metabolism would be helpful for the clinical diagnosis and therapy of hepatocellular carcinoma. To investigate the metabolic features of hepatocellular carcinoma, a non-targeted metabolic profiling strategy based on liquid chromatography-mass spectrometry was performed. The results revealed multiple metabolic changes in the tumor, and the principal changes included elevated glycolysis, inhibition of the tricarboxylic acid cycle, accelerated gluconeogenesis and β-oxidation for energy supply and down-regulated Δ-12 desaturase. Furthermore, increased levels of anti-oxidative molecules, such as glutathione, and decreased levels of inflammatory-related polyunsaturated fatty acids and the phospholipase A2 enzyme were also observed. The differential metabolites found in the tissue were tested in serum samples from the chronic hepatitis, cirrhosis and hepatocellular carcinoma patients. The combination of betaine and propionylcarnitine was confirmed to have a good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum samples further shows the combination biomarker is useful for hepatocellular carcinoma diagnosis.

Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement and 5-year recurrence. These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, it suggests that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/23828598

http://www.ncbi.nlm.nih.gov/pubmed/23827455

http://www.ncbi.nlm.nih.gov/pubmed/23776431

http://www.ncbi.nlm.nih.gov/pubmed/23824744

http://www.ncbi.nlm.nih.gov/pubmed/23824564

Published related articles on this open access online scientific journal:

 

World of Metabolites: Lawrence Berkeley National Laboratory developed Imaging Technique for their Capturing

 

Aviva Lev-Ari, PhD, RN 06/13/2013

 

http://pharmaceuticalintelligence.com/2013/06/13/world-of-metabolites-lawrence-berkeley-national-laboratory-developed-imaging-technique-for-their-capturing/

 

Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

 

Aviva Lev-Ari, PhD, RN 10/22/2012

 

http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

 

Metabolomics: its applications in food and nutrition research

 

Dr. Sudipta Saha, Ph.D., RN 05/12/2013

 

http://pharmaceuticalintelligence.com/2013/05/12/metabolomics-its-applications-in-food-and-nutrition-research/

 

Increased Cardiovascular Risk: Intestinal Microbial Metabolism

 

Aviva Lev-Ari, PhD, RN 05/07/2013

 

http://pharmaceuticalintelligence.com/2013/05/07/increased-cardiovascular-risk-intestinal-microbial-metabolism/

 

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

 

Dr. Sudipta Saha, Ph.D., RN 05/06/2013

 

http://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

 

Importance of Omega-3 Fatty Acids in Reducing Cardiovascular Disease

 

Dr. Sudipta Saha, Ph.D., RN 04/29/2013

 

http://pharmaceuticalintelligence.com/2013/04/29/importance-of-omega-3-fatty-acids-in-reducing-cardiovascular-disease/

 

Mitochondrial Metabolism and Cardiac Function

 

Larry H Bernstein, MD, FACP, RN 04/14/2013

 

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

 

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

 

Larry H Bernstein, MD, FACP, RN 04/04/2013

 

http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/

 

Ca2+ Signaling: Transcriptional Control

 

Larry H Bernstein, MD, FACP, RN 03/06/2013

 

http://pharmaceuticalintelligence.com/2013/03/06/ca2-signaling-transcriptional-control/

 

Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

 

Aviva Lev-Ari, PhD, RN 02/19/2013

 

http://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

 

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

 

Larry H Bernstein, MD, FACP, RN 12/03/2013

 

http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

 

Pancreatic Cell News: Beta cell dysfunction attributed to saturated non-esterified fatty acid palmitate

 

Aviva Lev-Ari, PhD, RN 11/27/2012

 

http://pharmaceuticalintelligence.com/2012/11/27/pancreatic-cell-news-beta-cell-dysfunction-attributed-to-saturated-non-esterified-fatty-acid-palmitate/

 

Metabolic drivers in aggressive brain tumors

 

Prabodh Kandala, PhD, RN 11/11/2012

 

http://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

 

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

 

Larry H Bernstein, MD, FACP, RN 10/22/2012

 

http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

 

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

 

Larry H Bernstein, MD, FACP, RN 09/24/2012

 

http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

 

Risks of Hypoglycemia in Diabetics with CKD

 

Larry H Bernstein, MD, FACP, RN 08/01/2012

 

http://pharmaceuticalintelligence.com/2012/08/01/risks-of-hypoglycemia-in-diabetics-with-ckd/

 

Nitric Oxide in bone metabolism

 

Aviral Vatsa, PhD, MBBS, RN 07/16/2012

 

http://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/