PubMed

A Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus. J Proteome Res. 2016 Mar 15; Authors: Marshall DD, Sadykov MR, Thomas VC, Bayles KW, Powers R Abstract The phosphotransacetylase-acetate kinase (Pta-AckA) pathway is thought to be a vital ATP generating pathway for Staphylococcus aureus. Disruption of the Pta-AckA pathway during overflow metabolism causes significant reduction in growth rate and viability, albeit not due to intracellular ATP depletion. Here we demonstrate that toxicity associated with inactivation of the Pta-AckA pathway resulted from an altered intracellular redox environment. Growth of the pta and ackA mutants under anaerobic conditions partially restored cell viability. NMR metabolomics analyses and 13C6-glucose metabolism tracing experiments revealed the activity of multiple pathways that promote redox (NADH/NAD+) turnover to be enhanced in the pta and ackA mutants during anaerobic growth. Restoration of redox homeostasis in the pta mutant by overexpressing L- lactate dehydrogenase, partially restored its viability under aerobic conditions. Together our findings suggest that during overflow metabolism the Pta-AckA pathway plays a critical role in preventing cell viability defects by promoting intracellular redox homeostasis. PMID: 26975873 [PubMed - as supplied by publisher]

Seminal biomarkers for the evaluation of male infertility. Asian J Androl. 2016 Mar 11; Authors: Bieniek JM, Drabovich AP, Lo KC Abstract For men struggling to conceive with their partners, diagnostic tools are limited and often consist of only a standard semen analysis. This baseline test serves as a crude estimation of male fertility, leaving patients and clinicians in need of additional diagnostic biomarkers. Seminal fluid contains the highest concentration of molecules from the male reproductive glands, therefore, this review focuses on current and novel seminal biomarkers in certain male infertility scenarios, including natural fertility, differentiating azoospermia etiologies, and predicting assisted reproductive technique success. Currently available tests include antisperm antibody assays, DNA fragmentation index, sperm fluorescence in situ hybridization, and other historical sperm functional tests. The poor diagnostic ability of current assays has led to continued efforts to find more predictive biomarkers. Emerging research in the fields of genomics, epigenetics, proteomics, transcriptomics, and metabolomics holds promise for the development of novel male infertility biomarkers. Seminal protein-based assays of TEX101, ECM1, and ACRV1 are already available or under final development for clinical use. Additional panels of DNA, RNA, proteins, or metabolites are being explored as we attempt to understand the pathophysiologic processes of male infertility. Future ventures will need to continue data integration and validation for the development of clinically useful infertility biomarkers to aid in male infertility diagnosis, treatment, and counseling. PMID: 26975492 [PubMed - as supplied by publisher]

[Investigation of metabolites of Triptergium wilfordii on liver toxicity by LC-MS]. Zhongguo Zhong Yao Za Zhi. 2015 Oct;40(19):3851-8 Authors: Zhao XM, Liu XY, Xu C, Ye T, Jin C, Zhao KJ, Ma ZJ, Xiao XH Abstract In this paper, biomarkers of liver toxicity of Triptergium wilfordii based on metabolomics was screened, and mechanism of liver toxicity was explored to provide a reference for the clinical diagnosis for liver toxicity of Triptergium wilfordii. MS method was carried on the analysis to metabolic fingerprint spectrum between treatment group and control group. The potential biomarkers were compared and screened using the multivariate statistical methods. As well, metabolic pathway would be detailed description. Combined with PCA and OPLS-DA pattern recognition analysis, 20 metabolites were selected which showed large differences between model group and blank group (VIP > 1.0). Seven possible endogenous biomarkers were analyzed and identified. They were 6-phosphate glucosamine, lysophospholipid, tryptophan, guanidine acetic acid, 3-indole propionic acid, cortisone, and ubiquinone. The level changes of above metabolites indicated that the metabolism pathways of amino acid, glucose, phospholipid and hormone were disordered. It is speculated that liver damage of T. wilfordii may be associated with the abnormal energy metabolism in citric acid cycle, amino acid metabolism in urea cycle, and glucose metabolism. It will be helpful to further research liver toxicity ingredients of Triptergium wilfordii. PMID: 26975113 [PubMed - in process]

