Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 19 min 38 sec ago

Evaluation of the anti-hypertensive effect of Tengfu Jiangya tablet by combination of UPLC-Q-exactive-MS-based metabolomics and iTRAQ-based proteomics technology.

Sun, 18/02/2018 - 14:19
Related Articles Evaluation of the anti-hypertensive effect of Tengfu Jiangya tablet by combination of UPLC-Q-exactive-MS-based metabolomics and iTRAQ-based proteomics technology. Biomed Pharmacother. 2018 Feb 13;100:324-334 Authors: Tian Y, Jiang F, Li Y, Jiang H, Chu Y, Zhu L, Guo W Abstract OBJECTIVE: Tengfu Jiangya tablet (TJT) is a traditional Chinese medicine formulation composed of Uncaria rhynchophylla and Semen raphani. It is a hospital preparation that is widely used in clinics for treating hypertension. A previous metabolomics study reported that TJT exerted a protective effect on hypertension by restoring impaired NO production, ameliorating the inflammatory state, and vascular remodeling. A clinical proteomics study also revealed five key target proteins during TJT intervention. This study aimed to integrate proteome and metabolome data sets for a holistic view of the molecular mechanisms of TJT in treating hypertension. METHODS: Serum samples from spontaneously hypertensive rats and Wistar Kyoto rats were analyzed using ultra-high performance liquid chromatography coupled to Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UPLC-Q-Exactive-MS)-based metabolomics technology and isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics technology. Moreover, we selected two candidate proteins and determined their expression levels in rat serum using an enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 20 potential biomarkers and 14 differential proteins in rat serum were identified. These substances were mainly involved in three biological pathways: the kallikrein-kinin pathway, the lipid metabolism pathway, and the PPARγ signaling pathway. CONCLUSIONS: The results suggested that TJT could effectively treat hypertension, partially by regulating the above three metabolic pathways. The combination of proteomics and metabolomics provided a feasible method to uncover the underlying interventional effect and therapeutic mechanism of TJT on spontaneously hypertensive rats. PMID: 29453042 [PubMed - as supplied by publisher]

Metabolomic profiling of Campylobacter jejuni with resistance gene ermB by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and tandem quadrupole mass spectrometry.

Sun, 18/02/2018 - 14:19
Related Articles Metabolomic profiling of Campylobacter jejuni with resistance gene ermB by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and tandem quadrupole mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Feb 10;1079:62-68 Authors: Fu Q, Liu D, Wang Y, Li X, Wang L, Yu F, Shen J, Xia X Abstract The metabolome changes of Campylobacter jejuni with resistant gene ermB remain unclear. Here, we described an untargeted metabolomic workflow based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry to investigate the metabolites perturbations mediated by ermB in C. jejuni. After optimization of extractants and chromatographic conditions, the combination of 100% methanol extraction with a 12 min gradient by C18 column was adopted for untargeted metabolomic profiling in reversed phase separation. Meanwhile, 60% methanol extraction followed by a 14 min separation using hydrophilic interaction chromatography column was suitable to complementally expand the metabolite coverage of C. jejuni. Multivariate statistical analysis was performed by means of orthogonal projection to latent structures-discriminant analysis to select metabolic features. The selected features were further confirmed by ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry. A total of thirty-six differential metabolites between the susceptible strain (C. jejuni NCTC 11168) and resistant stain (C. jejuni NCTC 11168 with ermB) were identified. These pivotal metabolites were primarily participated in biological processes as cell signaling, membrane integrity/stability, fuel and energy source/storage and nutrient. The biofilm formation capability of resistant strain was inferior to that of susceptible strain, confirming the influence of ermB on membrane integrity/stability of C. jejuni. Our findings revealed important metabolic regulatory pathways associated with resistant C. jejuni with ermB. PMID: 29453015 [PubMed - as supplied by publisher]

Metabolic and Lipidomic Reprogramming in Renal Cell Carcinoma Subtypes Reflects Regions of Tumor Origin.

