PubMed

Metabolomic profiles illuminate the efficacy of Chinese herbal Da-Cheng-Qi decoction on acute pancreatitis in rats. Pancreatology. 2015 May 11; Authors: Li J, Zhu SF, Zhao XL, Liu YX, Wan MH, Guo H, Liu YL, Gong HL, Chen GY, Tang WF Abstract BACKGROUND AND OBJECTIVES: Chinese herbal drug Da-Cheng-Qi decoction (DCQD) has been widely used for decades to treat acute pancreatitis (AP). Previous trials are mostly designed to state the potential mechanisms of the therapeutic effects rather than to detect its whole effect on metabolism. This study aimed to investigate the efficacy of DCQD on metabolism in AP. METHODS: Twenty-two male adult Sprague-Dawley rats were randomized into three groups. AP was induced by retrograde ductal infusion of 3.5% sodium taurocholate solution in DCQD and AP group, while 0.9% saline solution was used in sham operation (SO) group. Blood samples were obtained 12 h after drug administration and a 600 MHz superconducting Nuclear Magnetic Resonance (NMR) spectrometer was used to detected plasma metabolites. Principal Components Analysis (PCA) and Partial Least Squares-Discriminant Analysis after Orthogonal Signal Correction (OSC-PLS-DA) were applied to analyze the Longitudinal Eddy-delay (LED) and Carr-Purcell-Meiboom-Gill (CPMG) spectra. RESULTS: Differences in concentrations of metabolites among the three groups were detected by OSC-PLS-DA of 1HNMR spectra (both LED and CPMG). Compared with SO group, DCQD group had higher levels of plasma glycerol, glutamic acid, low density lipoprotein (LDL), saturated fatty acid (FA) and lower levels of alanine and glutamine, while the metabolic changes were reversed in the AP group. CONCLUSIONS: Our results demonstrated that DCQD was capable of altering the changed concentrations of metabolites in rats with AP and 1HNMR-based metabolomic approach provided a new methodological cue for systematically investigating the efficacies and mechanisms of DCQD in treating AP. PMID: 26048200 [PubMed - as supplied by publisher]

Metabolomic Endotype of Asthma. J Immunol. 2015 Jun 5; Authors: Comhair SA, McDunn J, Bennett C, Fettig J, Erzurum SC, Kalhan SC Abstract Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5-phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism. PMID: 26048149 [PubMed - as supplied by publisher]

Pavement cells: a model system for non-transcriptional auxin signalling and crosstalks. J Exp Bot. 2015 Jun 4; Authors: Chen J, Wang F, Zheng S, Xu T, Yang Z Abstract Auxin (indole acetic acid) is a multifunctional phytohormone controlling various developmental patterns, morphogenetic processes, and growth behaviours in plants. The transcription-based pathway activated by the nuclear TRANSPORT INHIBITOR RESISTANT 1/auxin-related F-box auxin receptors is well established, but the long-sought molecular mechanisms of non-transcriptional auxin signalling remained enigmatic until very recently. Along with the establishment of the Arabidopsis leaf epidermal pavement cell (PC) as an exciting and amenable model system in the past decade, we began to gain insight into non-transcriptional auxin signalling. The puzzle-piece shape of PCs forms from intercalated or interdigitated cell growth, requiring local intra- and inter-cellular coordination of lobe and indent formation. Precise coordination of this interdigitated pattern requires auxin and an extracellular auxin sensing system that activates plasma membrane-associated Rho GTPases from plants and subsequent downstream events regulating cytoskeletal reorganization and PIN polarization. Apart from auxin, mechanical stress and cytokinin have been shown to affect PC interdigitation, possibly by interacting with auxin signals. This review focuses upon signalling mechanisms for cell polarity formation in PCs, with an emphasis on non-transcriptional auxin signalling in polarized cell expansion and pattern formation and how different auxin pathways interplay with each other and with other signals. PMID: 26047974 [PubMed - as supplied by publisher]

