Levels Of Multiple Metabolites Research Articles

Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Measurement of Metabolite Changes in Senescent Cells by Mass Spectrometry.

Senescent cells display altered metabolic signatures that can either be causal for aspects the senescent phenotype, or act as biomarkers for senescence. Steady state levels of multiple metabolites change with senescence, and can be detected using analytical methods. Here, we describe a liquid chromatography-mass spectrometry (LC-MS) method for detecting altered metabolites from cultured senescent cells.

Endogenous nitric oxide production in the radioresistant bacterium deinococcus radiodurans determines lipid composition and is essential for rapid growth recovery after gamma-irradiation

The eubacteria Deinococcus radiodurans (Drad) is the most radioresistant organism known. The extreme radioresistance of Drad primarily owes to its efficiency at mitigating oxidative damage, repairing double-strand DNA breaks, and possibly additional mechanisms that await elucidation. Recently, it was found that a NOS knockout strain of Drad (ΔNOS) is highly-sensitive to UV irradiation, establishing a role for NO in growth recovery after UV exposure. To further test the involvement of Drad NOS in radiation resistance, WT and ΔNOS Drad strains were subjected to extreme doses of gamma-irradiation (3000 Gy, 60 Co source) and the impact of NO on post-irradiation growth recovery, metabolite, gene and protein expression were assessed. Notably, the ΔNOS cell line displayed severely retarded growth following gamma-irradiation, compared to WT cells. NO supplementation with the long-lived NO donor, DETA-NONOate (25 μM), rescued the ΔNOS defect in growth recovery, restoring it to the control level. Clonogenic assays demonstrated that NO selectively facilitates growth recovery, but does not diminish gamma-irradiation cell killing. To discover consequences of endogenously-produced NO on biochemical pathways in Drad, untargeted metabolite profiling studies were performed. NO gene-deletion was associated with profound changes in levels of multiple metabolites, including specific carotenoids, glycerolipids and some additional cell membrane/wall building blocks. Further studies aim to identify biochemical pathways, enzymes and molecular mechanisms by which NO regulates Drad metabolism and thereby attenuates radioresistance. In this effort, untargeted metabolite profiling is providing novel details about NO signaling and may rationalize the enigmatic basis for radiosensitization by NOS inhibitors of some mammalian tumors.

Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury

Emerging metabolomic tools have created the opportunity to establish metabolic signatures of myocardial injury. We applied a mass spectrometry-based metabolite profiling platform to 36 patients undergoing alcohol septal ablation treatment for hypertrophic obstructive cardiomyopathy, a human model of planned myocardial infarction (PMI). Serial blood samples were obtained before and at various intervals after PMI, with patients undergoing elective diagnostic coronary angiography and patients with spontaneous myocardial infarction (SMI) serving as negative and positive controls, respectively. We identified changes in circulating levels of metabolites participating in pyrimidine metabolism, the tricarboxylic acid cycle and its upstream contributors, and the pentose phosphate pathway. Alterations in levels of multiple metabolites were detected as early as 10 minutes after PMI in an initial derivation group and were validated in a second, independent group of PMI patients. A PMI-derived metabolic signature consisting of aconitic acid, hypoxanthine, trimethylamine N-oxide, and threonine differentiated patients with SMI from those undergoing diagnostic coronary angiography with high accuracy, and coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. Our results identify a role for metabolic profiling in the early detection of myocardial injury and suggest that similar approaches may be used for detection or prediction of other disease states.