PubMed

Child Stunting is Associated with Low Circulating Essential Amino Acids. EBioMedicine. 2016 Apr;6:246-52 Authors: Semba RD, Shardell M, Sakr Ashour FA, Moaddel R, Trehan I, Maleta KM, Ordiz MI, Kraemer K, Khadeer MA, Ferrucci L, Manary MJ Abstract BACKGROUND: Stunting affects about one-quarter of children under five worldwide. The pathogenesis of stunting is poorly understood. Nutritional interventions have had only modest effects in reducing stunting. We hypothesized that insufficiency in essential amino acids may be limiting the linear growth of children. METHODS: We used a targeted metabolomics approach to measure serum amino acids, glycerophospholipids, sphingolipids, and other metabolites using liquid chromatography-tandem mass spectrometry in 313 children, aged 12-59months, from rural Malawi. Children underwent anthropometry. FINDINGS: Sixty-two percent of the children were stunted. Children with stunting had lower serum concentrations of all nine essential amino acids (tryptophan, isoleucine, leucine, valine, methionine, threonine, histidine, phenylalanine, lysine) compared with nonstunted children (p<0.01). In addition, stunted children had significantly lower serum concentrations of conditionally essential amino acids (arginine, glycine, glutamine), non-essential amino acids (asparagine, glutamate, serine), and six different sphingolipids compared with nonstunted children. Stunting was also associated with alterations in serum glycerophospholipid concentrations. INTERPRETATION: Our findings support the idea that children with a high risk of stunting may not be receiving an adequate dietary intake of essential amino acids and choline, an essential nutrient for the synthesis of sphingolipids and glycerophospholipids. PMID: 27211567 [PubMed - in process]

Endogenous metabolites that are substrates of Organic Anion Transporter's (OATs) predict methotrexate clearance. Pharmacol Res. 2016 May 19; Authors: Kienana M, Benz-de Bretagne I, Nadal-Desbarats L, Blasco H, Gyan E, Choquet S, Montigny F, Emond P, Barin-Le Guellec C Abstract Variable pharmacokinetics of high-dose-methotrexate (MTX) is responsible for severe toxicities. Unpredictable overexposure still occurs during some courses despite having controlled the main factors known to play a role in its elimination. The aim of our study was to evaluate whether the urine metabolomic profile measured at the time of MTX administration is predictive of the drug's clearance and/or of treatment-related toxicity. We analyzed the urine content of endogenous metabolites before MTX administration in a cohort of adult patients treated for lymphoid malignancies. Individual MTX clearance (MTXCL) was estimated from population pharmacokinetic analyses of therapeutic drug monitoring data. We determined the urine metabolite content by gas chromatography-mass spectrometry (GC-MS) and applied Partial Least Square (PLS) analysis to assess the relationship between the urine metabolome and MTXCL. External validation was applied to evaluate the performances of the PLS model. We used orthogonal partial least squares discriminant analysis (OPLS-DA) to distinguish patients with normal or delayed elimination, and patients with or without toxicity. Sixty-two patients were studied. We obtained a very good prediction of individual MTX clearance using a set of 28 metabolites present in patient urine at baseline. The mean prediction error and precision were -0.36% and 21.4%, respectively, for patients not included in the model. The model included a set of endogenous organic anions, of which the tubular secretion depends on organic anion transporter (OAT) function. Our analyses did not allow us to discriminate between patients with or without delayed elimination or those who did or did not experience toxicity. Urinary metabolomics can be informative about an individual's ability to clear MTX. More broadly, it paves the way for the development of a biomarker of tubular secretion, easily measurable from endogenous substances. PMID: 27210722 [PubMed - as supplied by publisher]