Sulfur amino acid metabolism in Zucker diabetic fatty rats. Biochem Pharmacol. 2015 Jun 3; Authors: Kwak HC, Kim YM, Oh SJ, Kim SK Abstract The present study was aimed to investigate the metabolomics of sulfur amino acids in Zucker diabetic fatty (ZDF) rats, an obese type 2 diabetic animal model. Plasma levels of total cysteine, homocysteine and methionine, but not glutathione (GSH) were markedly decreased in ZDF rats. Hepatic methionine, homocysteine, cysteine, betaine, taurine, spermidine and spermine were also decreased. There are no significant difference in hepatic S-adenosylmethionine, S-adenosylhomocysteine, GSH, GSH disulfide, hypotaurine and putrescine between control and ZDF rats. Hepatic SAH hydrolase, betaine-homocysteine methyltransferase and methylene tetrahydrofolate reductase were up-regulated while activities of gamma-glutamylcysteine ligase and methionine synthase were decreased. The area under the curve (AUC) of methionine and methionine-d4 was not significantly different in control and ZDF rats treated with a mixture of methionine (60mg/kg) and methionine-d4 (20mg/kg). Moreover, the AUC of the increase in plasma total homocysteine was comparable between two groups, although the homocysteine concentration curve was shifted leftward in ZDF rats, suggesting that the plasma total homocysteine after the methionine loading was rapidly increased and normalized in ZDF rats. These results show that the AUC of plasma homocysteine is not responsive to the up-regulation of hepatic BHMT in ZDF rats. The present study suggests that the decrease in hepatic methionine may be responsible for the decreases in its metabolites, such as homocysteine, cysteine, and taurine in liver and consequently decreased plasma homocysteine levels. PMID: 26047850 [PubMed - as supplied by publisher]

Related Articles [Discrimination of common oral streptococcus with metabonomics method]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2009 Oct;27(5):553-6 Authors: Guo Q, Xiao LY, Zhou XD, Li MY, Lu WX, Xiong P, Jia XM, Li W Abstract OBJECTIVE: To evaluate the feasibility of identifying oral streptococcus by comparing their metabolic profiling, and to find a convenient and rapid way to discriminate oral microorganisms. METHODS: The pure cultivation of Streptococcus sanguis ATCC 10556 and Streptococcus sobrinus 6715 (reference strain) from solid culture were respectively inoculated in TPY liquid medium. Then the growth quantity was measured periodically by turbidimetry and the growth curves of the inoculated bacteria were completed. The culture solutions in the stationary phase of the two bacteria were centrifuged, and then tested with the 1H-nuclear magnetic resonance (1H-NMR) spectrometer respectively. The gained free induction decay (FID) data were all inputted into MestReC Soft and finally transformed into metabolic profiling. The metabolic profiles were integrated segmentingly and the results were inputted into SIMCA-P Soft for principal components analysis (PCA). RESULTS: The PCA results showed the obvious clustering phenomena and the points of two group data differentially centralized in two clusters. Therefore, the NMR-based metabonomics profiles can discriminate the two different kinds of bacteria. CONCLUSION: The metabonomics can be expected to be a kind of promising useful method in quick discrimination of oral streptococcus. PMID: 19927732 [PubMed - indexed for MEDLINE]

