PubMed

Related Articles p53-mediated regulation of bile acid disposition attenuates cholic acid-induced cholestasis in mice. Br J Pharmacol. 2017 Sep 14;: Authors: Chen P, Li D, Chen Y, Sun J, Fu K, Guan L, Zhang H, Jiang Y, Li X, Zeng X, Chen X, Huang M, Bi H Abstract BACKGROUND AND PURPOSE: Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic diseases. Here we investigated the role of p53 in the regulation bile acid disposition and cholestasis. EXPERIMENTAL APPROACH: Bile acid disposition related gene expression profile altered by p53 activation was assessed in mouse primary hepatocytes with p53 depletion and in Trp53-null mice. Dual luciferase reporter assay was used to detect the transcriptional activities of target genes. Anticholestatic effects of p53 activator doxorubicin (Dox) were investigated in a 0.5% cholic acid (CA)-fed mouse model of cholestasis. The changes of bile acids were analyzed using metabolomics analysis. KEY RESULTS: Dox-mediated p53 activation induced Cyp2b10, Sult2a1 and Abcc2/3/4 expression of mice in vitro and in vivo. ABCC3 and CYP2B6 (human ortholog of Cyp2b10) were identified as direct p53 target genes. Dox attenuated CA-induced cholestasis in mice, as demonstrated by shrunken gallbladder size, decreased serum total bile acid and total bilirubin levels and ALP activity. Targeted metabolomics analysis revealed that Dox enhanced the excretion of bile acid metabolites from serum and liver to intestine and feces. Upregulation of Cyp2b10, Sult2a1 and Abcc2/3/4 expression was further confirmed in cholestastic mice. p53 deficiency aggregated CA -induced cholestatic injury in mice and bile acid abundance was decreased in intestine and feces. CONCLUSION AND IMPLICATIONS: Our findings suggest a novel role of p53 in promoting bile acid disposition and alleviating cholestastic syndrome, which provides a potential therapeutic target for cholestasis. PMID: 28910492 [PubMed - as supplied by publisher]

Related Articles Correction: Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study. PLoS Genet. 2017 Sep;13(9):e1007002 Authors: Nowak C, Salihovic S, Ganna A, Brandmaier S, Tukiainen T, Broeckling CD, Magnusson PK, Prenni JE, Wang-Sattler R, Peters A, Strauch K, Meitinger T, Giedraitis V, Ärnlöv J, Berne C, Gieger C, Ripatti S, Lind L, Pedersen NL, Sundström J, Ingelsson E, Fall T Abstract [This corrects the article DOI: 10.1371/journal.pgen.1006379.]. PMID: 28910285 [PubMed - in process]

Related Articles The aetiology of cardiovascular disease: a role for mitochondrial DNA? Cardiovasc J Afr. 2017 Aug 25;28:1-12 Authors: Venter M, van der Westhuizen FH, Elson JL Abstract Cardiovascular disease (CVD) is a world-wide cause of mortality in humans and its incidence is on the rise in Africa. In this review, we discuss the putative role of mitochondrial dysfunction in the aetiology of CVD and consequently identify mitochondrial DNA (mtDNA) variation as a viable genetic risk factor to be considered. We then describe the contribution and pitfalls of several current approaches used when investigating mtDNA in relation to complex disease. We also propose an alternative approach, the adjusted mutational load hypothesis, which would have greater statistical power with cohorts of moderate size, and is less likely to be affected by population stratification. We therefore address some of the shortcomings of the current haplogroup association approach. Finally, we discuss the unique challenges faced by studies done on African populations, and recommend the most viable methods to use when investigating mtDNA variation in CVD and other common complex disease. PMID: 28906532 [PubMed - as supplied by publisher]