Related Articles Branched chain amino acids maintain the molecular weight of poly(γ-glutamic acid) of Bacillus licheniformis ATCC 9945 during the fermentation. J Biosci Bioeng. 2016 May 18; Authors: Mitsunaga H, Meissner L, Büchs J, Fukusaki E Abstract Poly(γ-glutamic acid) mainly produced by Bacillus spp. is an industrially important compound due to several useful features. Among them, molecular weight is an important characteristic affecting on the physical properties such as viscosities and negative charge densities. However, it is difficult to control the molecular size of PGA since it decreases during fermentation. Previous study reported that PGA produced in the media containing different carbon sources such as glucose and glycerol showed differences in molecular weight. Therefore in this study, the effect of carbon source on the PGA molecular weight was examined; with the aim of developing a strategy to maintain the high molecular weight of PGA during fermentation. Our result showed that the weight average molecular weight (Mw) of PGA of Bacillus licheniformis ATCC 9945 cultivated in the media containing PTS-sugars were higher than the medium containing glycerol (non-PTS). The result of metabolome analysis indicated the possibility of CodY (a global regulator protein) activation in the cells cultivated in the media containing PTS-sugars. To mimic this effect, branched-chain amino acids (BCAAs), which are activators of CodY, were added to a medium containing glycerol. As the result, the Mw of PGA in the BCAAs-supplemented media were maintained and high during the early production phase compared to the non BCAAs-supplemented medium. These results indicate that BCAAs can repress the PGA molecular weight reduction during fermentation in B. licheniformis ATCC 9945. PMID: 27209178 [PubMed - as supplied by publisher]

Application of metabolomics to investigate the antitumor mechanism of flavopiridol in MCF-7 breast cancer cells. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 May 9;1025:40-47 Authors: Shao X, Gao D, Wang Y, Jin F, Wu Q, Liu H Abstract Flavopiridol is reported to have potent antitumor effects by inhibition of cyclin-dependent kinases (CDKs). However, most studies of flavopiridol focus on specific genes and kinases, so the antitumor mechanism needs further elucidation at the metabolic level. In the present study, an UPLC/Q-TOF MS metabolomics approach was used to investigate its antiproliferative effects on MCF-7 breast cancer cells. Comparing flavopiridol-treated MCF-7 cells with vehicle control, 21 potential biomarkers involved in five metabolism pathways were identified. Two pathways involving glutathione metabolism and glycerophospholipid metabolism showed that glutathione (GSH) and phosphatidylcholines (PCs) levels were reduced while their oxidized products oxidized glutathione (GSSG) and lysophosphatidylcholines (LysoPCs) were greatly increased. Further investigation showed an apparent accumulation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential (MMP). Thus, we suggest that oxidative stress was provoked in MCF-7 cells to reduce the GSH and PCs levels and cause mitochondria lesions. Moreover, cell cycle analysis showed that flavopiridol blocked cells at G1 stage, which was consistent with the depletion of spermidine and spermine that are believed to promote cancer progression. Taking these together, we concluded that flavopiridol could induce oxidative stress and cell cycle arrest, which finally lead to cell apoptosis in MCF-7 cells. This study provides a new strategy for studying the antitumor mechanism of flavopiridol, which could be used for its further improvement and application. PMID: 27208856 [PubMed - as supplied by publisher]

Metabolomic characterization of renal ischemia and reperfusion in a swine model. Life Sci. 2016 May 18; Authors: Malagrino PA, Venturini G, Yogi PS, Dariolli R, Padilha K, Kiers B, Gois TC, Motta-Leal-Filho JM, Takimura CK, Girardi AC, Carnevale FC, Canevarolo R, Malheiros DM, de Mattos Zeri AC, Krieger JE, Pereira AC PMID: 27208650 [PubMed - as supplied by publisher]

