PubMed

[Determination of proteomic and metabolic composition of exhaled breath condensate of newborns]. Mol Biol (Mosk). 2016 May-Jun;50(3):540-544 Authors: Kononikhin AS, Chagovets VV, Starodubtseva NL, Ryndin AY, Bugrova AE, Kostyukevich YI, Popov IA, Frankevich VE, Ionov OV, Sukhikh GT, Nikolaev EN Abstract Here, the possibility of proteomic and metabolomic analysis of the composition of exhaled breath condensate of neonates with respiratory support. The developed method allows non-invasive collecting sufficient amount of the material for identification of disease-specific biomarkers. Samples were collected by using a condensing device that was incorporated into the ventilation system. The collected condensate was analyzed by liquid chromatography coupled with high resolution mass spectrometry and tandem mass spectrometry. The isolated substances were identified with a use of databases for proteins and metabolites. As a result, a number of compounds that compose the exhaled breath condensate was determined and can be considered as possible biomarkers of newborn diseases or stage of development. PMID: 27414793 [PubMed - as supplied by publisher]

High-mass-resolution MALDI mass spectrometry imaging of metabolites from formalin-fixed paraffin-embedded tissue. Nat Protoc. 2016 Aug;11(8):1428-1443 Authors: Ly A, Buck A, Balluff B, Sun N, Gorzolka K, Feuchtinger A, Janssen KP, Kuppen PJ, van de Velde CJ, Weirich G, Erlmeier F, Langer R, Aubele M, Zitzelsberger H, McDonnell L, Aichler M, Walch A Abstract Formalin-fixed and paraffin-embedded (FFPE) tissue specimens are the gold standard for histological examination, and they provide valuable molecular information in tissue-based research. Metabolite assessment from archived tissue samples has not been extensively conducted because of a lack of appropriate protocols and concerns about changes in metabolite content or chemical state due to tissue processing. We present a protocol for the in situ analysis of metabolite content from FFPE samples using a high-mass-resolution matrix-assisted laser desorption/ionization fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FT-ICR-MSI) platform. The method involves FFPE tissue sections that undergo deparaffinization and matrix coating by 9-aminoacridine before MALDI-MSI. Using this platform, we previously detected ∼1,500 m/z species in the mass range m/z 50-1,000 in FFPE samples; the overlap compared with fresh frozen samples is 72% of m/z species, indicating that metabolites are largely conserved in FFPE tissue samples. This protocol can be reproducibly performed on FFPE tissues, including small samples such as tissue microarrays and biopsies. The procedure can be completed in a day, depending on the size of the sample measured and raster size used. Advantages of this approach include easy sample handling, reproducibility, high throughput and the ability to demonstrate molecular spatial distributions in situ. The data acquired with this protocol can be used in research and clinical practice. PMID: 27414759 [PubMed - as supplied by publisher]

High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism. Biomed Res Int. 2016;2016:4125731 Authors: Chen M, Zheng H, Wei T, Wang D, Xia H, Zhao L, Ji J, Gao H Abstract Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID: 27413747 [PubMed - in process]

Circulating N-Linked Glycoprotein Side-Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial. J Am Heart Assoc. 2016 Jul;5(7) Authors: Akinkuolie AO, Glynn RJ, Padmanabhan L, Ridker PM, Mora S Abstract BACKGROUND: GlycA, a novel protein glycan biomarker of N-acetyl side chains of acute-phase proteins, was recently associated with incident cardiovascular disease (CVD) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown. METHODS AND RESULTS: In the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681), participants with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow-up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD: multivariable-adjusted hazard ratio (HR) per SD increment, 1.20 (95% CI, 1.08-1.34; P=0.0006). After additionally adjusting for hsCRP, this was slightly attenuated (HR, 1.18; 95% CI, 1.04-1.35; P=0.01). On-treatment GlycA levels were also associated with CVD; corresponding multivariable-adjusted HRs per SD before and after additionally adjusting for hsCRP: 1.27 (95% CI, 1.13-1.42; P<0.0001) and 1.24 (95% CI, 1.07-1.44; P=0.004), respectively. Tests for heterogeneity by treatment arm were not significant (P for interaction, >0.20). CONCLUSION: In the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hsCRP. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. PMID: 27413042 [PubMed - in process]