Related Articles [Preliminary study on the discrimination of putative periodontal pathogens with a metabonomics method]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2009 Jun;27(3):310-2, 316 Authors: Lu WX, Wu YF, Xiao LY, Li MY, Guo Q, Xiong P, Jia XM, Xiao XR, Zhu Z, Gong QM, Li W Abstract OBJECTIVE: To evaluate the feasibility of identifying oral pathogenic bacteria by comparing the metabolic profiling of putative periodontal pathogens and try to find a convenient and rapid way to discriminate oral microorganisms. METHODS: Suspensions of Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum with same density were prepared and cultured respectively at liquid BHI medium. Then the growth quantity was measured periodically through turbidimetry and the growth curves of the inoculated bacteria were completed. The culture solutions of stable growth phase were sampled and characterized by 1H-nuclear magnetic resonance 1H-NMR). The data of 1H-NMR spectroscope results were analyzed by principal components analysis (PCA). RESULTS: The PCA showed the obvious clustering phenomena and the points of three groups differentially centralized to three clusters. Therefore, the NMR-based metabonomics profiles could discriminate the three different kinds of bacteria. CONCLUSION: The metabonomics is a potential classable method to identify the oral pathogenic bacteria. PMID: 19637485 [PubMed - indexed for MEDLINE]

Related Articles [A preliminary investigation on plasma of non-syndromic cleft lip and/or palate using nuclear magnetic resonance-based metabonomics]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2009 Apr;27(2):147-9, 153 Authors: Song JK, Zhou JL, Luo H, Shi B, Huang J, Li W Abstract OBJECTIVE: To access the feasibility of employing metabonomics method in clinical studies. This pilot study intends to introduce nuclear magnetic resonance (NMR)-based metabonomics method to elucidate the metabolism of non-syndromic cleft lip and/or palate (NSCLP) patients. METHODS: High-resolution 1H NMR spectroscopy was performed on blood plasma obtained from NSCLP and non-malformed children. All signal of 1H NMR spectra were recognized within MESTRE-v4.7, and the 1H NMR spectra integration into bins (or buckets) across the spectral regions of bin 0.04 was performed automatically in MESTRE-v4.7. The resulting data matrix was further analyzed, which was performed by SIMCA-P 11.0. The principal component analysis (PCA) was applied to the centered data to explore any clustering behavior of the samples. RESULTS: The results demonstrated the metabonomic difference in plasma between NSCLP and non-malformed children at least lies in 3-Hydroxybutyrate gamma-CH3, arginine and valine. Arginine excretion appeared to be higher in the non-malformed children population, while NSCLP population excreted higher concentrations of 3-Hydroxybutyrate gamma-CH3 and valine. CONCLUSION: The present study clearly demonstrated the great potential of the NMR-based metabonomics approach in elucidating the NSCLP plasma metabolism and the possibility of application in clinic diagnosis and screening. PMID: 19472875 [PubMed - indexed for MEDLINE]

Related Articles [Initial study on the discrimination of oral microorganisms with a metabonomics method]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2008 Oct;26(5):537-40 Authors: Xiong P, Zhou JL, Xiao LY, Kong XL, Li JY, Jia XM, Li W Abstract OBJECTIVE: To establish the spectra of metabolites that coued be employed in identification of oral pathogenic bacteria, and try to find a convenient and rapid way to discriminate oral microorganisms. METHODS: Suspensions of Streptococcus mutans ATCC 25175, Streptococcus sanguis ATCC 10556 and Lactobacillus acidophilus ATCC 4356 with same density were preparecd and cultured respectively at improved TPY liquid culture medium. The growth quantity were measured periodically by a turbidimeter. And the growth curves of the inoculated bacteria were completed. The culture solutions in stationary phase of the three bacteria were tested with 1H-nuclear magnetic resonance (1H-NMR) spectroscopy respectively. The data of 1H-NMR spectroscopy results were analyzed by principal components analysis (PCA). RESULTS: The PCA showed the obvious clustering phenomena and the points of three group differentially centralized to three clusters. Therefore, the NMR-based metabonomics profiles could discriminate the three different kinds of bacteria. CONCLUSION: The metabonomics is a promising new technology for developing to a rapid discrimination method of oral pathogenic bacteria. PMID: 19007080 [PubMed - indexed for MEDLINE]