Mycorrhiza and heavy metal resistant bacteria enhance growth, nutrient uptake and alter metabolic profile of sorghum grown in marginal soil. Chemosphere. 2016 May 17;157:33-41 Authors: Dhawi F, Datta R, Ramakrishna W Abstract The main challenge for plants growing in nutrient poor, contaminated soil is biomass reduction, nutrient deficiency and presence of heavy metals. Our aim is to overcome these challenges using different microbial combinations in mining-impacted soil and focus on their physiological and biochemical impacts on a model plant system, which has multiple applications. In the current study, sorghum BTx623 seedlings grown in mining-impacted soil in greenhouse were subjected to plant growth promoting bacteria (PGPB or B) alone, PGPB with arbuscular mycorrhizal fungi (My), My alone and control group with no treatment. Root biomass and uptake of most of the elements showed significant increase in all treatment groups in comparison with control. Mycorrhiza group showed the best effect followed by My + B and B groups for uptake of majority of the elements by roots. On the contrary, biomass of both shoot and root was more influenced by B treatment than My + B and My treatments. Metabolomics identified compounds whose levels changed in roots of treatment groups significantly in comparison to control. Upregulation of stearic acid, sorbitol, sebacic acid and ferulic acid correlated positively with biomass and uptake of almost all elements. Two biochemical pathways, fatty acid biosynthesis and galactose metabolism, were regulated in all treatment groups. Three common pathways were upregulated only in My and My + B groups. Our results suggest that PGPB enhanced metabolic activities which resulted in increase in element uptake and sorghum root biomass whether accompanied with mycorrhiza or used solely. PMID: 27208643 [PubMed - as supplied by publisher]

Plasma metabolomics combined with lipidomics profiling reveals the potential antipyretic mechanisms of Qingkailing injection in a rat model. Chem Biol Interact. 2016 May 18; Authors: Qin L, Zhang Z, Guo M, Zhang Q, Wang Q, Lu Z, Zhao H, Liu Y, Fu S, Wang M, Gao X Abstract Qingkailing injection (QKLI) has a notable antipyretic effect and is widely used in China as a clinical emergency medicine. To elucidate the pharmacological action thoroughly, following the investigation of the urine metabolome and hypothalamus metabolome, plasma metabolomics combined with lipidomics profiling of the QKLI antipyretic effect in a rat model is described in this paper. Compared with pure metabolomics profiling, this non-targeted plasma metabolomics combined with lipidomics profiling based on ultra-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS) could be used for a large-scale detection of features in plasma samples. The results showed that 15 metabolites at the 1 h time point and 19 metabolites at the 2 h time point after QKLI administration were associated with the antipyretic effect of QKLI, including amino acid, phosphatidylcholine and lysophosphatidylcholine. The metabolism pathway analysis revealed that the potential biomarkers, which were important for the antipyretic mechanism of QKLI, were closely responsible for correcting the perturbed pathways of amino acid metabolism and lipid metabolism. In conclusion, the use of complementary UPLC Q-TOF/MS based metabolomics and lipidomics allows for the discovery of new potential plasma biomarkers in the QKLI antipyretic process and the associated pathways, and aided in advancing the understanding of the holism and synergism of the Chinese drug. PMID: 27208622 [PubMed - as supplied by publisher]

Automated resolution of chromatographic signals by independent component analysis-orthogonal signal deconvolution in comprehensive gas chromatography/mass spectrometry-based metabolomics. Comput Methods Programs Biomed. 2016 Jul;130:135-141 Authors: Domingo-Almenara X, Perera A, Ramírez N, Brezmes J Abstract Comprehensive gas chromatography-mass spectrometry (GC×GC-MS) provides a different perspective in metabolomics profiling of samples. However, algorithms for GC×GC-MS data processing are needed in order to automatically process the data and extract the purest information about the compounds appearing in complex biological samples. This study shows the capability of independent component analysis-orthogonal signal deconvolution (ICA-OSD), an algorithm based on blind source separation and distributed in an R package called osd, to extract the spectra of the compounds appearing in GC×GC-MS chromatograms in an automated manner. We studied the performance of ICA-OSD by the quantification of 38 metabolites through a set of 20 Jurkat cell samples analyzed by GC×GC-MS. The quantification by ICA-OSD was compared with a supervised quantification by selective ions, and most of the R(2) coefficients of determination were in good agreement (R(2)>0.90) while up to 24 cases exhibited an excellent linear relation (R(2)>0.95). We concluded that ICA-OSD can be used to resolve co-eluted compounds in GC×GC-MS. PMID: 27208528 [PubMed - as supplied by publisher]

Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis. Diabetes Care. 2016 May;39(5):833-46 Authors: Guasch-Ferré M, Hruby A, Toledo E, Clish CB, Martínez-González MA, Salas-Salvadó J, Hu FB Abstract OBJECTIVE: To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS: We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS: We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24-1.48]; I(2) = 9.5%), 36% for leucine (1.36 [1.17-1.58]; I(2) = 37.4%), 35% for valine (1.35 [1.19-1.53]; I(2) = 45.8%), 36% for tyrosine (1.36 [1.19-1.55]; I(2) = 51.6%), and 26% for phenylalanine (1.26 [1.10-1.44]; I(2) = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81-0.96] and 0.85 [0.82-0.89], respectively; both I(2) = 0.0%). CONCLUSIONS: In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes. PMID: 27208380 [PubMed - in process]

α-Hydroxybutyric Acid Is a Selective Metabolite Biomarker of Impaired Glucose Tolerance. Diabetes Care. 2016 Apr 5; Authors: Cobb J, Eckhart A, Motsinger-Reif A, Carr B, Groop L, Ferrannini E Abstract OBJECTIVE: Plasma metabolites that distinguish isolated impaired glucose tolerance (iIGT) from isolated impaired fasting glucose (iIFG) may be useful biomarkers to predict IGT, a high-risk state for the development of type 2 diabetes. RESEARCH DESIGN AND METHODS: Targeted metabolomics with 23 metabolites previously associated with dysglycemia was performed with fasting plasma samples from subjects without diabetes at time 0 of an oral glucose tolerance test (OGTT) in two observational cohorts: RISC (Relationship Between Insulin Sensitivity and Cardiovascular Disease) and DMVhi (Diabetes Mellitus and Vascular Health Initiative). Odds ratios (ORs) for a one-SD change in the metabolite level were calculated using multiple logistic regression models controlling for age, sex, and BMI to test for associations with iIGT or iIFG versus normal. Selective biomarkers of iIGT were further validated in the Botnia study. RESULTS: α-Hydroxybutyric acid (α-HB) was most strongly associated with iIGT in RISC (OR 2.54 [95% CI 1.86-3.48], P value 5E-9) and DMVhi (2.75 [1.81-4.19], 4E-5) while having no significant association with iIFG. In Botnia, α-HB was selectively associated with iIGT (2.03 [1.65-2.49], 3E-11) and had no significant association with iIFG. Linoleoyl-glycerophosphocholine (L-GPC) and oleic acid were also found to be selective biomarkers of iIGT. In multivariate IGT prediction models, addition of α-HB, L-GPC, and oleic acid to age, sex, BMI, and fasting glucose significantly improved area under the curve in all three cohorts. CONCLUSIONS: α-HB, L-GPC, and oleic acid were shown to be selective biomarkers of iIGT, independent of age, sex, BMI, and fasting glucose, in 4,053 subjects without diabetes from three European cohorts. These biomarkers can be used in predictive models to identify subjects with IGT without performing an OGTT. PMID: 27208342 [PubMed - as supplied by publisher]