Sun, 18/02/2018 - 14:19
Related Articles Metabolic and Lipidomic Reprogramming in Renal Cell Carcinoma Subtypes Reflects Regions of Tumor Origin. Eur Urol Focus. 2018 Feb 13;: Authors: Schaeffeler E, Büttner F, Reustle A, Klumpp V, Winter S, Rausch S, Fisel P, Hennenlotter J, Kruck S, Stenzl A, Wahrheit J, Sonntag D, Scharpf M, Fend F, Agaimy A, Hartmann A, Bedke J, Schwab M Abstract BACKGROUND: Renal cell carcinoma (RCC) consists of prognostic distinct subtypes derived from different cells of origin (eg, clear cell RCC [ccRCC], papillary RCC [papRCC], and chromophobe RCC [chRCC]). ccRCC is characterized by lipid accumulation and metabolic alterations, whereas data on metabolic alterations in non-ccRCC are limited. OBJECTIVE: We assessed metabolic alterations and the lipid composition of RCC subtypes and ccRCC-derived metastases. Moreover, we elucidated the potential of metabolites/lipids for subtype classification and identification of therapeutic targets. DESIGN, SETTING, AND PARTICIPANTS: Metabolomic/lipidomic profiles were quantified in ccRCC (n=58), chRCC (n=19), papRCC (n=14), corresponding nontumor tissues, and metastases (n=9) through a targeted metabolomic approach. Transcriptome profiling was performed in corresponding samples and compared with expression data of The Cancer Genome Atlas cohorts (patients with ccRCC, n=452; patients with papRCC, n=260; and patients with chRCC, n=59). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In addition to cluster analyses, metabolomic/transcriptomic data were analyzed to evaluate metabolic differences of ccRCC and chRCC using Welch's t test or paired t test as appropriate. Where indicated, p values were adjusted for multiple testing using Bonferroni or Benjamini-Hochberg correction. RESULTS AND LIMITATIONS: Based on their metabolic profiles, RCC subtypes clustered into two groups separating ccRCC and papRCC from chRCC, which mainly reflected the different cells of origin. ccRCC-derived metastases clustered with primary ccRCCs. In addition to differences in certain lipids (lysophosphatidylcholines and sphingomyelins), the coregulation network of lipids differed between ccRCC and chRCC. Consideration of metabolic gene expression indicated, for example, alterations of the polyamine pathway at metabolite and transcript levels. In vitro treatment of RCC cells with the ornithine-decarboxylase inhibitor difluoromethylornithine resulted in reduced cell viability and mitochondrial activity. Further evaluation of clinical utility was limited by the retrospective study design and cohort size. CONCLUSIONS: In summary, we provide novel insight into the metabolic profiles of ccRCC and non-ccRCC, thereby confirming the different ontogeny of RCC subtypes. Quantification of differentially regulated metabolites/lipids improves classification of RCC with an impact on the identification of novel therapeutic targets. PATIENT SUMMARY: Several subtypes of renal cell carcinoma (RCC) with different metastatic potentials and prognoses exist. In the present study, we provide novel insight into the metabolism of these different subtypes, which improves classification of subtypes and helps identify novel targets for RCC therapy. PMID: 29452772 [PubMed - as supplied by publisher]

Investigation of the urinary metabolic variations and the application in bladder cancer biomarker discovery.

Sat, 17/02/2018 - 13:58
Related Articles Investigation of the urinary metabolic variations and the application in bladder cancer biomarker discovery. Int J Cancer. 2018 Feb 16;: Authors: Liu X, Cheng X, Liu X, He L, Zhang W, Wang Y, Sun W, Ji Z Abstract Urine metabolomics have been used to identify biomarkers for clinical diseases. However, inter-individual variations and effect factors need to be further evaluated. In the present study, we explored the urine metabolome in a cohort of 203 health adults, 6 patients with benign bladder lesions, and 53 patients with bladder cancer (BCa) using liquid chromatography coupled with high resolution mass spectrometry. Inter-individual analysis of both healthy controls and bladder cancer patients showed that the urine metabolome was relatively stable. Further analysis indicated that sex and age affect inter-individual variations of urine metabolome. Metabolic pathways such as tryptophan metabolism, the citrate cycle, and pantothenate and CoA biosynthesis were found to be related to sex and age. To eliminate age and sex interference, additional BCa urine metabolomic biomarkers were explored using age and sex-matched urine samples (Test group: 44 health adults vs. 33 patients with BCa). Metabolic profiling of urine could significantly differentiate the cases with cancer from the controls and high-grade from low-grade BCa. A metabolite panel consisting of trans-2-dodecenoylcarnitine, serinyl-valine, feruloyl-2-hydroxyputrescine, and 3-hydroxynonanoyl carnitine were discovered to have good predictive ability for BCa with an area under the curve (AUC) of 0.956 (cross validation: AUC=0.924). A panel of indolylacryloylglycine, N2 -galacturonyl-L-lysine, and aspartyl-glutamate was used to establish a robust model for high and low-grade BCa distinction with AUC of 0.937 (cross validation: AUC=0.891).External sample(26 control vs. 20 BCa) validation verified the acceptable accuracy of these models for BCa detection.This study showed that urinary metabolomics is a useful strategy for differential analysis and biomarker discovery. This article is protected by copyright. All rights reserved. PMID: 29451296 [PubMed - as supplied by publisher]