Related Articles Mendelian randomization: where are we now and where are we going? Int J Epidemiol. 2015 Apr;44(2):379-88 Authors: Burgess S, Timpson NJ, Ebrahim S, Davey Smith G PMID: 26085674 [PubMed - indexed for MEDLINE]

Related Articles Aromatic L-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma. Mol Genet Metab. 2015 Jun-Jul;115(2-3):91-4 Authors: Atwal PS, Donti TR, Cardon AL, Bacino CA, Sun Q, Emrick L, Reid Sutton V, Elsea SH Abstract Aromatic L-amino acid decarboxylase (AADC) deficiency is an inborn error of metabolism affecting the biosynthesis of serotonin, dopamine, and catecholamines. We report a case of AADC deficiency that was detected using the Global MAPS platform. This is a novel platform that allows for parallel clinical testing of hundreds of metabolites in a single plasma specimen. It uses a state-of-the-art mass spectrometry platform, and the resulting spectra are compared against a library of ~2500 metabolites. Our patient is now a 4 year old boy initially seen at 11 months of age for developmental delay and hypotonia. Multiple tests had not yielded a diagnosis until exome sequencing revealed compound heterozygous variants of uncertain significance (VUS), c.286G>A (p.G96R) and c.260C>T (p.P87L) in the DDC gene, causal for AADC deficiency. CSF neurotransmitter analysis confirmed the diagnosis with elevated 3-methoxytyrosine (3-O-methyldopa). Metabolomic profiling was performed on plasma and revealed marked elevation in 3-methoxytyrosine (Z-score +6.1) consistent with the diagnosis of AADC deficiency. These results demonstrate that the Global MAPS platform is able to diagnose AADC deficiency from plasma. In summary, we report a novel and less invasive approach to diagnose AADC deficiency using plasma metabolomic profiling. PMID: 25956449 [PubMed - indexed for MEDLINE]

Related Articles Chemical methods for the simultaneous quantitation of metabolites and proteins from single cells. J Am Chem Soc. 2015 Apr 1;137(12):4066-9 Authors: Xue M, Wei W, Su Y, Kim J, Shin YS, Mai WX, Nathanson DA, Heath JR Abstract We describe chemical approaches for integrated metabolic and proteomic assays from single cells. Quantitative assays for intracellular metabolites, including glucose uptake and three other species, are designed as surface-competitive binding assays with fluorescence readouts. This enables integration into a microarray format with functional protein immunoassays, all of which are incorporated into the microchambers of a single-cell barcode chip (SCBC). By using the SCBC, we interrogate the response of human-derived glioblastoma cancer cells to epidermal growth factor receptor inhibition. We report, for the first time, on both the intercellular metabolic heterogeneity as well as the baseline and drug-induced changes in the metabolite-phosphoprotein correlation network. PMID: 25789560 [PubMed - indexed for MEDLINE]

Related Articles Fructose restores susceptibility of multidrug-resistant Edwardsiella tarda to kanamycin. J Proteome Res. 2015 Mar 6;14(3):1612-20 Authors: Su YB, Peng B, Han Y, Li H, Peng XX Abstract Edwardsiella tarda, the causative agent of Edwardsiellosis, imposes medical challenges in both the clinic and aquaculture. The emergence of multidrug resistant strains makes antibiotic treatment impractical. The identification of molecules that facilitate or promote antibiotic efficacy is in high demand. In the present study, we aimed to identify small molecules whose abundance is correlated with kanamycin resistance in E. tarda by gas chromatography-mass spectrometry. We found that the abundance of fructose was greatly suppressed in kanamycin-resistant strains. The incubation of kanamycin-resistant bacteria with exogenous fructose sensitized the bacteria to kanamycin. Moreover, the fructose also functioned in bacteria persisters and biofilm. The synergistic effects of fructose and kanamycin were validated in a mouse model. Furthermore, the mechanism relies on fructose in activating TCA cycle to produce NADH, which generates proton motive force to increase the uptake of the antibiotics. Therefore, we present a novel approach in fighting against multidrug resistant bacteria through exploration of antibiotic-suppressed molecules. PMID: 25675328 [PubMed - indexed for MEDLINE]