New insight on obesity and adipose-derived stem cells by comprehensive metabolomics. Biochem J. 2016 May 19; Authors: Mastrangelo A, Panadero MI, Pérez LM, Gálvez BG, García A, Barbas C, Rupérez FJ Abstract Obesity affects the functional capability of adipose-derived stem cells (ASCs) and their effective use in regenerative medicine through mechanisms still poorly understood. Here we employed a multiplatform (LC/MS, CE/MS, GC/MS) metabolomics untargeted approach to investigate the metabolic alteration underlying the inequalities observed in obese-derived ASCs. The metabolic fingerprint (metabolites within the cells) and footprint (metabolites secreted in the culture medium) from humans or mice, obese and non-obese derived ASCs, were characterized by providing valuable information. Metabolites associated to glycolysis, TCA, pentose phosphate pathway and polyol pathway were increased in the footprint of obese-derived human ASCs indicating alterations in the carbohydrate metabolism; whereas from the murine model, deep differences in lipid and amino acid catabolism were highlighted. Therefore, new insights on the ASCs metabolome were provided that enhance our understanding of the processes underlying the ASCs stemness capacity and its relationship with obesity, in different cell models. PMID: 27208167 [PubMed - as supplied by publisher]

Metabolic networks and metabolites underlie associations between maternal glucose during pregnancy and newborn size at birth. Diabetes. 2016 Apr 5; Authors: Scholtens DM, Bain JR, Reisetter AC, Muehlbauer MJ, Nodzenski M, Stevens RD, Ilkayeva O, Lowe LP, Metzger BE, Newgard CB, Lowe WL, HAPO Study Cooperative Research Group. Abstract Maternal metabolites and metabolic networks underlying associations between maternal glucose during pregnancy and newborn birth weight and adiposity demand fuller characterization. We performed targeted and non-targeted gas-chromatography/mass-spectrometry metabolomics on maternal serum collected at fasting and 1-hour following Trutol consumption during an oral glucose tolerance test for 400 Northern European mothers at ∼28 weeks gestation in the Hyperglycemia and Adverse Pregnancy Outcome Study. Amino acids, fatty acids, acylcarnitines and products of lipid metabolism decreased and triglycerides increased following glucose ingestion during the OGTT. Analyses of individual metabolites indicated limited maternal glucose associations at fasting, but broader associations including amino acids, fatty acids, carbohydrates and lipids at 1-hour. Network analyses modeling metabolite correlations provided context for individual metabolite associations and elucidated collective associations of multiple classes of metabolic fuels with newborn size and adiposity, including acylcarnitines, fatty acids, carbohydrates and organic acids. Random forest analyses indicated improved ability to predict newborn size outcomes using maternal metabolomics data beyond traditional risk factors including maternal glucose. Broad scale association of fuel metabolites with maternal glucose is evident during pregnancy, with unique maternal metabolites potentially contributing specifically to newborn birth weight and adiposity. PMID: 27207545 [PubMed - as supplied by publisher]

Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. BMC Neurosci. 2016;17(1):25 Authors: Zhang T, Wang W, Huang J, Liu X, Zhang H, Zhang N Abstract BACKGROUND: To get a broader view of global ischemia-induced cerebral disorders at the metabolic level, a nuclear magnetic resonance-based metabolomic study was performed to evaluate the metabolic profile changes on regional brain tissues of female and male mice upon bilateral common carotid arteries occlusion (BCCAO) operation. RESULTS: Significant metabolic disorders were observed in both cerebral cortex and hippocampus tissues of the experimental mice upon global cerebral ischemic attack. Multiple amino acids were identified as the dominantly perturbed metabolites. It was also shown that although the metabolic profile change patterns in the brain tissues were quite similar in male and female BCCAO mice, metabolic disorders in the cortex tissues were more severe in the female mice than in the male mice. CONCLUSIONS: In the present study, significant changes in amino acid metabolic pathways were confirmed in the early stage of global ischemia. Meanwhile, cerebral metabolic dysfunctions were more severe in the female BCCAO mice than in the male mice, suggesting that gender may play a role in different metabolic responses to the ischemic attack, which may provide an important hypothesis for a better understanding of the clinically observed gender-dependent pathological outcome of cerebral ischemia. PMID: 27206925 [PubMed - as supplied by publisher]

