Metabolomics, which is the metabolites profiling in biological matrices, is a key tool for biomarker discovery and personalized medicine and has great potential to elucidate the ultimate product of the genomic processes. Over the last decade, metabolomics studies have identified several relevant biomarkers involved in complex clinical phenotypes using diverse biological systems. Most diseases result in signature metabolic profiles that reflect the sums of external and internal cellular activities. Metabolomics has a major role in clinical practice as it represents >95% of the workload in clinical laboratories worldwide. Many of these metabolites require different analytical platforms, such as Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), and Ultra Performance Liquid Chromatography (UPLC), while many clinically relevant metabolites are still not routinely amenable to detection using currently available assays. Combining metabolomics with genomics, transcriptomics, and proteomics studies will result in a significantly improved understanding of the disease mechanisms and the pathophysiology of the target clinical phenotype. This comprehensive approach will represent a major step forward toward providing precision medical care, in which individual is accounted for variability in genes, environment, and personal lifestyle. In this review, we compare and evaluate the metabolomics strategies and studies that focus on the discovery of biomarkers that have "personalized" diagnostic, prognostic, and therapeutic value, validated for monitoring disease progression and responses to various management regimens.

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Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-Tyrosine Phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, though the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2+ xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2+ BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The Moyamoya disease gene product RNF213 , an E3 ligase, is negatively regulated by PTP1B in HER2+ BC cells. RNF213 knockdown reverses the effects of PTP1B-deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2+ BC cells, and partially restores tumourigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2+ BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

Seven allergenic proteins are present in prawns, which are mostly heat-stable and form dimers or oligomers. Thermal treatment enhanced antibody reactivity to prawn allergens as well as fragments and should be considered in the diagnosis of prawn allergy and detection of crustacean allergens in processed food.

De novo uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis requires glucose, glutamine, acetyl-CoA and uridine, however GlcNAc salvaged from glycoconjugate turnover and dietary sources also makes a significant contribution to the intracellular pool. Herein we ask whether dietary GlcNAc regulates nutrient transport and intermediate metabolism in C57BL/6 mice by increasing UDP-GlcNAc and in turn Golgi N-glycan branching. GlcNAc added to the drinking water showed a dose-dependent increase in growth of young mice, while in mature adult mice fat and body-weight increased without affecting calorie-intake, activity, energy expenditure, or the microbiome. Oral GlcNAc increased hepatic UDP-GlcNAc and N-glycan branching on hepatic glycoproteins. Glucose homeostasis, hepatic glycogen, lipid metabolism and response to fasting were altered with GlcNAc treatment. In cultured cells GlcNAc enhanced uptake of glucose, glutamine and fatty-acids, and enhanced lipid synthesis, while inhibition of Golgi N-glycan branching blocked GlcNAc-dependent lipid accumulation. The N-acetylglucosaminyltransferase enzymes of the N-glycan branching pathway (Mgat1,2,4,5) display multistep ultrasensitivity to UDP-GlcNAc, as well as branching-dependent compensation. Indeed, oral GlcNAc rescued fat accumulation in lean Mgat5−/− mice and in cultured Mgat5−/− hepatocytes, consistent with N-glycan branching compensation. Our results suggest GlcNAc reprograms cellular metabolism by enhancing nutrient uptake and lipid storage through the UDP-GlcNAc supply to N-glycan branching pathway.

Dexamethasone (Dex) is a synthetic glucocorticoid that has anti-inflammatory and immunosuppressant effects and is used in several conditions such as asthma and severe allergy. Patients receiving Dex, either at a high dose or for a long time, might develop several side effects such as hyperglycemia, weight change, or osteoporosis due to its in vivo non-selectivity. Herein, we used liquid chromatography-tandem mass spectrometry-based comprehensive targeted metabolomic profiling as well as radiographic imaging techniques to study the side effects of Dex treatment in rats. The Dex-treated rats suffered from a ∼20% reduction in weight gain, hyperglycemia (145 mg/dL), changes in serum lipids, and reduction in total serum alkaline phosphatase (ALP) (∼600 IU/L). Also, compared to controls, Dex-treated rats showed a distinctive metabolomics profile. In particular, serum amino acids metabolism showed six-fold reduction in phenylalanine, lysine, and arginine levels and upregulation of tyrosine and hydroxyproline reflecting perturbations in gluconeogenesis and protein catabolism which together lead to weight loss and abnormal bone metabolism. Sorbitol level was markedly elevated secondary to hyperglycemia and reflecting activation of the polyol metabolism pathway causing a decrease in the availability of reducing molecules (glutathione, NADPH, NAD+). Overexpression of succinylacetone (4,6-dioxoheptanoic acid) suggests a novel inhibitory effect of Dex on hepatic fumarylacetoacetate hydrolase. The acylcarnitines, mainly the very long chain species (C12, C14:1, C18:1) were significantly increased after Dex treatment which reflects degradation of the adipose tissue. In conclusion, long-term Dex therapy in rats is associated with a distinctive metabolic profile which correlates with its side effects. Therefore, metabolomics based profiling may predict Dex treatment-related side effects and may offer possible novel therapeutic interventions.

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Background:The hexosamine biosynthesis pathway to UDP-GlcNAc has been implicated in glucose homeostasis. Results: UDP-GlcNAc and Golgi N-acetylglucosaminyltransferases modify the N-glycans on glucagon receptor, which increases sensitivity to glucagon in vivo. Conclusion: The hexosamine biosynthesis pathway contributes to glucose homeostasis, in part through N-glycan branching on glucagon receptor. Significance: Hepatic Mgat5 and the N-glycan branching pathway may be a therapeutic target for control of glycemia.