Related Articles Metabonomic profiling of bladder cancer. J Proteome Res. 2015 Feb 6;14(2):587-602 Authors: Chan EC, Pasikanti KK, Hong Y, Ho PC, Mahendran R, Raman Nee Mani L, Chiong E, Esuvaranathan K Abstract Early diagnosis and life-long surveillance are clinically important to improve the long-term survival of bladder cancer patients. Currently, a noninvasive biomarker that is as sensitive and specific as cystoscopy in detecting bladder tumors is lacking. Metabonomics is a complementary approach for identifying perturbed metabolic pathways in bladder cancer. Significant progress has been made using modern metabonomic techniques to characterize and distinguish bladder cancer patients from control subjects, identify marker metabolites, and shed insights on the disease biology and potential therapeutic targets. With its rapid development, metabonomics has the potential to impact the clinical management of bladder cancer patients in the future by revolutionizing the diagnosis and life-long surveillance strategies and stratifying patients for diagnostic, surgical, and therapeutic clinical trials. An introduction to metabonomics, typical metabonomic workflow, and critical evaluation of metabonomic investigations in identifying biomarkers for the diagnosis of bladder cancer are presented. PMID: 25388527 [PubMed - indexed for MEDLINE]

Enabling Metabolomics Based Biomarker Discovery Studies Using Molecular Phenotyping of Exosome-Like Vesicles. PLoS One. 2016;11(3):e0151339 Authors: Altadill T, Campoy I, Lanau L, Gill K, Rigau M, Gil-Moreno A, Reventos J, Byers S, Colas E, Cheema AK Abstract Identification of sensitive and specific biomarkers with clinical and translational utility will require smart experimental strategies that would augment expanding the breadth and depth of molecular measurements within the constraints of currently available technologies. Exosomes represent an information rich matrix to discern novel disease mechanisms that are thought to contribute to pathologies such as dementia and cancer. Although proteomics and transcriptomic studies have been reported using Exosomes-Like Vesicles (ELVs) from different sources, exosomal metabolome characterization and its modulation in health and disease remains to be elucidated. Here we describe methodologies for UPLC-ESI-MS based small molecule profiling of ELVs from human plasma and cell culture media. In this study, we present evidence that indeed ELVs carry a rich metabolome that could not only augment the discovery of low abundance biomarkers but may also help explain the molecular basis of disease progression. This approach could be easily translated to other studies seeking to develop predictive biomarkers that can subsequently be used with simplified targeted approaches. PMID: 26974972 [PubMed - as supplied by publisher]

Dissect style response to pollination using metabolite profiling in self-compatible and self-incompatible tomato species. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Feb 23;1017-1018:153-162 Authors: Zhao P, Pan Q, Yu W, Zhao L Abstract Tomato style is the pathway for pollen germination and pollen tubes growth from the stigma to the ovules where fertilization occurs. It is essential to supplying the nutrients for pollen tube growth and guidance for the pollen tubes. To our knowledge, style also regulates gametophytic self-incompatibility (SI) in tomato species. This study identified the metabolites and monitored the metabolic changes of self-incompatible and self-compatible tomato with self-pollinated or unpollinated styles by gas chromatography-mass spectrometry (GC-MS). A total of 9 classes of compounds were identified in SI and self-compatibility (SC) self-pollinated and unpollinated styles which included amino acids, sugars, fatty acids/lipids, amines, organic acids, alcohols, nitriles, inorganic acids and other compounds. The contents of d-Mannose-6-phosphate, Cellobiose, Myristic acid, 2,4-Diaminobutyric acid, Inositol and Urea were significantly decreased and the rest did not significantly change in SI styles. But change of metabolites content significantly happened in SC styles. In addition, among the total 9 classes of compounds, the different metabolites accounted for a different proportion in amino acids, sugars, amines, organic acids and alcohols compared SC and SI. The result indicated that the physiological changes of styles existed differences in SC and SI after self pollination. PMID: 26974868 [PubMed - as supplied by publisher]

Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in Leydig cells. Mol Endocrinol. 2016 Mar 14;:me20151282 Authors: Sondhi V, Owen BM, Liu J, Chomic R, Kliewer SA, Hughes BA, Arlt W, Mangelsdorf DJ, Auchus RJ Abstract Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase, CYP17A1). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared to littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone (17OHP) accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed following hCG stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase/17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17OHP accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse P450 17A1 is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings. PMID: 26974035 [PubMed - as supplied by publisher]

GATA4 regulates blood-testis barrier function and lactate metabolism in mouse Sertoli cells. Endocrinology. 2016 Mar 14;:en20151927 Authors: Schrade A, Kyrönlahti A, Akinrinade O, Pihlajoki M, Fischer S, Rodriguez VM, Otte K, Velagapudi V, Toppari J, Wilson DB, Heikinheimo M Abstract Conditional deletion of Gata4 in Sertoli cells (SCs) of adult mice has been shown to increase permeability of the blood-testis barrier (BTB) and disrupt spermatogenesis. To gain insight into the molecular underpinnings of these phenotypic abnormalities, we assessed the impact of Gata4 gene silencing in cell culture models. Microarray hybridization identified genes dysregulated by siRNA-mediated inhibition of Gata4 in TM4 cells, an immortalized mouse SC line. Differentially expressed genes were validated by qRT-PCR analysis of primary cultures of Gata4(flox/flox) mouse SCs that had been subjected to cre-mediated recombination in vitro. Depletion of GATA4 in TM4 cells and primary SCs was associated with altered expression of genes involved in key facets of BTB maintenance, including tight/adherens junction formation (Tjp1, Cldn12, Vcl, Tnc, Csk) and extracellular matrix reorganization (Lamc1, Col4a1, Col4a5, Mmp10, Mmp23, Timp2). Western blotting and immunocytochemistry demonstrated reduced levels of TJP1, a prototypical tight junction protein, in GATA4-depleted cells. These changes were accompanied by a loss of morphologically-recognizable junctional complexes and a decline in trans-epithelial membrane resistance. Furthermore, Gata4 gene silencing was associated with altered expression of Hk1, Gpi1, Pfkp, Pgam1, Gls2, Pdk3, Pkd4, and Ldhb, genes regulating the production of lactate, a key nutrient that SCs provide to developing germ cells. Comprehensive metabolomic profiling demonstrated impaired lactate production in GATA4-deficient SCs. We conclude that GATA4 plays a pivotal role in the regulation of BTB function and lactate metabolism in mouse SCs. PMID: 26974005 [PubMed - as supplied by publisher]

The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma. Oncoscience. 2016;3(1):31-41 Authors: Zhang J, Medina-Cleghorn D, Bernal-Mizrachi L, Bracci PM, Hubbard A, Conde L, Riby J, Nomura DK, Skibola CF Abstract Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m(2); 118%, P < 0.001) compared to those with a BMI < 25 kg/m(2). DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs. PMID: 26973858 [PubMed]

Metabolomics and Its Application to Acute Lung Diseases. Front Immunol. 2016;7:44 Authors: Stringer KA, McKay RT, Karnovsky A, Quémerais B, Lacy P Abstract Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a "snapshot" in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision-making and investigators can use them to design clinical trials. PMID: 26973643 [PubMed]