Access to the CNS: Biomarker Strategies for Dopaminergic Treatments.

Sat, 17/02/2018 - 13:58
Related Articles Access to the CNS: Biomarker Strategies for Dopaminergic Treatments. Pharm Res. 2018 Feb 15;35(3):64 Authors: van den Brink WJ, Palic S, Köhler I, de Lange ECM Abstract Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson's disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development. PMID: 29450650 [PubMed - in process]

Plant Genetics and Molecular Biology: An Introduction.

Sat, 17/02/2018 - 13:58
Related Articles Plant Genetics and Molecular Biology: An Introduction. Adv Biochem Eng Biotechnol. 2018 Feb 16;: Authors: Varshney RK, Pandey MK, Chitikineni A Abstract The rapidly evolving technologies can serve as a potential growth engine in agriculture as many of these technologies have revolutionized several industries in the recent past. The tremendous advancements in biotechnology methods, cost-effective sequencing technology, refinement of genomic tools, and standardization of modern genomics-assisted breeding methods hold great promise in taking the global agriculture to the next level through development of improved climate-smart seeds. These technologies can dramatically increase our capacity to understand the molecular basis of traits and utilize the available resources for accelerated development of stable high-yielding, nutritious, input-use efficient, and climate-smart crop varieties. This book aimed to document the monumental advances witnessed during the last decade in multiple fields of plant biotechnology such as genetics, structural and functional genomics, trait and gene discovery, transcriptomics, proteomics, metabolomics, epigenomics, nanotechnology, and analytical tools. This book will serve to update the scientific community, academicians, and other stakeholders in global agriculture on the rapid progress in various areas of agricultural biotechnology. This chapter provides a summary of the book, "Plant Genetics and Molecular Biology." Graphical Abstract. PMID: 29450572 [PubMed - as supplied by publisher]

Calycosin Orchestrates Osteogenesis of Danggui Buxue Tang in Cultured Osteoblasts: Evaluating the Mechanism of Action by Omics and Chemical Knock-out Methodologies.

Sat, 17/02/2018 - 13:58
Related Articles Calycosin Orchestrates Osteogenesis of Danggui Buxue Tang in Cultured Osteoblasts: Evaluating the Mechanism of Action by Omics and Chemical Knock-out Methodologies. Front Pharmacol. 2018;9:36 Authors: Gong AGW, Duan R, Wang HY, Dong TTX, Tsim KWK Abstract Danggui Buxue Tang (DBT), an ancient Chinese herbal decoction commonly used to mitigate menopausal osteoporosis, contains two herbs: Astragali Radix (AR) and Angelicae Sinensis Radix (ASR). The exact efficacy of individual chemical(s) within DBT, or in any herbal mixture, is hard to be revealed. Calycosin and ferulic acid have been reported to be the predominant chemicals found within DBT, and its roles in regulating osteoblastic differentiation have been proposed here. To probe the roles of calycosin and ferulic acid, these chemicals were specifically depleted from the DBT extracts. Here, calycosin-depleted DBT (DBTΔcal) and ferulic acid-depleted DBT (DBTΔfa), generated by semi-preparative HPLC, were coupled with RNA-seq and metabolomics analyses to reveal the synergistic functions of individual chemicals within a complex herbal mixture. The expressions of osteogenic differentiation markers were significantly increased under the treatments of DBT and DBTΔfa. The DBT-induced genes were markedly reduced in the absent of calycosin, i.e., DBTΔcal. In cultured osteoblasts, the DBT-activated Wnt/β-catenin and MAPK/Erk and signaling pathways were greatly affected when calycosin was depleted. By metabolomics analysis in DBT-treated osteoblasts, the profile of metabolites triggered by DBTΔcal showed distinction to that of DBT and/or DBTΔfa. Thus, our findings indicated that calycosin, rather than ferulic acid, could be an indispensable chemical in DBT to orchestrate multi-components of DBT in achieving maximal osteogenic properties. PMID: 29449812 [PubMed]

Changes in grape polyphenols (V. vinifera L.) as a consequence of post-harvest withering by high-resolution mass spectrometry: Raboso Piave versus Corvina.