Related Articles Benefits and Limitations of DNA Barcoding and Metabarcoding in Herbal Product Authentication. Phytochem Anal. 2017 Sep 14;: Authors: Raclariu AC, Heinrich M, Ichim MC, de Boer H Abstract INTRODUCTION: Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono-substance medicines. Current quality and authentication assessment methods rely mainly on morphology and analytical phytochemistry-based methods detailed in pharmacopoeias. Herbal products however are often highly processed with numerous ingredients, and even if these analytical methods are accurate for quality control of specific lead or marker compounds, they are of limited suitability for the authentication of biological ingredients. OBJECTIVE: To review the benefits and limitations of DNA barcoding and metabarcoding in complementing current herbal product authentication. METHOD: Recent literature relating to DNA based authentication of medicinal plants, herbal medicines and products are summarised to provide a basic understanding of how DNA barcoding and metabarcoding can be applied to this field. RESULTS: Different methods of quality control and authentication have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. CONCLUSIONS: DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. Standardisation of protocols for DNA barcoding and DNA sequence-based identification are necessary before DNA-based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures. Copyright © 2017 John Wiley & Sons, Ltd. PMID: 28906059 [PubMed - as supplied by publisher]

Related Articles Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women. Am J Clin Nutr. 2017 Sep 13;: Authors: Savolainen O, Lind MV, Bergström G, Fagerberg B, Sandberg AS, Ross A Abstract Background: Diet is frequently associated with both the development and prevention of type 2 diabetes (T2D), but there is a lack of objective tools for assessing the relation between diet and T2D. Biomarkers of dietary intake are unconfounded by recall and reporting bias, and using multiple dietary biomarkers could help strengthen the link between a healthy diet and the prevention of T2D.Objective: The objective of this study was to explore how diet is related to glucose tolerance status (GTS) and to future development of T2D irrespective of common T2D and cardiovascular disease risk factors by using multiple dietary biomarkers.Design: Dietary biomarkers were measured in plasma from 64-y-old Swedish women with different GTS [normal glucose tolerance (NGT; n = 190), impaired glucose tolerance (IGT; n = 209), and diabetes (n = 230)]. The same subjects were followed up after 5 y to determine changes in glucose tolerance (n = 167 for NGT, n = 174 for IGT, and n = 159 for diabetes). ANCOVA and logistic regression were used to explore baseline data for associations between dietary biomarkers, GTS, and new T2D cases at follow-up (n = 69).Results: Of the 10 dietary biomarkers analyzed, β-alanine (beef) (P-raw < 0.001), alkylresorcinols C17 and C19 (whole-grain wheat and rye) (P-raw = 0.003 and 0.011), eicosapentaenoic acid (fish) (P-raw = 0.041), 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) (fish) (P-raw = 0.002), linoleic acid (P-raw < 0.001), oleic acid (P-raw = 0.003), and α-tocopherol (margarine and vegetable oil) (P-raw < 0.001) were associated with GTS, and CMPF (fish) (OR: 0.72; 95% CI: 0.56, 0.93; P-raw = 0.013) and α-tocopherol (OR: 0.71; 95% CI: 0.51, 0.98; P-raw = 0.041) were inversely associated with future T2D development.Conclusions: Several circulating dietary biomarkers were strongly associated with GTS after correction for known T2D risk factors, underlining the role of diet in the development and prevention of T2D. To our knowledge, this study is the first to use multiple dietary biomarkers to investigate the link between diet and disease risk. PMID: 28903960 [PubMed - as supplied by publisher]

Related Articles Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon. Cancer Res. 2017 Jun 15;77(12):3352-3363 Authors: Dermadi D, Valo S, Ollila S, Soliymani R, Sipari N, Pussila M, Sarantaus L, Linden J, Baumann M, Nyström M Abstract Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. Cancer Res; 77(12); 3352-63. ©2017 AACR. PMID: 28416481 [PubMed - indexed for MEDLINE]