Related Articles [Initial study on discrimination of oral microorganisms with the metabonomics technique]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2007 Aug;25(4):342-4 Authors: Li M, Xiao LY, Li JY, Kong XL, Yu JH, Zhou JL, Xiao XR, Zhu Z, Gong QM, Li W Abstract OBJECTIVE: To evaluate the feasibility of employing metabonomics method in identification of oral pathogenic bacteria. METHODS: The Streptococcus mutans ATCC25175 and Actinomyces viscosus ATCC15987 were respectively inoculated in same certain culture medium. The growth curves of the inoculated bacteria were drown by turbidimetry. The culture solutions in four different growth phases of the both bacteria were used to test with the 1H-Nuclear magnetic resonance (1H-NMR) spectroscopy respectively. The data of 1H-NMR spectroscopy results were analyzed by principal components analysis (PCA). RESULTS: The PCA showed the obvious clustering phenomena and the points of two group data stayed differentially together by two clusters. Therefore, the NMR-based metabonomics profiles can discriminate the two different kind of bacteria. CONCLUSION: The metabonomics can be expected to be a kind of promising useful method in quick discrimination of oral pathogenic bacteria. PMID: 17896487 [PubMed - indexed for MEDLINE]

Integrative Metabolic Signatures for Hepatic Radiation Injury. PLoS One. 2015;10(6):e0124795 Authors: Kurland IJ, Broin PÓ, Golden A, Su G, Meng F, Liu L, Mohney R, Kulkarni S, Guha C Abstract BACKGROUND: Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice. METHODS: Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry. RESULTS: Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine). CONCLUSIONS : We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney. PMID: 26046990 [PubMed - as supplied by publisher]

A comprehensive quantification method for eicosanoids and related compounds by using liquid chromatography/mass spectrometry with high speed continuous ionization polarity switching. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 May 27;995-996C:74-84 Authors: Yamada M, Kita Y, Kohira T, Yoshida K, Hamano F, Tokuoka SM, Shimizu T Abstract Fatty acids and related metabolites, comprising several hundreds of molecular species, are an important target in disease metabolomics, as they are involved in various mammalian pathologies and physiologies. Selected reaction monitoring (SRM) analysis, which is capable of monitoring hundreds of compounds in a single run, has been widely used for comprehensive quantification. However, it is difficult to monitor a large number of compounds with different ionization polarity, as polarity switching requires a sub-second period per cycle in classical mass spectrometers. In the present study, we developed and evaluated a comprehensive quantification method for eicosanoids and related compounds by using LC/MS with high-speed continuous ionization polarity switching. The new method employs a fast (30ms/cycle) continuous ionization polarity switching, and differentiates 137 targets either by chromatography or by SRM transition. Polarity switching did not affect the lower limits of quantification, which ranged similarly from 0.5 to 200pg on column. Lipid extracts from mouse tissues were analyzed by this method, and 65 targets were quantitatively detected in the brain, including 6 compounds analyzed in the positive ion mode. We demonstrated that a fast continuous ionization polarity switching enables the quantification of a wide variety of lipid mediator species without compromising the sensitivity and reliability. PMID: 26046978 [PubMed - as supplied by publisher]

MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism. Oncotarget. 2015 Jun 3; Authors: Shukla SK, Gunda V, Abrego J, Haridas D, Mishra A, Souchek J, Chaika NV, Yu F, Sasson AR, Lazenby AJ, Batra SK, Singh PK Abstract MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in primary tumor tissue specimens from human pancreatic adenocarcinoma cancer patients. Overall, our results demonstrate that MUC16 plays an important role in metabolic reprogramming of pancreatic cancer cells by increasing glycolysis and enhancing motility and invasiveness. PMID: 26046375 [PubMed - as supplied by publisher]

Related Articles The holy grail of cystic fibrosis research: pharmacological repair of the F508del-CFTR mutation. Ann Transl Med. 2015 May;3(Suppl 1):S24 Authors: Maiuri L, De Stefano D, Raia V, Kroemer G PMID: 26046070 [PubMed]

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 2015/06/05PubMed 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.

18 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 2015/06/04PubMed 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.