Sat, 17/02/2018 - 13:58
Related Articles Changes in grape polyphenols (V. vinifera L.) as a consequence of post-harvest withering by high-resolution mass spectrometry: Raboso Piave versus Corvina. J Mass Spectrom. 2016 Sep;51(9):750-60 Authors: Rosso MD, Soligo S, Panighel A, Carraro R, Vedova AD, Maoz I, Tomasi D, Flamini R Abstract Grape dehydration is an oenological process used for the production of high-quality reinforced and sweet wines. Corvina and Raboso Piave are two red grape varieties used for production of high-quality Italian wines, such as Recioto, Amarone di Valpolicella and Raboso Passito. Changes of polyphenolic composition of the grapes as a consequence of the withering were studied by ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC/QTOF); for identification of compounds a homemade HR-MS database of grape and wine metabolites, was used. Concomitant with trans-resveratrol and viniferins, relevant increases of other stilbenes (piceatannol, resveratrol trimers and tetramers) and antioxidant compounds (quercetin, syringetin and tamarixetin) were observed. These compounds are part of the induced metabolism occurring during the withering process and in general improve the nutraceutical properties of grapes and wines. On the other hand, longer processes showed to decrease flavan-3-ols and glycoside flavonols. Constant increase of E/Z ε-viniferin ratio was observed in all samples, and this parameter can be used to monitor the process. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 27491020 [PubMed - indexed for MEDLINE]

Metabolomic study of wild and cultivated caper (Capparis spinosa L.) from different areas of Sardinia and their comparative evaluation.

Sat, 17/02/2018 - 13:58
Related Articles Metabolomic study of wild and cultivated caper (Capparis spinosa L.) from different areas of Sardinia and their comparative evaluation. J Mass Spectrom. 2016 Sep;51(9):716-28 Authors: Maldini M, Foddai M, Natella F, Addis R, Chessa M, Petretto GL, Tuberoso CI, Pintore G Abstract Capparis spinosa L. (Capparidaceae), also known as caper, is widely known for its very aromatic flower buds (capers),that are largely employed as a flavouring in cooking. Capparis species are regarded as a potential source of important bioactive compounds, in fact, due to their botanical relationship with Brassica species; they contain glucosinolates, secondary plant metabolites, that have been studied for their potential anticarcinogenic properties. In addition, the presence of other numerous beneficial compounds such as polyphenols, alkaloids, lipids, vitamins and minerals have been reported. The aim of this study was to individuate and determinate the principal bioactive compounds occurring in different part (leaves, buds and flowers) of wild and cultivated C. spinosa collected from different area of Sardinia (Italy). Ultra-high performance liquid chromatography-triple quadrupole/linear ion trap tandem mass spectrometry methods were used for identification and simultaneous determination of 27 bioactive molecules. Analysis of different samples revealed qualitative and quantitative differences in the content of flavonoids, glucosinolates, anthocyanins and phenolic acids. In particular, glucocapparin resulted the most abundant with values ranging from 112 to 364 mg/100 g Fresh Weight (FW); followed by rutin with highest value of 126 mg/100 g FW, 4-hydroxyglucobrassicin with highest value of 42 mg/100 g FW and isorhamnetin 3-O-rutinoside with highest value of 24 mg/100 g FW. Based on this metabolomic targeted approach, quantitative results were treated by principal component analysis to explore and visualise correlation and discrimination among collections of C. spinosa samples. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 27489055 [PubMed - indexed for MEDLINE]

6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates colon carcinogenesis via blockade of IL-6 mediated signals.