Related Articles Impact of Maillard Reaction products on Nutrition and Health: Current knowledge and need to understand their fate in the human digestive system. Crit Rev Food Sci Nutr. 2017 Sep 13;:0 Authors: ALJahdali N, Carbonero F Abstract The Maillard Reaction (MR) is a non-enzymatic chemical reaction which results in the linkage between the amino group of amino acids and the carbonyl group of reduced sugars. MR products (MRPs) are common components of processed foods, mainly as a result of heating, especially in the Western diet. MRPs are classified as into three stages: initial, intermediate, and final stages, indicative of increased complexity and size, incurring different flavor, aroma, and texture. MRPs presence is known to reduce the nutritional quality of foods, particularly by reducing protein digestibility. Early reports have linked MRPs, especially advanced glycation end-products (AGEs) present in high concentration in the typical Western diet, to health conditions and diseases. However conflicting data has since been reported, and only a few (acrylamide, heterocyclic amines and 5-Hydroxymethylfurfural) MRPs have documented potential toxic or carcinogenic effects. High molecular weight MRPs are not available for direct absorption in the higher gastrointestinal tract, and are thus mostly metabolized by resident colonic microbes. MRPs have been the subject of sparse research interest in comparison with other non-digestible dietary elements. In this review, we outline the state of knowledge on MRPs in nutrition and health, and highlight the need to develop the limited knowledge on their impact on the gut microbiota and which metabolites derive from MRPs fermentation. PMID: 28901784 [PubMed - as supplied by publisher]

Related Articles UPLC‑QTOFMS‑based metabolomic analysis of the serum of hypoxic preconditioning mice. Mol Med Rep. 2017 Sep 13;: Authors: Liu J, Zhan G, Chen D, Chen J, Yuan ZB, Zhang EL, Gao YX, Xu G, Sun BD, Liao W, Gao YQ Abstract Hypoxic preconditioning (HPC) is well‑known to exert a protective effect against hypoxic injury; however, the underlying molecular mechanism remains unclear. The present study utilized a serum metabolomics approach to detect the alterations associated with HPC. In the present study, an animal model of HPC was established by exposing adult BALB/c mice to acute repetitive hypoxia four times. The serum samples were collected by orbital blood sampling. Metabolite profiling was performed using ultra‑performance liquid chromatography‑quadrupole time‑of‑flight mass spectrometry (UPLC‑QTOFMS), in conjunction with univariate and multivariate statistical analyses. The results of the present study confirmed that the HPC mouse model was established and refined, suggesting significant differences between the control and HPC groups at the molecular levels. HPC caused significant metabolic alterations, as represented by the significant upregulation of valine, methionine, tyrosine, isoleucine, phenylalanine, lysophosphatidylcholine (LysoPC; 16:1), LysoPC (22:6), linoelaidylcarnitine, palmitoylcarnitine, octadecenoylcarnitine, taurine, arachidonic acid, linoleic acid, oleic acid and palmitic acid, and the downregulation of acetylcarnitine, malate, citrate and succinate. Using MetaboAnalyst 3.0, a number of key metabolic pathways were observed to be acutely perturbed, including valine, leucine and isoleucine biosynthesis, in addition to taurine, hypotaurine, phenylalanine, linoleic acid and arachidonic acid metabolism. The results of the present study provided novel insights into the mechanisms involved in the acclimatization of organisms to hypoxia, and demonstrated the protective mechanism of HPC. PMID: 28901489 [PubMed - as supplied by publisher]

Related Articles Comparative study on microsampling techniques in metabolic fingerprinting studies applying gas chromatography-MS analysis. Bioanalysis. 2017 Sep 13;: Authors: Cala MP, Meesters RJ Abstract AIM: Sample collection and preparation are important steps in the metabolomics workflow. Any improvement should be aimed toward making them simpler, faster and more reproducible. This paper describes the evaluation of different types of whole blood microsampling techniques applied in a metabolic fingerprinting study of breast cancer patients. RESULTS: A total of 139, 124 and 128 metabolites were identified in protein precipitation, dried matrix on paper discs and Mitra(®) volumetric absorptive microsampling, respectively in 80% of the sample sets, where the quality control samples had a relative standard deviation of <30%. Ten metabolites in breast cancer samples were detected as being altered significantly (p < 0.05). CONCLUSION: Our results suggest that whole blood microsampling techniques do not obtain statistically different results in comparison with the metabolomics applied standard reference method of protein precipitation, in terms of the number of detected compounds, the reproducibility and modeling of differences between the groups. PMID: 28901168 [PubMed - as supplied by publisher]