Early developmental stages of Ascaris lumbricoides featured by high-resolution mass spectrometry. Parasitol Res. 2016 Jul 13; Authors: Melo CF, Esteves CZ, de Oliveira RN, Guerreiro TM, de Oliveira DN, Lima EO, Miné JC, Allegretti SM, Catharino RR Abstract Ascaris lumbricoides is responsible for a highly disseminated helminth parasitic disease, ascariosis, a relevant parasitosis that responds for great financial burden on the public health system of developing countries. In this work, metabolic fingerprinting using high-resolution mass spectrometry (HRMS) was employed to identify marker molecules from A. lumbricoides in different development stages. We have identified nine biomarkers, such as pheromones and steroidal prohormones in early stages, among other molecules in late development stages, making up four molecules for fertilized eggs, four marker molecules for first larvae (L1) and one marker molecule for third larvae (L3). Therefore, our findings indicate that this approach is suitable for biochemical characterization of A. lumbricoides development stages. Moreover, the straightforward analytical method employed, with almost no sample preparation from a complex matrix (feces) using high-resolution mass spectrometry, suggests that it is possible to seek for an easier and faster way to study animal molding processes. PMID: 27412760 [PubMed - as supplied by publisher]

Mastitomics, the integrated omics of bovine milk in an experimental model of Streptococcus uberis mastitis: 3. Untargeted metabolomics. Mol Biosyst. 2016 Jul 14; Authors: Thomas FC, Mudaliar M, Tassi R, McNeilly TN, Burchmore R, Burgess K, Herzyk P, Zadoks RN, Eckersall PD Abstract Intramammary infection leading to bovine mastitis is the leading disease problem affecting dairy cows and has marked effects on the milk produced by infected udder quarters. An experimental model of Streptococcus uberis mastitis has previously been investigated for clinical, immunological and pathophysiological alteration in milk, and has been the subject of peptidomic and quantitative proteomic investigation. The same sample set has now been investigated with a metabolomics approach using liquid chromatography and mass spectrometry. The analysis revealed over 3000 chromatographic peaks, of which 690 were putatively annotated with a metabolite. Hierarchical clustering analysis and principal component analysis demonstrated that metabolite changes due to S. uberis infection were maximal at 81 hours post challenge with metabolites in the milk from the resolution phase at 312 hours post challenge being closest to the pre-challenge samples. Metabolic pathway analysis revealed that the majority of the metabolites mapped to carbohydrate and nucleotide metabolism show a decreasing trend in concentration up to 81 hours post-challenge whereas an increasing trend was found in lipid metabolites and di-, tri- and tetra-peptides up to the same time point. The increase in these peptides coincides with an increase in larger peptides found in the previous peptidomic analysis and is likely to be due to protease degradation of milk proteins. Components of bile acid metabolism, linked to the FXR pathway regulating inflammation, were also increased. Metabolomic analysis of the response in milk during mastitis provides an essential component to the full understanding of the mammary gland's response to infection. PMID: 27412568 [PubMed - as supplied by publisher]

Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016 Jul 11;30(1):147-60 Authors: Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, Senovilla L, Marino G, Aranda F, Durand S, Sica V, Chery A, Lachkar S, Sigl V, Bloy N, Buque A, Falzoni S, Ryffel B, Apetoh L, Di Virgilio F, Madeo F, Maiuri MC, Zitvogel L, Levine B, Penninger JM, Kroemer G Abstract Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed. PMID: 27411589 [PubMed - in process]

Transomics: Mitochondrial Systems Analyses Get Supercomplex. Cell Metab. 2016 Jul 12;24(1):13-4 Authors: Pagliarini DJ Abstract New "omics" tools are accelerating our ability to connect genomic variation to complex traits. Williams et al. (2016) reveal the power of layering quantitative proteomics and metabolomics measurements into a "systems genetics" analysis of recombinant inbred mouse strains to unravel new aspects of mitochondrial metabolism. PMID: 27411007 [PubMed - in process]