Neurotransmitter and their metabolite concentrations in different areas of the HPRT knockout mouse brain. J Neurol Sci. 2016 Jun 15;365:169-74 Authors: Tschirner SK, Gutzki F, Schneider EH, Seifert R, Kaever V Abstract Lesch-Nyhan syndrome (LNS) is characterized by uric acid overproduction and severe neurobehavioral symptoms, such as recurrent self-mutilative behavior. To learn more about the pathophysiology of the disease, we quantified neurotransmitters and their metabolites in the cerebral hemisphere, cerebellum and the medulla oblongata of HPRT knockout mice, an animal model for LNS, in comparison to the corresponding wild-type. Our analyses included l-glutamate, 4-aminobutanoic acid (GABA), acetylcholine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, l-normetanephrine, epinephrine and l-metanephrine and were conducted via high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS). Among these neurotransmitter systems, we did not find any abnormalities in the HPRT knockout mouse brains. On one side, this might indicate that HPRT deficiency most severely affects dopamine signaling, while brain functioning based on other neurotransmitters is more or less spared. On the other hand, our findings may reflect a compensating mechanism for impaired purine salvage that protects the brain in HPRT-deficient mice but not in LNS patients. PMID: 27206901 [PubMed - in process]

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth. Oncotarget. 2016 May 19; Authors: Trousil S, Kaliszczak M, Schug Z, Nguyen Q, Tomasi G, Favicchio R, Brickute D, Fortt R, Twyman FJ, Carroll L, Kalusa A, Navaratnam N, Adejumo T, Carling D, Gottlieb E, Aboagye EO Abstract The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2-2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids. PMID: 27206796 [PubMed - as supplied by publisher]

17 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 2016/05/21PubMed 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.

Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence. Cancer Epidemiol Biomarkers Prev. 2016 Apr 6; Authors: Kelly RS, Vander Heiden MG, Giovannucci E, Mucci LA Abstract Metabolite profiling is being increasing employed in the study of prostate cancer as a means of identifying predictive, diagnostic, and prognostic biomarkers. This review provides a summary and critique of the current literature. Thirty-three human case-control studies of prostate cancer exploring disease prediction, diagnosis, progression, or treatment response were identified. All but one demonstrated the ability of metabolite profiling to distinguish cancer from benign, tumor aggressiveness, cases who recurred, and those who responded well to therapy. In the subset of studies where biomarker discriminatory ability was quantified, high AUCs were reported that would potentially outperform the current gold standards in diagnosis, prognosis, and disease recurrence, including PSA testing. There were substantial similarities between the metabolites and the associated pathways reported as significant by independent studies, and important roles for abnormal cell growth, intensive cell proliferation, and dysregulation of lipid metabolism were highlighted. The weight of the evidence therefore suggests metabolic alterations specific to prostate carcinogenesis and progression that may represent potential metabolic biomarkers. However, replication and validation of the most promising biomarkers is currently lacking and a number of outstanding methodologic issues remain to be addressed to maximize the utility of metabolomics in the study of prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 1-20. ©2016 AACR. PMID: 27197278 [PubMed - as supplied by publisher]

Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy. Cancer Res. 2016 May 16; Authors: Vacchelli E, Enot DP, Pietrocola F, Zitvogel L, Kroemer G Abstract Pattern recognition receptors allow the innate immune system to perceive the presence of microbial products and to launch the first steps of the defense response. Some pattern recognition receptors also sense endogenous ligands that are released from uninfected dying cells, thereby activating immune responses against dead-cell antigens. This applies to toll-like receptors 3 and 4 (TLR3, TLR4), which sense double-stranded RNA and high-mobility group protein B1 (HMGB1), respectively, as well as to formyl peptide receptor-1 (FPR1), which interacts with Annexin A1 (ANXA1) from dead cells. Breast cancer patients who bear loss-of-function alleles in TLR3, TLR4, and FPR1 exhibit a reduced metastasis-free and overall survival after treatment with anthracycline-based adjuvant chemotherapy. These genetic defects are epistatic with respect to each other, suggesting that they act on the same pathway, linking chemotherapy to a therapeutically relevant anticancer immune response. Loss-of-function alleles in TLR4 and FPR1 also affect the prognosis of colorectal cancer patients treated with oxaliplatin-based chemotherapy. Altogether, these results support the idea that conventional anticancer treatments rely on stimulation of anticancer immune responses to become fully efficient. Cancer Res; 76(11); 1-5. ©2016 AACR. PMID: 27197163 [PubMed - as supplied by publisher]