Related Articles Serum and Brain Metabolomic Variations Reveal Perturbation of Sleep Deprivation on Rats and Ameliorate Effect of Total Ginsenoside Treatment. Int J Genomics. 2017;2017:5179271 Authors: Gou XJ, Cen F, Fan ZQ, Xu Y, Shen HY, Zhou MM Abstract Sleep loss or sleep deprivation (SD) refers to shorter sleep than average baseline need, and SD has been a serious problem of modern societies which affects health and well-being. Panax ginseng is a well-known traditional Chinese medicine (TCM). Our previous study has demonstrated that total ginsenosides (GS), the extracts from Panax ginseng, could effectively improve cognition and behavior on SD rats. However, little is known about its metabolomic study. In this study, serum and brain metabolomic method based on gas chromatography coupled with mass spectrometry (GC/MS) was employed to evaluate the efficacy and study the mechanism of GS on a rat model of SD. With pattern recognition analysis of serum and brain tissue metabolite profile, a clear separation of the model group and control group was acquired for serum and brain tissue samples; the MGS (model + GS) group showed a tendency of recovering when compared to control group, which was consistent with behavioral and biochemical parameters. 39 and 40 potential biomarkers of brain tissues and serum samples, respectively, were identified and employed to explore the possible mechanism. Our work revealed that GS has significant protective effects on SD, and metabolomics is a useful tool for evaluating efficacy and elucidating mechanism in TCM. PMID: 28900617 [PubMed]

Related Articles Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach. Sci Rep. 2017 Sep 12;7(1):11433 Authors: Chang H, Meng HY, Liu SM, Wang Y, Yang XX, Lu F, Wang HY Abstract Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl4-induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early prediction and to reveal significant fibrotic pathways and their dynamic changes in different stages of liver fibrosis. Finally, nine differential metabolites in urine and ten in serum were selected and identified involving the most relevant metabolic pathways. Perturbations of tryptophan, valine, leucine, isoleucine, and citrate (TCA) cycle metabolites, along with sphingolipid and glycerophospholipid metabolites, occurred from the onset of liver fibrosis. Furthermore, dysregulation of valine and bile acid biosynthesis metabolites occurred in the intermediate and advanced stages. More importantly, among these metabolites, urinary kynurenic acid, 5-hydroxyindoleacetyl glycine, 4-(2-amino-3-hydroxyphenyl)-2,4-dioxobutanoic acid and serum sphinganine, sphingomyelin, L-leucine, L-tryptophan, and LysoPC(17:0) changed at all time points and may serve as potential early biomarkers for the diagnosis of hepatic fibrosis and as therapeutic targets. Overall, this work evaluates the potential of these metabolites for the early detection of liver fibrosis. PMID: 28900168 [PubMed - in process]

Related Articles Military training elicits marked increases in plasma metabolomic signatures of energy metabolism, lipolysis, fatty acid oxidation, and ketogenesis. Physiol Rep. 2017 Sep;5(17): Authors: Karl JP, Margolis LM, Murphy NE, Carrigan CT, Castellani JW, Madslien EH, Teien HK, Martini S, Montain SJ, Pasiakos SM Abstract Military training studies provide unique insight into metabolic responses to extreme physiologic stress induced by multiple stressor environments, and the impacts of nutrition in mediating these responses. Advances in metabolomics have provided new approaches for extending current understanding of factors modulating dynamic metabolic responses in these environments. In this study, whole-body metabolic responses to strenuous military training were explored in relation to energy balance and macronutrient intake by performing nontargeted global metabolite profiling on plasma collected from 25 male soldiers before and after completing a 4-day, 51-km cross-country ski march that produced high total daily energy expenditures (25.4 MJ/day [SD 2.3]) and severe energy deficits (13.6 MJ/day [SD 2.5]). Of 737 identified metabolites, 478 changed during the training. Increases in 88% of the free fatty acids and 91% of the acylcarnitines, and decreases in 88% of the mono- and diacylglycerols detected within lipid metabolism pathways were observed. Smaller increases in 75% of the tricarboxylic acid cycle intermediates, and 50% of the branched-chain amino acid metabolites detected were also observed. Changes in multiple metabolites related to lipid metabolism were correlated with body mass loss and energy balance, but not with energy and macronutrient intakes or energy expenditure. These findings are consistent with an increase in energy metabolism, lipolysis, fatty acid oxidation, ketogenesis, and branched-chain amino acid catabolism during strenuous military training. The magnitude of the energy deficit induced by undereating relative to high energy expenditure, rather than macronutrient intake, appeared to drive these changes, particularly within lipid metabolism pathways. PMID: 28899914 [PubMed - in process]