Related Articles Metabolomic Profiles of Body Mass Index in the Framingham Heart Study Reveal Distinct Cardiometabolic Phenotypes. PLoS One. 2016;11(2):e0148361 Authors: Ho JE, Larson MG, Ghorbani A, Cheng S, Chen MH, Keyes M, Rhee EP, Clish CB, Vasan RS, Gerszten RE, Wang TJ Abstract BACKGROUND: Although obesity and cardiometabolic traits commonly overlap, underlying pathways remain incompletely defined. The association of metabolite profiles across multiple cardiometabolic traits may lend insights into the interaction of obesity and metabolic health. We sought to investigate metabolic signatures of obesity and related cardiometabolic traits in the community using broad-based metabolomic profiling. METHODS AND RESULTS: We evaluated the association of 217 assayed metabolites and cross-sectional as well as longitudinal changes in cardiometabolic traits among 2,383 Framingham Offspring cohort participants. Body mass index (BMI) was associated with 69 of 217 metabolites (P<0.00023 for all), including aromatic (tyrosine, phenylalanine) and branched chain amino acids (valine, isoleucine, leucine). Additional metabolic pathways associated with BMI included the citric acid cycle (isocitrate, alpha-ketoglutarate, aconitate), the tryptophan pathway (kynurenine, kynurenic acid), and the urea cycle. There was considerable overlap in metabolite profiles between BMI, abdominal adiposity, insulin resistance [IR] and dyslipidemia, modest overlap of metabolite profiles between BMI and hyperglycemia, and little overlap with fasting glucose or elevated blood pressure. Metabolite profiles were associated with longitudinal changes in fasting glucose, but the involved metabolites (ornithine, 5-HIAA, aminoadipic acid, isoleucine, cotinine) were distinct from those associated with baseline glucose or other traits. Obesity status appeared to "modify" the association of 9 metabolites with IR. For example, bile acid metabolites were strongly associated with IR among obese but not lean individuals, whereas isoleucine had a stronger association with IR in lean individuals. CONCLUSIONS: In this large-scale metabolite profiling study, body mass index was associated with a broad range of metabolic alterations. Metabolite profiling highlighted considerable overlap with abdominal adiposity, insulin resistance, and dyslipidemia, but not with fasting glucose or blood pressure traits. PMID: 26863521 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2016/07/14PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Serum metabolomics profiles in response to n-3 fatty acids in Chinese patients with type 2 diabetes: a double-blind randomised controlled trial. Sci Rep. 2016;6:29522 Authors: Zheng JS, Lin M, Imamura F, Cai W, Wang L, Feng JP, Ruan Y, Tang J, Wang F, Yang H, Li D Abstract We aimed to investigate the change of serum metabolomics in response to n-3 fatty acid supplements in Chinese patients with type 2 diabetes (T2D). In a double-blind parallel randomised controlled trial, 59 Chinese T2D patients were randomised to receive either fish oil (FO), flaxseed oil (FSO) or corn oil capsules (CO, served as a control group) and followed up for 180 days. An additional 17 healthy non-T2D participants were recruited at baseline for cross-sectional comparison between cases and non-cases. A total of 296 serum metabolites were measured among healthy controls and T2D patients before and after the intervention. Serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (P-interaction = 1.8 × 10(-7)) was the most significant metabolite identified by repeated-measures ANOVA, followed by eicosapentaenoate (P-interaction = 4.6 × 10(-6)), 1-eicosapentaenoylglycerophosphocholine (P-interaction = 3.4 × 10(-4)), docosahexaenoate (P-interaction = 0.001), linolenate (n-3 or n-6, P-interaction = 0.005) and docosapentaenoate (n-3, P-interaction = 0.021). CMPF level was lower in T2D patients than in the healthy controls (P = 0.014) and it was significantly increased in the FO compared with CO group (P = 1.17 × 10(-7)). Furthermore, change of CMPF during the intervention was negatively correlated with change of serum triglycerides (P = 0.016). In conclusion, furan fatty acid metabolite CMPF was the strongest biomarker of fish oil intake. The association of CMPF with metabolic markers warrants further investigation. PMID: 27404516 [PubMed - as supplied by publisher]