Ecotoxicogenomic Approaches for Understanding Molecular Mechanisms of Environmental Chemical Toxicity Using Aquatic Invertebrate, Daphnia Model Organism. Int J Mol Sci. 2015;16(6):12261-12287 Authors: Kim HJ, Koedrith P, Seo YR Abstract Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term "ecotoxicogenomics" has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics) into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development's toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s) and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses) necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics. PMID: 26035755 [PubMed - as supplied by publisher]

Comparison of Fruits of Forsythia suspensa at Two Different Maturation Stages by NMR-Based Metabolomics. Molecules. 2015;20(6):10065-10081 Authors: Jia J, Zhang F, Li Z, Qin X, Zhang L Abstract Forsythiae Fructus (FF), the dried fruit of Forsythia suspensa, has been widely used as a heat-clearing and detoxifying herbal medicine in China. Green FF (GF) and ripe FF (RF) are fruits of Forsythia suspensa at different maturity stages collected about a month apart. FF undergoes a complex series of physical and biochemical changes during fruit ripening. However, the clinical uses of GF and RF have not been distinguished to date. In order to comprehensively compare the chemical compositions of GF and RF, NMR-based metabolomics coupled with HPLC and UV spectrophotometry methods were adopted in this study. Furthermore, the in vitro antioxidant and antibacterial activities of 50% methanol extracts of GF and RF were also evaluated. A total of 27 metabolites were identified based on NMR data, and eight of them were found to be different between the GF and RF groups. The GF group contained higher levels of forsythoside A, forsythoside C, cornoside, rutin, phillyrin and gallic acid and lower levels of rengyol and β-glucose compared with the RF group. The antioxidant activity of GF was higher than that of RF, but no significant difference was observed between the antibacterial activities of GF and RF. Given our results showing their distinct chemical compositions, we propose that NMR-based metabolic profiling can be used to discriminate between GF and RF. Differences in the chemical and biological activities of GF and RF, as well as their clinical efficacies in traditional Chinese medicine should be systematically investigated in future studies. PMID: 26035103 [PubMed - as supplied by publisher]

A 1H-NMR-Based Metabonomic Study on the Anti-Depressive Effect of the Total Alkaloid of Corydalis Rhizoma. Molecules. 2015;20(6):10047-10064 Authors: Wu H, Wang P, Liu M, Tang L, Fang J, Zhao Y, Zhang Y, Li D, Xu H, Yang H Abstract Corydalis Rhizoma, named YuanHu in China, is the dried tuber of Corydalis yanhusuo W.T. Wang which is used in Traditional Chinese Medicine for pain relief and blood activation. Previous pharmacological studies showed that apart from analgesics, the alkaloids from YuanHu may be useful in the therapy of depression by acting on the GABA, dopamine and benzodiazepine receptors. In this study, the antidepressive effect of the total alkaloid of YuanHu (YHTA) was investigated in a chronic unpredictable mild stress (CUMS) rat model using 1H-NMR-based metabonomics. Plasma metabolic profiles were analyzed and multivariate data analysis was applied to discover the metabolic biomarkers in CUMS rats. Thirteen biomarkers of CUMS-introduced depression were identified, which are myo-inositol, glycerol, glycine, creatine, glutamine, glutamate, β-glucose, α-glucose, acetoacetate, 3-hydroxybutyrate, leucine and unsaturated lipids (L7, L9). Moreover, a metabolic network of the potential biomarkers in plasma perturbed by CUMS was detected. After YHTA treatment, clear separation between the model group and YHTA-treated group was achieved. The levels of all the abnormal metabolites mentioned above showed a tendency of restoration to normal levels. The results demonstrated the therapeutic efficacy of YHTA against depression and suggested that NMR-based metabolomics can provide a simple and easy tool for the evaluation of herbal therapeutics. PMID: 26035102 [PubMed - as supplied by publisher]