Related Articles Melaleuca quinquenervia essential oil inhibits α-melanocyte-stimulating hormone-induced melanin production and oxidative stress in B16 melanoma cells. Phytomedicine. 2017 Oct 15;34:191-201 Authors: Chao WW, Su CC, Peng HY, Chou ST Abstract BACKGROUND: Essential oils are odorous, volatile products of plant secondary metabolism, which are found in many leaves and stems. They show important biological activities, which account for the development of aromatherapy used in complementary and alternative medicine. The essential oil extracted from Melaleuca quinquenervia (Cav.) S.T. Blake (paperbark) (MQ-EO) has various functional properties. PURPOSE: The aim of this study is to investigate the chemical composition of MQ-EO by using gas chromatography-mass spectrometry (GC-MS) and evaluate its tyrosinase inhibitory activity. METHODS: Gas chromatography-mass spectrometry (GC-MS)-based metabolomics was used to identify 18 components in MQ-EO. The main components identified were 1,8-cineole (21.60%), α-pinene (15.93%), viridiflorol (14.55%), and α-terpineol (13.73%). B16 melanoma cells were treated with α-melanocyte-stimulating hormone (α-MSH) in the presence of various concentrations of MQ-EO or its major compounds. Cell viability was accessed by MTT assay and cellular tyrosinase activity and melanin content were determined by using spectrophotographic methods. The antioxidant mechanism of MQ-EO in α-MSH stimulated B16 cells was also investigated. RESULTS: In α-melanocyte-stimulating hormone (α-MSH)-stimulated murine B16 melanoma cells, MQ-EO, 1,8-cineole, α-pinene, and α-terpineol significantly reduced melanin content and tyrosinase activity. Moreover, MQ-EO, 1,8-cineole, α-pinene, and α-terpineol decreased malondialdehyde (MDA) levels. In addition, restored glutathione (GSH) levels, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities were increased in α-MSH-stimulated B16 cells. MQ-EO not only decreased apoptosis but also reduced DNA damage in α-MSH stimulated B16 cells. These results showed that MQ-EO and its main components, 1,8-cineole, α-pinene, and α-terpineol, possessed potent anti-tyrosinase and anti-melanogenic activities besides the antioxidant properties. CONCLUSIONS: The active functional components of MQ-EO were found to be 1,8-cineole, α-pinene, and α-terpineol. Consequently, the results of present study suggest that MQ-EO is non-cytotoxic and can be used as a skin-whitening agent, both medically and cosmetically. PMID: 28899502 [PubMed - in process]