Murine Depression Model and its Potential Applications for Discovering Foods and Farm Products with Antidepressant-Like Effects. Front Neurosci. 2016;10:72 Authors: Goto T, Tomonaga S, Okayama T, Toyoda A Abstract Advanced societies face increased health problems related to various stresses. Chronic psychological stress is a major risk factor for psychiatric disorders such as depression. Although therapeutic agents reduce several symptoms of depression, most have side effects in a broad range of the population. Furthermore, some victims of depression do not show significant improvement with any drugs, so alternative approaches are needed. Good dietary habits may potentially reduce depressive symptoms, but there is little scientific evidence thus far. Murine depression models are useful to test nutritional approaches in vivo. Our model mice subjected to a subchronic mild social defeat stress (sCSDS) paradigm show several alterations in physiological parameters and social behavior. These stress-induced symptoms in sCSDS mice can be used as cues to identify antidepressant-like natural resources including foods and farm products. We previously discovered that sCSDS mice show more vulnerability to social stress by changing dietary condition. In addition, we developed a more objective system for analyzing mouse behavior using a 3D depth-sensing camera to understand relationships between diet and behavior. The combination of sCSDS mice with 3D behavioral analysis is a powerful method for screening ingredients in foods and farm products for antidepressant-like effects. PMID: 26973450 [PubMed]

The metabolomic detection of lung cancer biomarkers in sputum. Lung Cancer. 2016 Apr;94:88-95 Authors: Cameron SJ, Lewis KE, Beckmann M, Allison GG, Ghosal R, Lewis PD, Mur LA Abstract OBJECTIVES: Developing screening and diagnosis methodologies based on novel biomarkers should allow for the detection of the lung cancer (LC) and possibly at an earlier stage and thereby increase the effectiveness of clinical interventions. Here, our primary objective was to evaluate the potential of spontaneous sputum as a source of non-invasive metabolomic biomarkers for LC status. MATERIALS AND METHODS: Spontaneous sputum was collected and processed from 34 patients with suspected LC, alongside 33 healthy controls. Of the 34 patients, 23 were subsequently diagnosed with LC (LC(+), 16 NSCLC, six SCLC, and one radiological diagnosis), at various stages of disease progression. The 67 samples were analysed using flow infusion electrospray ion mass spectrometry (FIE-MS) and gas-chromatography mass spectrometry (GC-MS). RESULTS: Principal component analysis identified negative mode FIE-MS as having the main separating power between samples from healthy and LC. Discriminatory metabolites were identified using ANOVA and Random Forest. Indications of potential diagnostic accuracy involved the use of receiver operating characteristic/area under the curve (ROC/AUC) analyses. This approach identified metabolites changes that were only observed with LC. Metabolites with AUC values of greater than 0.8 which distinguished between LC(+)/LC(-) binary classifications where identified and included Ganglioside GM1 which has previously been linked to LC. CONCLUSION: This study indicates that metabolomics based on sputum can yield metabolites that can be used as a diagnostic and/or discriminator tool. These could aid clinical intervention and targeted diagnosis of LC within an 'at risk' LC(-) population group. The use of sputum as a non-invasive source of metabolite biomarkers may aid in the development of an at-risk population screening programme for lung cancer or enhanced clinical diagnostic pathways. PMID: 26973212 [PubMed - in process]

The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A. Cell Rep. 2016 Mar 8; Authors: Segura I, Lange C, Knevels E, Moskalyuk A, Pulizzi R, Eelen G, Chaze T, Tudor C, Boulegue C, Holt M, Daelemans D, Matondo M, Ghesquière B, Giugliano M, Ruiz de Almodovar C, Dewerchin M, Carmeliet P Abstract Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition. PMID: 26972007 [PubMed - as supplied by publisher]

