PubMed

MetaboCraft: Building a Minecraft plugin for metabolomics. Bioinformatics. 2018 Mar 28;: Authors: Megalios A, Daly R, Burgess K Abstract Motivation: The rapid advances in metabolomics pose a significant challenge in presentation and interpretation of results. Development of new, engaging visual aids is crucial to advancing our understanding of new findings. Results: We have developed MetaboCraft, a Minecraft plugin which creates immersive visualisations of metabolic networks and pathways in a 3-D environment and allows the results of user experiments to be viewed in this context, presenting a novel approach to exploring the metabolome. Availability and implementation: https://github.com/argymeg/MetaboCraft/; https://hub.docker.com/r/ronandaly/metabocraft/. Contact: karl.burgess@glasgow.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 29608638 [PubMed - as supplied by publisher]

Targeted and non-targeted metabolite identification of MAM-2201 in human, mouse, and rat hepatocytes. Drug Test Anal. 2018 Apr 02;: Authors: Kim JH, Kong TY, Moon JY, Choi KH, Cho YY, Kang HC, Lee JY, Lee HS Abstract MAM-2201 is a fluorinated naphthoylindole synthetic cannabinoid with potent psychoactive properties that has been detected as an active ingredient in herbal incense blends. To gain a greater understanding of MAM-2201 metabolism and to compare the metabolic fate in humans with those in animals, the metabolism of MAM-2201 in human, mouse, and rat hepatocytes was investigated using liquid chromatography-high-resolution mass spectrometry combined with targeted and non-targeted metabolite profiling approaches. Nineteen phase I metabolites (M1-M19) reported previously in human liver microsomes and 13 novel metabolites were identified in human, mouse, and rat hepatocytes: one phase I metabolite (M20) and 12 phase II metabolites including six glucuronides (G1-G6), one sulfate (S1), and five glutathione (GSH) conjugates (GS1-GS5) of MAM-2201 metabolites. G3 was human-specific, but M20, G1, G2, and 5 GSH conjugates were rat-specific, indicating species-related differences in MAM-2201 metabolism. The findings in the present study can be useful for the experimental design and assessment of metabolism-mediated toxic risk of MAM-2201. PMID: 29608249 [PubMed - as supplied by publisher]

Investigation of Metabolomic Changes in Sunitinib-Resistant Human Renal Carcinoma 786-O Cells by Capillary Electrophoresis-Time of Flight Mass Spectrometry. Biol Pharm Bull. 2018;41(4):619-627 Authors: Hatakeyama H, Fujiwara T, Sato H, Terui A, Hisaka A Abstract Acquired resistance to sunitinib is a challenge in the treatment of renal cell carcinoma (RCC). The dysregulation of cellular metabolism is prevalent during resistance acquisition. It is known that in sunitinib-resistant RCC 786-O (786-O Res) cells sunitinib is mainly sequestered in the intracellular lysosomes. However, the relevance between sunitinib resistance and cellular metabolism has not been examined. In this study, we examined the metabolic changes in 786-O Res by using capillary electrophoresis-time of flight mass spectrometry. The cell line 786-O Res was established via persistent treatment with sunitinib, where increase in intracellular sunitinib, and sizes of lysosomes and nuclei were enhanced as compared with those in the parental 786-O (786-O Par) cells. Metabolic analyses revealed that out of the 110 metabolites examined, 13 were up-regulated and 4 were down-regulated in the 786-O Res cells. The glycolysis, tricarboxylic acid cycle and pentose phosphate pathway (PPP) were identified as being altered in the sunitinib-resistant cells, which resulted in the enhanced metabolisms of energy, nucleic acids, and glutathione redox cycle. As sunitinib was sequestered in the enlarged lysosomes in 786-O Res, the enriched energy metabolism might contribute to the maintenance of luminal pH in lysosomes via the H+ ATPase. The changes in the PPP could contribute to nuclei enlargement through up-regulation of nucleic acid biosynthesis and protect 786-O Res from cytotoxicity induced by sunitinib through up-regulation of reduced glutathione. Though the direct link between sunitinib resistance and metabolic alternation remains to be elucidated, this metabolomics study provides fundamental insights into acquisition of sunitinib resistance. PMID: 29607935 [PubMed - in process]