Related Articles Mixomics analysis of Bacillus subtilis: effect of oxygen availability on riboflavin production. Microb Cell Fact. 2017 Sep 12;16(1):150 Authors: Hu J, Lei P, Mohsin A, Liu X, Huang M, Li L, Hu J, Hang H, Zhuang Y, Guo M Abstract BACKGROUND: Riboflavin, an intermediate of primary metabolism, is one kind of important food additive with high economic value. The microbial cell factory Bacillus subtilis has already been proven to possess significant importance for the food industry and have become one of the most widely used riboflavin-producing strains. In the practical fermentation processes, a sharp decrease in riboflavin production is encountered along with a decrease in the dissolved oxygen (DO) tension. Influence of this oxygen availability on riboflavin biosynthesis through carbon central metabolic pathways in B. subtilis is unknown so far. Therefore the unveiled effective metabolic pathways were still an unaccomplished task till present research work. RESULTS: In this paper, the microscopic regulation mechanisms of B. subtilis grown under different dissolved oxygen tensions were studied by integrating (13)C metabolic flux analysis, metabolomics and transcriptomics. It was revealed that the glucose metabolic flux through pentose phosphate (PP) pathway was lower as being confirmed by smaller pool sizes of metabolites in PP pathway and lower expression amount of ykgB at transcriptional level. The latter encodes 6-phosphogluconolactonase (6-PGL) under low DO tension. In response to low DO tension in broth, the glucose metabolic flux through Embden-Meyerhof-Parnas (EMP) pathway was higher and the gene, alsS, encoding for acetolactate synthase was significantly activated that may result due to lower ATP concentration and higher NADH/NAD(+) ratio. Moreover, ResE, a membrane-anchored protein that is capable of oxygen regulated phosphorylase activity, and ResD, a regulatory protein that can be phosphorylated and dephosphorylated by ResE, were considered as DO tension sensor and transcriptional regulator respectively. CONCLUSIONS: This study shows that integration of transcriptomics, (13)C metabolic flux analysis and metabolomics analysis provides a comprehensive understanding of biosynthesized riboflavin's regulatory mechanisms in B. subtilis grown under different dissolved oxygen tension conditions. The two-component system, ResD-ResE, was considered as the signal receiver of DO tension and gene regulator that led to differences between biomass and riboflavin production after triggering the shifts in gene expression, metabolic flux distributions and metabolite pool sizes. PMID: 28899391 [PubMed - in process]

Related Articles Investigation of Dioscorea bulbifera rhizome-induced hepatotoxicity in rats by a multi-sample integrated metabolomics approach. Chem Res Toxicol. 2017 Sep 13;: Authors: Zhao DS, Jiang LL, Fan YX, Wang LL, Li ZQ, Shi W, Li P, Li HJ Abstract The use of herbal medicines continues to expand globally, meanwhile, herb-associated hepatotoxicity is becoming a safety issue. Dioscorea bulbifera rhizome (DBR), a traditionally used medicinal plant in China, is reported to induce hepatotoxicity. However, the precise molecular mechanism involved has not been comprehensively explored. The objectives of the present study were to profile entire endogenous metabolites in a biological system and provide additional insight into the molecular mechanism of the hepatotoxicity induced by DBR using a multi-sample integrated metabolomics strategy. Gas chromatography-mass spectrometry coupled with multivariate analysis was employed to discover differentiating metabolites in metabolomics data of rat plasma, urine, and feces. In total, 55 metabolites distributed in 33 metabolic pathways were identified as being significantly altered in DBR-treated rats. Correlation network analysis revealed that the hub metabolites of hepatotoxicity were mainly associated with amino acid, bile acid, purine, pyrimidine, lipid, and energy metabolism. As such, DBR affected the physiological and biological functions of liver via the regulation of multiple metabolic pathways to an abnormal state. Notably, our findings also demonstrated that the multi-sample integrated metabolomics strategy has a great potential for identifying more biomarkers and pathways to unravel the mechanistic complexity of toxicity of traditional Chinese medicine. PMID: 28899093 [PubMed - as supplied by publisher]