Metabolomic Identification of a Novel Pathway of Blood Pressure Regulation Involving Hexadecanedioate. Hypertension. 2015 Jun 1; Authors: Menni C, Graham D, Kastenmüller G, Alharbi NH, Alsanos SM, McBride M, Mangino M, Titcombe P, Shin SY, Psatha M, Geisendorfer T, Huber A, Peters A, Wang-Sattler R, Xu T, Brosnan MJ, Trimmer J, Reichel C, Mohney RP, Soranzo N, Edwards MH, Cooper C, Church AC, Suhre K, Gieger C, Dominiczak AF, Spector TD, Padmanabhan S, Valdes AM Abstract High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9 10(-5)). Replication was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar-Kyoto rats; (2) circulating metabolite change after salt-induced blood pressure elevation in spontaneously hypertensive stroke-prone rats; and (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarboxylic acid, showed concordant association with blood pressure (systolic BP [SBP]: β [95% confidence interval], 1.31 [0.83-1.78], P=6.81×10(-8); diastolic BP [DBP]: 0.81 [0.5-1.11], P=2.96×10(-7)) and mortality (hazard ratio [95% confidence interval], 1.49 [1.08-2.05]; P=0.02) in TwinsUK. The blood pressure association was replicated in KORA and Hertfordshire. In the animal experiments, we showed that oral hexadecanedioate increased both circulating hexadecanedioate and blood pressure in Wistar-Kyoto rats, whereas blood pressure elevation with oral sodium chloride in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity to noradrenaline was significantly increased in mesenteric resistance arteries from hexadecanedioate-treated rats compared with controls, indicated by the shift to the left of the concentration-response curve (P=0.013). Relaxation to carbachol did not show any difference. Our findings indicate that hexadecanedioate is causally associated with blood pressure regulation through a novel pathway that merits further investigation. PMID: 26034203 [PubMed - as supplied by publisher]

Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis. 2015 Jun 1; Authors: Kerkman PF, Fabre E, van der Voort EI, Zaldumbide A, Rombouts Y, Rispens T, Wolbink G, Hoeben RC, Spits H, Baeten DL, Huizinga TW, Toes RE, Scherer HU Abstract OBJECTIVES: Immunity to citrullinated antigens is a hallmark of rheumatoid arthritis (RA). We set out to elucidate its biology by identifying and characterising citrullinated antigen-specific B cells in peripheral blood of patients with RA. METHODS: Differentially labelled streptavidin and extravidin tetramers were conjugated to biotinylated CCP2 or control antigens and used in flow cytometry to identify citrullinated antigen-specific B cells in peripheral blood. Tetramer-positive and tetramer-negative B cells were isolated by fluorescence activated cell sorting (FACS) followed by in vitro culture and analysis of culture supernatants for the presence of antibodies against citrullinated protein antigens (ACPA) by ELISA. Cells were phenotypically characterised by flow cytometry. RESULTS: By combining differentially labelled CCP2 tetramers, we successfully separated citrullinated antigen-specific B cells from non-specific background signals. Isolated tetramer-positive B cells, but not tetramer-negative cells, produced large amounts of ACPA upon in vitro stimulation. Phenotypic analyses revealed that citrullinated antigen-specific B cells displayed markers of class-switched memory B cells and plasmablasts, whereas only few cells displayed a naïve phenotype. The frequency of tetramer-positive cells was high (up to 1/500 memory B cells with a median of 1/12 500 total B cells) and correlated with ACPA serum titres and spontaneous ACPA production in culture. CONCLUSIONS: We developed a technology to identify and isolate citrullinated antigen-specific B cells from peripheral blood of patients with RA. Most cells have a memory phenotype, express IgA or IgG and are present in relatively high frequencies. These data pave the path for a direct and detailed molecular characterisation of ACPA-expressing B cells and could lead to the identification of novel therapeutic targets. PMID: 26034045 [PubMed - as supplied by publisher]