Lower Concentrations of Circulating Medium and Long Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV. AIDS Res Hum Retroviruses. 2018 Apr 01;: Authors: Bailin S, Jenkins C, Petucci C, Culver JA, Shepherd BE, Fessel JP, Hulgan T, Koethe JR Abstract In HIV-negative individuals, a plasma metabolite profile characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 non-diabetic, HIV-positive individuals (50% with body mass index ≥ 30 kg/m2) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (< 50 copies/mL) for at least 2 years and a CD4+ count over 350 cells/µL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4+ count was 701 cells/µL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p=0.01), but not BCAA or C5 acylcarnitines. Insulin resistance was also associated with lower levels of C18, C16, C12, and C2 acylcarnitines (p≤0.03 for all), and lower C18 and C16 acylcarnitine:free fatty acid ratios (p=0.002, and p=0.03, respectively). Insulin resistance in HIV-positive persons is characterized by lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, suggesting impaired fatty acid uptake and/or oxidation is a central feature of glucose intolerance in this population. PMID: 29607651 [PubMed - as supplied by publisher]

Urinary Metabolomic Study of Chlorogenic Acid in a Rat Model of Chronic Sleep Deprivation Using Gas Chromatography-Mass Spectrometry. Int J Genomics. 2018;2018:1361402 Authors: Ma WN, Zhou MM, Gou XJ, Zhao L, Cen F, Xu Y, Shen HY Abstract The urinary metabolomic study based on gas chromatography-mass spectrometry (GC-MS) had been developed to investigate the possible antidepressant mechanism of chlorogenic acid (CGA) in a rat model of sleep deprivation (SD). According to pattern recognition analysis, there was a clear separation among big platform group (BP), sleep deprivation group (SD), and the CGA (model + CGA), and CGA group was much closer to the BP group by showing a tendency of recovering towards BP group. Thirty-six significantly changed metabolites related to antidepressant by CGA were identified and used to explore the potential mechanism. Combined with the result of the classic behavioral tests and biochemical indices, CGA has significant antidepressant effects in a rat model of SD, suggesting that the mechanism of action of CGA might be involved in regulating the abnormal pathway of nicotinate and nicotinamide metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and arginine and proline metabolism. Our results also show that metabolomics analysis based on GC-MS is a useful tool for exploring biomarkers involved in depression and elucidating the potential therapeutic mechanisms of Chinese medicine. PMID: 29607310 [PubMed]

Bayesian estimation of the number of protonation sites for urinary metabolites from NMR spectroscopic data. Metabolomics. 2018;14(5):56 Authors: Ye L, De Iorio M, Ebbels TMD Abstract Introduction: To aid the development of better algorithms for [Formula: see text]H NMR data analysis, such as alignment or peak-fitting, it is important to characterise and model chemical shift changes caused by variation in pH. The number of protonation sites, a key parameter in the theoretical relationship between pH and chemical shift, is traditionally estimated from the molecular structure, which is often unknown in untargeted metabolomics applications. Objective: We aim to use observed NMR chemical shift titration data to estimate the number of protonation sites for a range of urinary metabolites. Methods: A pool of urine from healthy subjects was titrated in the range pH 2-12, standard [Formula: see text]H NMR spectra were acquired and positions of 51 peaks (corresponding to 32 identified metabolites) were recorded. A theoretical model of chemical shift was fit to the data using a Bayesian statistical framework, using model selection procedures in a Markov Chain Monte Carlo algorithm to estimate the number of protonation sites for each molecule. Results: The estimated number of protonation sites was found to be correct for 41 out of 51 peaks. In some cases, the number of sites was incorrectly estimated, due to very close pKa values or a limited amount of data in the required pH range. Conclusions: Given appropriate data, it is possible to estimate the number of protonation sites for many metabolites typically observed in [Formula: see text]H NMR metabolomics without knowledge of the molecular structure. This approach may be a valuable resource for the development of future automated metabolite alignment, annotation and peak fitting algorithms. PMID: 29606928 [PubMed]

Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids. EBioMedicine. 2018 Mar 27;: Authors: Sauvat A, Chen G, Müller K, Tong M, Aprahamian F, Durand S, Cerrato G, Bezu L, Leduc M, Franz J, Rockenfeller P, Sadoshima J, Madeo F, Kepp O, Kroemer G Abstract Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids. PMID: 29606629 [PubMed - as supplied by publisher]

Application of sequential and orthogonalised-partial least squares (SO-PLS) regression to predict sensory properties of Cabernet Sauvignon wines from grape chemical composition. Food Chem. 2018 Aug 01;256:195-202 Authors: Niimi J, Tomic O, Næs T, Jeffery DW, Bastian SEP, Boss PK Abstract The current study determined the applicability of sequential and orthogonalised-partial least squares (SO-PLS) regression to relate Cabernet Sauvignon grape chemical composition to the sensory perception of the corresponding wines. Grape samples (n = 25) were harvested at a similar maturity and vinified identically in 2013. Twelve measures using various (bio)chemical methods were made on grapes. Wines were evaluated using descriptive analysis with a trained panel (n = 10) for sensory profiling. Data was analysed globally using SO-PLS for the entire sensory profiles (SO-PLS2), as well as for single sensory attributes (SO-PLS1). SO-PLS1 models were superior in validated explained variances than SO-PLS2. SO-PLS provided a structured approach in the selection of predictor chemical data sets that best contributed to the correlation of important sensory attributes. This new approach presents great potential for application in other explorative metabolomics studies of food and beverages to address factors such as quality and regional influences. PMID: 29606438 [PubMed - in process]

Related Articles Chemical profiling of two congeneric sea mat corals along the Brazilian coast: adaptive and functional patterns. Chem Commun (Camb). 2018 Feb 20;54(16):1952-1955 Authors: Costa-Lotufo LV, Carnevale-Neto F, Trindade-Silva AE, Silva RR, Silva GGZ, Wilke DV, Pinto FCL, Sahm BDB, Jimenez PC, Mendonça JN, Lotufo TMC, Pessoa ODL, Lopes NP Abstract Metabolomic profiles were explored to understand environmental and taxonomic influences on the metabolism of two congeneric zoanthids, Palythoa caribaeorum and P. variabilis, collected across distinct geographical ranges. Integrated mass spectrometry data suggested the major influence of geographical location on chemical divergence when compared to species differentiation. PMID: 29323379 [PubMed - indexed for MEDLINE]

Related Articles Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev. 2017 Jun;36(2):289-303 Authors: Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D, Hawk E, Vilar E, Bhattacharya P, Millward S Abstract After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism. PMID: 28762014 [PubMed - indexed for MEDLINE]

Regulation of Kynurenine Metabolism by a Ketogenic Diet. J Lipid Res. 2018 Mar 31;: Authors: Heischmann S, Gano LB, Quinn K, Liang LP, Klepacki J, Christians U, Reisdorph N, Patel M Abstract Ketogenic diets (KDs) are increasingly utilized as treatments for epilepsy, other neurological diseases, and cancer. Despite their long history in suppressing seizures, the distinct molecular mechanisms of action of KDs are still largely unknown. The goal of this study was to identify key metabolites and pathways altered in hippocampus and plasma of rats fed a KD vs. control diet either ad libitum or calorically restricted to 90% of the recommended intake. This was accomplished using a combination of targeted methods and untargeted mass spectrometry-based metabolomics analyses. Various metabolites of and related to the tryptophan degradation pathway, such as kynurenine and kynurenic acid, as well as enzyme cofactors showed significant changes between groups fed different diets and/or calorie amounts in plasma and/or the hippocampus. Kynurenine was significantly downregulated in both matrices in animals of the control diet-calorically restricted, KD-ad libitum, and KD-calorically restricted groups compared to the control diet-ad libitum group. Our data suggest that the tryptophan degradation pathway is a key target of the KD. PMID: 29605816 [PubMed - as supplied by publisher]