Related Articles From the Cover: Metabolomics Reveals a Role of Betaine in Prenatal DBP Exposure-Induced Epigenetic Transgenerational Failure of Spermatogenesis in Rats. Toxicol Sci. 2017 Aug 01;158(2):356-366 Authors: Yuan B, Wu W, Chen M, Gu H, Tang Q, Guo D, Chen T, Chen Y, Lu C, Song L, Xia Y, Chen D, Rehan VK, Sha J, Wang X Abstract There is increasing concern that early-life exposure to endocrine disruptors affects male offspring reproduction. However, whether di-n-butyl phthalate (DBP), a widely used endocrine disruptor, has transgenerational effects and, if so, the exact underlying molecular mechanisms involved remain unknown. In our study, 5 of time-mated pregnant SD rats were exposed to 0 and 500 mg/kg DBP with corn oil as the vehicle via oral gavage from embryonic days (E8-E14). Epigenetic and metabolomic of testis were analyzed after post-natal 60 days. Sperm and testicular cell functions were examined to confirm the transgenerational effects. DBP exposure significantly decreased the sperm counts in F1 through F3 generation. We found distinct metabolic changes in the testis of both F1 and F3 generation offspring, specifically, a significantly increased level of betaine, which is an important methyl donor. In contrast, the expression of betaine homocysteine S-methyltransferase (BHMT), which catalyzes the transfer of methyl moiety from betaine to homocysteine, significantly decreased. There was accompanying global DNA hypomethylation, along with a reduction in follistatin-like 3 (Fstl3) promoter hypomethylation, which is a known modulator of Sertoli cell number and spermatogenesis. In summary, we conclude that metabolomic and epigenetic changes induced by the aberrant expression of BHMT represent a novel mechanism linking in utero DBP exposure to transgenerational spermatogenesis failure. PMID: 28898977 [PubMed - in process]

Related Articles Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis. J Invest Dermatol. 2016 May;136(5):994-1001 Authors: Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, Semeraro M, Jégou S, Flores C, Chen L, Kwon BS, Borg C, Weide B, Aubin F, Dalle S, Kohrt H, Ayyoub M, Kroemer G, Marabelle A, Cavalcanti A, Eggermont A, Zitvogel L Abstract Stage III metastatic melanomas require adequate adjuvant immunotherapy to prevent relapses. Prognostic factors are awaited to optimize the clinical management of these patients. The magnitude of metastatic lymph node invasion and the BRAF(V600) activating mutation have clinical significance. Based on a comprehensive immunophenotyping of 252 parameters per patient in paired blood and metastatic lymph nodes performed in 39 metastatic melanomas, we found that blood markers were as contributive as tumor-infiltrated lymphocyte immunotypes, and parameters associated with lymphocyte exhaustion/suppression showed higher clinical significance than those related to activation or lineage. High frequencies of CD45RA(+)CD4(+) and CD3(-)CD56(-) tumor-infiltrated lymphocytes appear to be independent prognostic factors of short progression-free survival. High NKG2D expression on CD8(+)tumor-infiltrated lymphocytes, low level of regulatory T-cell tumor-infiltrated lymphocytes, and low PD-L1 expression on circulating T cells were retained in the multivariate Cox analysis model to predict prolonged overall survival. Prospective studies are needed to determine whether such immunological markers may guide adjuvant therapies in stage III metastatic melanomas. PMID: 26829031 [PubMed - indexed for MEDLINE]

Related Articles SERUM METABOLIC FINGERPRINTING IDENTIFIED PUTATIVELY ANNOTATED SPHINGANINE ISOMER AS A BIOMARKER OF WOLFRAM SYNDROME. J Proteome Res. 2017 Sep 12;: Authors: Zmyslowska A, Ciborowski M, Borowiec M, Fendler W, Pietrowska K, Parfieniuk E, Antosik K, Pyziak A, Waszczykowska A, Kretowski A, Mlynarski W Abstract Wolfram syndrome (WFS) is an example of a rare neurodegenerative disease with coexisting endocrine symptoms including diabetes mellitus as the first clinical symptom. Treatment of WFS is still only symptomatic and associated with poor prognosis. Potential markers of disease progression which could be useful for possible intervention trials are not available. Metabolomics has potential to identify such markers. In the present study serum fingerprinting by LC-QTOF-MS was performed in patients with WFS (n=13) and in patients with T1D (n=27). Based on obtained results aminoheptadecanediol (17:0 sphinganine isomer) (+50%, p=0.02), as the most discriminatory metabolite, was selected for validation. The 17:0 sphinganine isomer level was determined using the LC-QQQ method in the samples from WFS patients at two time points and compared with samples obtained from patients with T1D (n=24) and healthy controls (n=24). Validation analysis showed higher 17:0 sphinganine isomer level in patients with WFS compared to patients with T1D (p=0.0097) and control group (p<0.0001) with progressive reduction of its level after two-year follow-up period. Patients with WFS show a unique serum metabolic fingerprint, differentiating them from patients with T1D. Sphinganine derivate seems to be a marker of the ongoing process of neurodegeneration in WFS patients. PMID: 28895401 [PubMed - as supplied by publisher]