Novel Chemical Ligands to Ebola Virus and Marburg Virus Nucleoproteins Identified by Combining Affinity Mass Spectrometry and Metabolomics Approaches. Sci Rep. 2016;6:29680 Authors: Fu X, Wang Z, Li L, Dong S, Li Z, Jiang Z, Wang Y, Shui W Abstract The nucleoprotein (NP) of Ebola virus (EBOV) and Marburg virus (MARV) is an essential component of the viral ribonucleoprotein complex and significantly impacts replication and transcription of the viral RNA genome. Although NP is regarded as a promising antiviral druggable target, no chemical ligands have been reported to interact with EBOV NP or MARV NP. We identified two compounds from a traditional Chinese medicine Gancao (licorice root) that can bind both NPs by combining affinity mass spectrometry and metabolomics approaches. These two ligands, 18β-glycyrrhetinic acid and licochalcone A, were verified by defined compound mixture screens and further characterized with individual ligand binding assays. Accompanying biophysical analyses demonstrate that binding of 18β-glycyrrhetinic acid to EBOV NP significantly reduces protein thermal stability, induces formation of large NP oligomers, and disrupts the critical association of viral ssRNA with NP complexes whereas the compound showed no such activity on MARV NP. Our study has revealed the substantial potential of new analytical techniques in ligand discovery from natural herb resources. In addition, identification of a chemical ligand that influences the oligomeric state and RNA-binding function of EBOV NP sheds new light on antiviral drug development. PMID: 27403722 [PubMed - as supplied by publisher]

Metabolomics in necrotizing enterocolitis: the state of the art. Expert Rev Mol Diagn. 2016 Jul 12; Authors: Dessì A, Pintus R, Marras S, Cesare Marincola F, De Magistris A, Fanos V Abstract INTRODUCTION: Necrotizing enterocolitis (NEC) is a serious inflammation of the bowel that most often affects premature infants. The exact cause of NEC is still poorly understood but investigators believe that these different factors can play an important role: prematurity and immaturity of the intestine of the preterm newborns, differences in the intestinal bacterial colonization and an abnormal immune response. Since the early symptoms of NEC are often rather non-specific, the diagnosis of NEC can be difficult. Therefore, the search for diagnostic biomarkers for NEC remains warranted. This review focuses on the results of recent metabolomics investigations on NEC, providing important contributions to the understanding of the biochemical process characterizing this disease. AREAS COVERED: Only a few metabolomics applications of NEC are reported in the literature. The metabolic pathway principally altered in NEC patients is suggested to be linked to the carbohydrates metabolism and the role of gluconate as a predictive marker for this pathology is investigated. Expert commentary: Biomarkers are crucial as a confident diagnostic tool to make NEC therapy more efficient. Although only a few metabolomics studies have been performed in NEC research, this technique proved to be helpful to understand the pathophysiological mechanisms of this disease. PMID: 27403597 [PubMed - as supplied by publisher]

Parent-of-origin tumorigenesis is mediated by an essential imprinted modifier in SDHD-linked paragangliomas: SLC22A18 and CDKN1C are candidate tumor modifiers. Hum Mol Genet. 2016 Jul 8; Authors: Hoekstra AS, Addie RD, Ras C, Seifar RM, Ruivenkamp CA, Briaire-de Bruijn IH, Hes FJ, Jansen JC, Corssmit EP, Corver WE, Morreau H, Bovée JV, Bayley JP, Devilee P Abstract Mutations in SDHD and SDHAF2 (both located on chromosome 11) give rise to hereditary paraganglioma almost exclusively after paternal transmission of the mutation, and tumors often show loss of the entire maternal copy of chromosome 11. The 'Hensen' model postulates that a tumor modifier gene located on chromosome 11p15, a region known to harbor a cluster of imprinted genes, is essential to tumor formation. We observed decreased protein expression of the 11p15 candidate genes CDKN1C, SLC22A18 and ZNF215 evaluated in 60 SDHD-mutated tumors compared to normal carotid body tissue and non-SDH mutant tumors.We then created stable knockdown in vitro models, reasoning that the simultaneous knockdown of SDHD and a maternally expressed 11p15 modifier gene would enhance paraganglioma-related cellular characteristics compared to SDHD knockdown alone. Knockdown of SDHD in SNB19 and SHSY5Y cells resulted in the accumulation of succinate, the stabilization of HIF1 protein and a reduction in cell proliferation.Compared to single knockdown of SDHD, knockdown of SDHD together with SLC22A18 or with CDKN1C led to small but significant increases in cell proliferation and resistance to apoptosis, and to a gene expression profile closely related to the known transcriptional profile of SDH-deficient tumors. Of the 60 SDHD tumors investigated, 4 tumors showing retention of chromosome 11 showed SLC22A18 and CDKN1C expression levels comparable to levels in tumors showing loss of chromosome 11, suggesting loss of protein expression despite chromosomal retention.Our data strongly suggest that SLC22A18 and/or CDKN1C are tumor modifier genes involved in the tumorigenesis of SDHD-linked paraganglioma. PMID: 27402879 [PubMed - as supplied by publisher]