Baseline levels of metabolites in different tissues of mussel Mytilus galloprovincialis (Bivalvia: Mytilidae). Comp Biochem Physiol Part D Genomics Proteomics. 2018 Mar 27;26:32-39 Authors: Cappello T, Giannetto A, Parrino V, Maisano M, Oliva S, De Marco G, Guerriero G, Mauceri A, Fasulo S Abstract The Mediterranean mussel Mytilus galloprovincialis (Lamarck 1819) is a popular shellfish commonly included in human diet and is routinely used as bioindicator in environmental monitoring programmes worldwide. Recently, metabolomics has emerged as a powerful tool both in food research and ecotoxicology for monitoring mussels' freshness and assessing the effects of environmental changes. However, there is still a paucity of data on complete metabolic baseline of mussel tissues. To mitigate this knowledge gap, similarities and differences in metabolite profile of digestive gland (DG), gills (G), and posterior adductor muscle (PAM) of aquaculture-farmed M. galloprovincialis were herein investigated by a proton nuclear magnetic resonance (1H NMR)-based metabolomic approach and discussed considering their physiological role. A total of 44 metabolites were identified in mussel tissues and grouped in amino acids, energy metabolites, osmolytes, neurotransmitters, nucleotides, alkaloids, and miscellaneous metabolites. A PCA showed that mussel tissues clustered separately from each other, suggesting a clear differentiation in their metabolic profiles. A Venn diagram revealed that mussel DG, G and PAM shared 27 (61.36%) common metabolites, though with different concentrations. Osmolytes were found to dominate the metabolome of all tissues. The DG exhibited higher level of glutathione and carbohydrates. The G showed greater level of osmolytes and the exclusive presence of neurotransmitters, namely acetylcholine and serotonin. In PAM higher levels of energetics-related metabolites were found. Overall, findings from this study are helpful for a better understanding of mussel tissue-specific physiological functions as well as for future NMR-based metabolomic investigations of marine mussel health and safety. PMID: 29605489 [PubMed - as supplied by publisher]

Related Articles Identification of metabolites in plasma for predicting survival in glioblastoma. Mol Carcinog. 2018 Mar 30;: Authors: Shen J, Song R, Hodges TR, Heimberger AB, Zhao H Abstract Circulating metabolomics profiling holds prognostic potential. However, such efforts have not been extensively carried out in glioblastoma. In this study, two-step (training and testing) metabolomics profiling was conducted from the plasma samples of 159 glioblastoma patients. Metabolomics profiling was tested for correlation with 2-year overall and disease-free survivals. Arginine, methionine, and kynurenate levels were significantly associated with 2-year overall survival in both the training and testing sets. In the combined sets, elevated levels of arginine and methionine were associated with a 34% and 37% increased probability whereas kynurenate was associated with a 55% decreased probability of 2-year overall survival. These three metabolites were also significantly associated with 2-year disease-free survival. Risk scores were generated using the linear combination of levels of these significant metabolites. Glioblastoma patients with a high-risk score exhibited a 2.41-fold decreased probability of 2-year overall survival (hazard ratio (HR) = 2.41; 95% Confidence Interval (CI) = 1.20-4.93) and a 3.17 fold decreased probability of 2-year disease free survival (HR = 3.17, 95% CI = 1.42-7.54) relative to those with a low-risk score. In conclusion, we identified a unique plasma metabolite profile that is predictive of glioblastoma prognosis. This article is protected by copyright. All rights reserved. PMID: 29603794 [PubMed - as supplied by publisher]