Related Articles ExSTA: External Standard Addition Method for Accurate High-throughput Quantitation in Targeted Proteomics Experiments. Proteomics Clin Appl. 2017 Sep 11;: Authors: Mohammed Y, Pan J, Zhang S, Han J, Borchers CH Abstract PURPOSE: Targeted proteomics using multiple reaction monitoring (MRM) with stable-isotope-labeled internal-standard (SIS) peptides is the current method of choice for protein quantitation in complex biological matrices. Better quantitation can be achieved with the internal standard-addition method, where successive increments of synthesized natural form (NAT) of the endogenous analyte are added to each sample, a response curve is generated, and the endogenous concentration is determined at the x-intercept. Internal NAT-addition, however, requires multiple analyses of each sample, resulting in increased sample consumption and analysis time. EXPERIMENTAL DESIGN: We used an MRM assay for 34 high-to-moderate abundance human plasma proteins to compare three methods: classical internal SIS-addition, internal NAT-addition, and external NAT-addition - generated in buffer using NAT and SIS peptides. We also evaluated the accuracy using endogenous-free chicken plasma. RESULTS: The internal NAT-addition outperformed the other two in precision and accuracy. However, the curves derived by internal vs. external NAT-addition differed by only ∼3.8% in slope, providing comparable accuracies and precision with good CV values. CONCLUSIONS AND CLINICAL RELEVANCE: While the internal NAT-addition method may be "ideal", our new external NAT-addition can be used to determine the concentration of high-to-moderate abundance endogenous plasma proteins, providing a robust and cost-effective alternative for clinical analyses or other high-throughput applications. This article is protected by copyright. All rights reserved. PMID: 28895300 [PubMed - as supplied by publisher]

Related Articles The use of (1) H-NMR Metabolomics to Optimise the Extraction and Preliminary Identification of Anthelmintic Products from the Leaves of Lysiloma latisiliquum. Phytochem Anal. 2017 Sep 12;: Authors: Hernández-Bolio GI, Kutzner E, Eisenreich W, de Jesús Torres-Acosta JF, Peña-Rodríguez LM Abstract INTRODUCTION: Tannin-rich forages are recognised as an important alternative for the control of gastrointestinal nematodes in small ruminants. Lysiloma latisiliquum, a forage commonly consumed by goats and sheep, has shown anthelmintic activity when tested against Haemonchus contortus. However, to date, the metabolites responsible for the activity are not known. OBJECTIVE: To use (1) H-NMR metabolomics in the extraction and identification of anthelmintic metabolites from L. latisiliquum. METHODOLOGY: Eight different solvent systems were compared for the optimum extraction of anthelmintic metabolites from L. latisiliquum. (1) H-NMR spectra of the tannin-free extracts were measured in methanol-d4 using trimethylsilylpropanoic acid (TSP) as internal standard. Extracts were also evaluated for their anthelmintic activity using the larval exsheathment inhibition assay against H. contortus. These data were correlated by multivariate analysis [principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA)] and analysed. To validate the results obtained after the OPLS-DA, a bioassay-guided isolation of bioactive metabolites was conducted. RESULTS: The PCA of the (1) H-NMR data allowed the identification of hydrophilic solvents as those best suited for the extraction of anthelmintics from L. latisiliquum and indicated that the bioactive metabolites are high-polarity, glycosylated products. Similarly, OPLS-DA of the data enabled the detection of activity-related signals, assigned to the glycosylated metabolites quercitrin and arbutin obtained from the bioassay-guided purification of the extract. CONCLUSION: The results of this investigation confirm metabolomics as a useful tool in the detection of bioactive metabolites in plants without previous phytochemical studies. Copyright © 2017 John Wiley & Sons, Ltd. PMID: 28895238 [PubMed - as supplied by publisher]