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer. Lipids Health Dis. 2016;15(1):56 Authors: Flote VG, Vettukattil R, Bathen TF, Egeland T, McTiernan A, Frydenberg H, Husøy A, Finstad SE, Lømo J, Garred Ø, Schlichting E, Wist EA, Thune I Abstract BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5 %. Most (93 %) of the patients had estrogen receptor (ER) positive tumors (≥1 % ER+), and 82 % had progesterone receptor (PgR) positive tumors (≥10 % PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies. PMID: 26970778 [PubMed - as supplied by publisher]

Related Articles Gene-gene and gene-environment interactions on risk of male infertility: Focus on the metabolites. Environ Int. 2016 Mar 9;91:188-195 Authors: Hu W, Chen M, Wu W, Lu J, Zhao D, Pan F, Lu C, Xia Y, Hu L, Chen D, Sha J, Wang X Abstract Infertility affects about 17% couples, and males contribute to half of the cases. Compared with independent effects of genetic and environmental factors, interactions between them help in the understanding of the susceptibility to male infertility. Thus, we genotyped 25 polymorphisms, measured 16 urinary chemical concentrations and explored interactions between gene-gene and gene-environment in 1039 Han Chinese using metabolomic analysis. We first observed that GSTT1 might interact with GSTM1 (Pinter=6.33×10(-8)). Furthermore, an interaction between GSTM1 and 4-n-octylphenol (4-n-OP) was identified (Pinter=7.00×10(-3)), as well as a 2-order interaction among GSTT1, GSTM1 and 4-n-OP (Pinter=0.04). Subjects with GSTT1-present and GSTM1-null genotypes were susceptible to male infertility when exposed to 4-n-OP (OR=14.05, 95% CI=4.78-60.20, P=2.34×10(-5)). Most metabolites identified were involved in the tricarboxylic acid cycle. In conclusion, it is a novel study of the interaction on male infertility from the aspect of metabolomics. PMID: 26970590 [PubMed - as supplied by publisher]

Related Articles Product ion isotopologue pattern: A tool to improve the reliability of elemental composition elucidations of unknown compounds in complex matrices. Rapid Commun Mass Spectrom. 2016 Apr 15;30(7):791-799 Authors: Kaufmann A, Walker S, Mol G Abstract RATIONALE: Elucidation of the elemental compositions of unknown compounds (e.g., in metabolomics) generally relies on the availability of accurate masses and isotopic ratios. This study focuses on the information provided by the abundance ratio within a product ion pair (monoisotopic versus the first isotopic peak) when isolating and fragmenting the first isotopic ion (first isotopic mass spectrum) of the precursor. METHODS: This process relies on the capability of the quadrupole within the Q Orbitrap instrument to isolate a very narrow mass window. Selecting only the first isotopic peak (first isotopic mass spectrum) leads to the observation of a unique product ion pair. The lighter ion within such an isotopologue pair is monoisotopic, while the heavier ion contains a single carbon isotope. The observed abundance ratio is governed by the percentage of carbon atoms lost during the fragmentation and can be described by a hypergeometric distribution. RESULTS: The observed carbon isotopologue abundance ratio (product ion isotopologue pattern) gives reliable information regarding the percentage of carbon atoms lost in the fragmentation process. It therefore facilitates the elucidation of the involved precursor and product ions. Unlike conventional isotopic abundances, the product ion isotopologue pattern is hardly affected by isobaric interferences. Furthermore, the appearance of these pairs greatly aids in cleaning up a 'matrix-contaminated' product ion spectrum. CONCLUSIONS: The product ion isotopologue pattern is a valuable tool for structural elucidation. It increases confidence in results and permits structural elucidations for heavier ions. This tool is also very useful in elucidating the elemental composition of product ions. Such information is highly valued in the field of multi-residue analysis, where the accurate mass of product ions is required for the confirmation process. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 26969920 [PubMed - as supplied by publisher]