Related Articles Changes in Plasma Metabolite Concentrations after a Low-Glycemic Index Diet Intervention. Mol Nutr Food Res. 2018 Mar 30;:e1700975 Authors: Hernández-Alonso P, Giardina S, Cañueto D, Salas-Salvadó J, Cañellas N, Bulló M Abstract SCOPE: To examine whether a low-glycemic index (LGI) diet improves a set of plasma metabolites related to different metabolic diseases and compared to a high-glycemic index (HGI) diet and a low-fat (LF) diet. METHODS AND RESULTS: We conducted a parallel, randomized trial with three intervention diets: a LGI diet, a HGI diet and a LF diet. A total of 122 adult overweight and obese subjects were enrolled in the study for 6 months. Blood samples were collected at baseline and at the end of the intervention. We analyzed the plasma metabolomic profile of 102 subjects using three different approaches: GC/quadrupole-TOF, LC/quadrupole-TOF and NMR. Both univariate and multivariate analysis were performed. Serine levels were significantly higher following the LGI diet compared to both the HGI and LF diets (q = 0.002), whereas leucine (q = 0.015) and valine (q = 0.024) were lower in the LGI diet compared to the LF diet. A set of two sphingomyelins, two lysophosphatidylcholines and six phosphatidylcholines were significantly modulated after the LGI diet compared to the HGI and LF diets (q<0.05). We found significant correlations between changes in plasma amino acids and lipid species with changes in body weight, glucose, insulin and some inflammatory markers. CONCLUSION: Our results suggest that a LGI diet modulates certain circulating amino acids and lipid levels. These findings may explain the health benefits attributed to LGI diets in metabolic diseases such as type 2 diabetes. This article is protected by copyright. All rights reserved. PMID: 29603657 [PubMed - as supplied by publisher]

Related Articles Hepatic Abundance and Activity of Androgen and Drug Metabolizing Enzyme, UGT2B17, are Associated with Genotype, Age, and Sex. Drug Metab Dispos. 2018 Mar 30;: Authors: Bhatt DK, Basit A, Zhang H, Gaedigk A, Lee SB, Claw KG, Mehrotra A, Chaudhry AS, Pearce RE, Gaedigk R, Broeckel U, Thornton TA, Nickerson DA, Schuetz EG, Amory J, Leeder JS, Prasad B Abstract The major objective of this study was to investigate association of genetic and non-genetic factors with variability in protein abundance and in vitro activity of the androgen metabolizing enzyme, UGT2B17, in human liver microsomes (n=455). UGT2B17 abundance was quantified by LC-MS/MS proteomics and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age and sex with its mRNA expression, abundance and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627 and rs4860305) were associated with gene expression, protein levels and androgen glucuronidation rates in a gene-dose dependent manner. UGT2B17 protein (mean ± SD pmol per mg microsomal protein) is sparsely expressed in children below 9 years (0.12 ± 0.24), but profoundly increases from age 9 years to adults (~10 fold) with ~2.6-fold higher abundance in males than females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was only observed in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures. PMID: 29602798 [PubMed - as supplied by publisher]

Related Articles Metabolomics and Metabolic Reprogramming in Kidney Cancer. Semin Nephrol. 2018 Mar;38(2):175-182 Authors: Weiss RH Abstract Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that commonly is seen in the general practice of nephrology. Despite this state of affairs, this fascinating and highly morbid disease frequently is under-represented, or even absent, from the curriculum of nephrologists in training and generally is underemphasized in national nephrology meetings, both scientific as well as clinical. Although classic concepts in cancer research in general had led to the concept that cancer is a disease resulting from mutations in the control of growth-regulating pathways, reinforced by the discovery of oncogenes, more contemporary research, particularly in kidney cancer, has uncovered changes in metabolic pathways mediated by those same genes that control tumor energetics and biosynthesis. This adaptation of classic biochemical pathways to the tumor's advantage has been labeled metabolic reprogramming. For example, in the case of kidney cancer there exists a near-universal presence of von Hippel-Lindau tumor suppressor (pVHL) inactivation in the most common form, clear cell RCC (ccRCC), leading to activation of hypoxia-relevant and other metabolic pathways. Studies of this and other pathways in clear cell RCC (ccRCC) have been particularly revealing, leading to the concept that ccRCC can itself be considered a metabolic disease. For this reason, the relatively new method of metabolomics has become a useful technique in the study of ccRCC to tease out those pathways that have been reprogrammed by the tumor to its maximum survival advantage. Furthermore, identification of the nodes of such pathways can lead to novel areas for drug intervention in a disease for which such targets are seriously lacking. Further research and dissemination of these concepts, likely using omics techniques, will lead to clinical trials of therapeutics specifically targeted to tumor metabolism, rather than those generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective than existing drugs and to have far fewer adverse effects. This review provides a general overview of the technique of metabolomics and then discusses how it and other omics techniques have been used to further our understanding of the basic biology of kidney cancer as well as to identify new therapeutic approaches. PMID: 29602399 [PubMed - in process]