Evidence for Escherichia coli diguanylate cyclase DgcZ interlinking surface sensing and adhesion via multiple regulatory routes. J Bacteriol. 2016 Jul 11; Authors: Lacanna E, Bigosch C, Kaever V, Boehm A, Becker A Abstract DgcZ is the main cyclic dimeric GMP (c-di-GMP)-producing diguanylate cyclase (DGC) controlling biosynthesis of the exopolysaccharide poly-beta-1,6-N-acetyl-glucosamine (poly-GlcNAc or PGA), which is essential for surface attachment of Escherichia coli. Though the complex regulation of DgcZ has previously been investigated, its primary role and the physiological conditions under which the protein is active are not fully understood. Transcription of dgcZ is regulated by the two component system CpxAR activated by the lipoprotein NlpE in response to surface sensing. Here, we show that the negative effect of a cpxR mutation and the positive effect of nlpE overexpression on biofilm formation both depend on DgcZ. Co-immunoprecipitation data suggest several potential interaction partners of DgcZ. Interaction with FrdB, a subunit of the fumarate reductase complex (FRD) involved in anaerobic respiration and in control of flagella assembly, was further supported by a bacterial-two-hybrid assay. Furthermore, the FRD complex was required for the increase in DgcZ-mediated biofilm formation upon induction of oxidative stress by addition of paraquat. A DgcZ-mVENUS fusion protein was found to localize at one bacterial cell pole in response to alkaline pH and carbon starvation. Based on our data and previous knowledge an integrative role of DgcZ in regulation of surface attachment is proposed. We speculate that both DgcZ-stimulated PGA biosynthesis and interaction of DgcZ with the FRD complex contribute to impeding bacterial escape from the surface. IMPORTANCE: Bacterial cells can grow by clonal expansion to surface-associated biofilms that are ubiquitous in the environment, but also constitute a pervasive problem related to bacterial infections. Cyclic dimeric GMP (c-di-GMP) is a widespread bacterial second messenger involved in regulation of motility and biofilm formation, and plays a primary role in bacterial surface attachment. E. coli possesses a plethora of c-di-GMP producing diguanylate cyclases, including DgcZ. Our study expands the knowledge on the role of DgcZ in regulation of surface attachment and suggests that it interconnects surface sensing and adhesion via multiple routes. PMID: 27402625 [PubMed - as supplied by publisher]

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice. Endocr Relat Cancer. 2016 Jul 8; Authors: Montales MT, Melnyk SB, Liu S, Simmen F, Liu Y, Simmen RC Abstract The emerging links between breast cancer and metabolic dysfunctions spawned by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status to affect disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well-defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1-transgenic offspring exposed to a metabolically-compromised environment imposed by maternal high-fat diet; control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, when compared to control diet exposure. However, doxorubicin-treated tumors from high-fat diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1), and basal stem cell-like (CD29hiCD24+) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations [CD29hiCD24+, CD29loCD24+, CD29hiCD24+Thy1+] in tumors from high-fat diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced mammosphere-formation ability and decreased apoptosis, relative to doxorubicin only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny and may inform clinical management of disease. PMID: 27402613 [PubMed - as supplied by publisher]