Huangqi Decoction Alleviates Dimethylnitrosamine-induced Liver Fibrosis: an Analysis of Bile Acids Metabolic Mechanism. J Ethnopharmacol. 2016 May 16; Authors: Song YN, Zhang GB, Lu YY, Chen QL, Yang L, Wang ZT, Liu P, Su SB Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Decoction (HQD), a classical traditional Chinese medicine (TCM) formula, is used to treating liver injury in China. The aim of the study is to investigate mechanisms of HQD against dimethylnitrosamine (DMN)-induced liver fibrosis underlying metabolic profiles of bile acids. MATERIALS AND METHODS: DMN-induced liver fibrosis rats were administrated HQD and its compounds, astragalosides (AS), glycyrrhizic acid (GA) and their combination. The anti-fibrosis effects were evaluated and targeted metabolomics by UPLC-MS was used to examine whether HQD had an influence on bile acid metabolism. The levels of mRNAs associated with bile acid metabolism were expressed by RT-PCR. Chenodeoxycholic acid (CDCA)-induced hepatic stellate cells (HSCs) proliferation and activation were examined using MTS assay and Western blot. RESULTS: Histopathological changes and serum liver function in HQD group had significant improvements (P<0.01). Concentrations of free bile acids and taurine conjugates were significantly increased in DMN group (P<0.05). HQD and its compounds restored the increased bile acids to normal levels, and HQD was more effected on parts of bile acids. Furthermore, the levels of mRNAs related bile acid synthesis and reabsorption such as CYP7A1, CYP8B1, CYP27A1, OATP2, OATP3, OATP4 and NTCP were significantly down-regulated in DMN group (P<0.05), mRNAs related excretion such as MRP3 and BESP were up-regulated (P<0.01), and CYP7A1, CYP8B1, OATP3, OATP4, NTCP and MRP3 restored to normal levels by HQD treatment. Moreover, CDCA-induced HSCs proliferation and activation were weaken by HQD (P<0.05) with down-regulated α-SMA, TGF-β1, p-Smad2 and p-Smad3 expressions. CONCLUSIONS: HQD alleviated DMN-induced liver fibrosis with a better effect than its compounds, which may be involved in the regulation of bile acid metabolism enzyme. Moreover, HQD may inhibit CDCA-induced HSCs proliferation and activation. PMID: 27196295 [PubMed - as supplied by publisher]

Role of metabolism during viral infections, and crosstalk with the innate immune system. Intractable Rare Dis Res. 2016 May;5(2):90-6 Authors: González Plaza JJ, Hulak N, Kausova G, Zhumadilov Z, Akilzhanova A Abstract Viruses have been for long polemic biological particles which stand in the twilight of being living entities or not. As their genome is reduced, they rely on the metabolic machinery of their host in order to replicate and be able to continue with their infection process. The understanding of their metabolic requirements is thus of paramount importance in order to develop tailored drugs to control their population, without affecting the normal functioning of their host. New advancements in high throughput technologies, especially metabolomics are allowing researchers to uncover the metabolic mechanisms of viral replication. In this short review, we present the latest discoveries that have been made in the field and an overview of the intrinsic relationship between metabolism and innate immunity as an important part of the immune system. PMID: 27195191 [PubMed]