Related Articles Genome-Wide Association Studies of Metabolite Concentrations (mGWAS): Relevance for Nephrology. Semin Nephrol. 2018 Mar;38(2):151-174 Authors: Köttgen A, Raffler J, Sekula P, Kastenmüller G Abstract Metabolites are small molecules that are intermediates or products of metabolism, many of which are freely filtered by the kidneys. In addition, the kidneys have a central role in metabolite anabolism and catabolism, as well as in active metabolite reabsorption and/or secretion during tubular passage. This review article illustrates how the coupling of genomics and metabolomics in genome-wide association analyses of metabolites can be used to illuminate mechanisms underlying human metabolism, with a special focus on insights relevant to nephrology. First, genetic susceptibility loci for reduced kidney function and chronic kidney disease (CKD) were reviewed systematically for their associations with metabolite concentrations in metabolomics studies of blood and urine. Second, kidney function and CKD-associated metabolites reported from observational studies were interrogated for metabolite-associated genetic variants to generate and discuss complementary insights. Finally, insights originating from the simultaneous study of both blood and urine or by modeling intermetabolite relationships are summarized. We also discuss methodologic questions related to the study of metabolite concentrations in urine as well as among CKD patients. In summary, genome-wide association analyses of metabolites using metabolite concentrations quantified from blood and/or urine are a promising avenue of research to illuminate physiological and pathophysiological functions of the kidney. PMID: 29602398 [PubMed - in process]

Related Articles A Systems-Level View of Renal Metabolomics. Semin Nephrol. 2018 Mar;38(2):142-150 Authors: Rhee EP Abstract The measurement of select circulating metabolites such as creatinine, glucose, and cholesterol are integral to clinical medicine, with implications for diagnosis, prognosis, and treatment. Metabolomics studies in nephrology research seek to build on this paradigm, with the goal to identify novel markers and causal participants in the pathogenesis of kidney disease and its complications. This article reviews three themes pertinent to this goal. Each is rooted in long-established principles of human physiology, with recent updates enabled by metabolomics and other tools. First, the kidney has a broad and heterogeneous impact on circulating metabolites, with progressive loss of kidney function resulting in a multitude of small molecule alterations. Second, an increasing number of circulating metabolites have been shown to possess functional roles, in some cases acting as ligands for specific G-protein-coupled receptors. Third, circulating metabolites traffic through varied, and sometimes complex, interorgan circuits. Taken together, these themes emphasize the importance of viewing renal metabolomics at the systems level, recognizing the diverse origins and physiologic effects of blood metabolites. However, how to synthesize these themes and how to establish clinical relevance remain uncertain and will require further investigation. PMID: 29602397 [PubMed - in process]

Related Articles Lipidomics and Biomarker Discovery in Kidney Disease. Semin Nephrol. 2018 Mar;38(2):127-141 Authors: Afshinnia F, Rajendiran TM, Wernisch S, Soni T, Jadoon A, Karnovsky A, Michailidis G, Pennathur S Abstract Technological advances in mass spectrometry-based lipidomic platforms have provided the opportunity for comprehensive profiling of lipids in biological samples and shown alterations in the lipidome that occur in metabolic disorders. A lipidomic approach serves as a powerful tool for biomarker discovery and gaining insight to molecular mechanisms of disease, especially when integrated with other -omics platforms (ie, transcriptomics, proteomics, and metabolomics) in the context of systems biology. In this review, we describe the workflow commonly applied to the conduct of lipidomic studies including important aspects of study design, sample preparation, biomarker identification and quantification, and data processing and analysis, as well as crucial considerations in clinical applications. We also review some recent studies of the application of lipidomic platforms that highlight the potential of lipid biomarkers and add to our understanding of the molecular basis of kidney disease. PMID: 29602396 [PubMed - in process]

Related Articles The Warburg Effect in Diabetic Kidney Disease. Semin Nephrol. 2018 Mar;38(2):111-120 Authors: Zhang G, Darshi M, Sharma K Abstract Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine. PMID: 29602394 [PubMed - in process]