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice. Physiol Rep. 2016 Jul;4(13) Authors: Chandler JD, Wongtrakool C, Banton SA, Li S, Orr ML, Barr DB, Neujahr DC, Sutliff RL, Go YM, Jones DP Abstract Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades-long half-life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low-dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd-treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low-dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low-dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low-dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma. PMID: 27401458 [PubMed]

Related Articles Cannabinoid receptor signaling regulates liver development and metabolism. Development. 2016 Feb 15;143(4):609-22 Authors: Liu LY, Alexa K, Cortes M, Schatzman-Bone S, Kim AJ, Mukhopadhyay B, Cinar R, Kunos G, North TE, Goessling W Abstract Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function. PMID: 26884397 [PubMed - indexed for MEDLINE]

Related Articles Impact of Azithromycin on the Quorum Sensing-Controlled Proteome of Pseudomonas aeruginosa. PLoS One. 2016;11(1):e0147698 Authors: Swatton JE, Davenport PW, Maunders EA, Griffin JL, Lilley KS, Welch M Abstract The macrolide antibiotic, azithromycin (AZM), has been reported to improve the clinical outcome of cystic fibrosis patients, many of whom are chronically-infected with Pseudomonas aeruginosa. However, the highest clinically-achievable concentrations of this drug are well-below the minimum inhibitory concentration for P. aeruginosa, raising the question of why AZM exhibits therapeutic activity. One possibility that has been raised by earlier studies is that AZM inhibits quorum sensing (QS) by P. aeruginosa. To explicitly test this hypothesis the changes brought about by AZM treatment need to be compared with those associated with specific QS mutants grown alongside in the same growth medium, but this has not been done. In this work, we used quantitative 2D-difference gel electrophoresis and 1H-NMR spectroscopy footprint analysis to examine whether a range of clinically-relevant AZM concentrations elicited proteomic and metabolomic changes in wild-type cultures that were similar to those seen in cultures of defined QS mutants. Consistent with earlier reports, over half of the AZM-induced spot changes on the 2D gels were found to affect QS-regulated proteins. However, AZM modulated very few protein spots overall (compared with QS) and collectively, these modulated proteins comprised only a small fraction (12-13%) of the global QS regulon. We conclude that AZM perturbs a sub-regulon of the QS system but does not block QS per se. Reinforcing this notion, we further show that AZM is capable of attenuating virulence factor production in another Gram-negative species that secretes copious quantities of exoenzymes (Serratia marcescens), even in the absence of a functional QS system. PMID: 26808156 [PubMed - indexed for MEDLINE]

Related Articles Systematic review regarding metabolic profiling for improved pathophysiological understanding of disease and outcome prediction in respiratory infections. Respir Res. 2015;16:125 Authors: Nickler M, Ottiger M, Steuer C, Huber A, Anderson JB, Müller B, Schuetz P Abstract Metabolic profiling through targeted quantification of a predefined subset of metabolites, performed by mass spectrometric analytical techniques, allows detailed investigation of biological pathways and thus may provide information about the interaction of different organic systems, ultimately improving understanding of disease risk and prognosis in a variety of diseases. Early risk assessment, in turn, may improve patient management in regard to cite-of-care decisions and treatment modalities. Within this review, we focus on the potential of metabolic profiling to improve our pathophysiological understanding of disease and management of patients. We focus thereby on lower respiratory tract infections (LRTI) including community-acquired pneumonia (CAP) and chronic obstructive pulmonary disease (COPD), an important disease responsible for high mortality, morbidity and costs worldwide. Observational data from numerous clinical and experimental studies have provided convincing data linking metabolic blood biomarkers such as lactate, glucose or cortisol to patient outcomes. Also, identified through metabolomic studies, novel innovative metabolic markers such as steroid hormones, biogenic amines, members of the oxidative status, sphingo- and glycerophospholipids, and trimethylamine-N-oxide (TMAO) have shown promising results. Since many uncertainties remain in predicting mortality in these patients, further prospective and retrospective observational studies are needed to uncover metabolic pathways responsible for mortality associated with LRTI. Improved understanding of outcome-specific metabolite signatures in LRTIs may optimize patient management strategies, provide potential new targets for future individual therapy, and thereby improve patients' chances for survival. PMID: 26471192 [PubMed - indexed for MEDLINE]