Fri, 16/02/2018 - 13:44
6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates colon carcinogenesis via blockade of IL-6 mediated signals. Biomed Pharmacother. 2018 Feb 12;100:282-295 Authors: Mishra P, Raj V, Bhadauria AS, Singh AK, Rai A, Kumar P, Keshari AK, De A, Samanta A, Kumar U, Kumar D, Maity B, Nath S, Prakash A, Ansari KM, Saha S Abstract In this study, we investigated the in vivo antiproliferative activity of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) using albino Wistar rats. M1 was administered to DMH induced CRC rats at 10 and 25 mg/kg doses for 15 days. Various physiological, oxidative parameters, histopathology, ELISA, gene and protein expression studies were conducted to evaluate the anti-CRC potential of M1. The histopathology and biochemical tests indicated the protective action of M1 in DMH-induced colon cancer. ELISA confirms that M1 reduced the increased concentration of IL-6 more prominently than those of IL-2 and COX-2. Gene expression analysis revealed that M1 attenuated the increased mRNA over-expression of IL-6, JAK2 and STAT3. The result obtained from quantitative western blot analysis demonstrated that the CRC condition was produced by the IL-6 induced activation/phosphorylation of JAK2 and STAT3 and further down-regulated with M1 treatment. This evidence was supported well with the application of data-based mathematical modeling. Applying the fitted model, we predicted the quantitative behavior of STAT3 populations not accessible to experimental measurement. Later, 1H NMR based serum metabolic profiling was carried out using rat sera to investigate the impact of M1 on CRC-induced metabolic alterations. M1 showed its ability to restore the perturbed metabolites in CRC condition. Altogether, our study provided the first time evidence that M1 exhibits anti-CRC potential through the blockade of IL-6/JAK2/STAT3 oncogenic signaling. PMID: 29448205 [PubMed - as supplied by publisher]

Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models.

Fri, 16/02/2018 - 13:44
Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models. Biomaterials. 2018 Feb 08;162:144-153 Authors: Armiñán A, Palomino-Schätzlein M, Deladriere C, Arroyo-Crespo JJ, Vicente-Ruiz S, Vicent MJ, Pineda-Lucena A Abstract Metabolomics is becoming a relevant tool for understanding the molecular mechanisms involved in the response to new drug delivery systems. The applicability of this experimental approach to cell cultures and animal models makes metabolomics a useful tool for establishing direct connections between in vitro and in vivo data, thus providing a reliable platform for the characterization of chemotherapeutic agents. Herein, we used metabolomic profiles based on nuclear magnetic resonance (NMR) spectroscopy to evaluate the biochemical pathways involved in the response to a chemotherapeutic anthracycline drug (Doxorubicin, Dox) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-conjugated form (HPMA-Dox) in an in vitro cell culture model and an in vivo orthotopic breast cancer model. We also used protein expression and flow cytometry studies to obtain a better coverage of the biochemical alterations associated with the administration of these compounds. The overall analysis revealed that polymer conjugation leads to increased apoptosis, reduced glycolysis, and reduced levels of phospholipids when compared to the free chemotherapeutic drug. Our results represent a first step in the application of integrated in vitro and in vivo metabolomic studies to the evaluation of drug delivery systems. PMID: 29448142 [PubMed - as supplied by publisher]

Advances in analytical tools for high throughput strain engineering.

Fri, 16/02/2018 - 13:44
Advances in analytical tools for high throughput strain engineering. Curr Opin Biotechnol. 2018 Feb 12;54:33-40 Authors: Marcellin E, Nielsen LK Abstract The emergence of inexpensive, base-perfect genome editing is revolutionising biology. Modern industrial biotechnology exploits the advances in genome editing in combination with automation, analytics and data integration to build high-throughput automated strain engineering pipelines also known as biofoundries. Biofoundries replace the slow and inconsistent artisanal processes used to build microbial cell factories with an automated design-build-test cycle, considerably reducing the time needed to deliver commercially viable strains. Testing and hence learning remains relatively shallow, but recent advances in analytical chemistry promise to increase the depth of characterization possible. Analytics combined with models of cellular physiology in automated systems biology pipelines should enable deeper learning and hence a steeper pitch of the learning cycle. This review explores the progress, advances and remaining bottlenecks of analytical tools for high throughput strain engineering. PMID: 29448095 [PubMed - as supplied by publisher]

Salicin-7-sulfate: A new salicinoid from willow and implications for herbal medicine.

Fri, 16/02/2018 - 13:44
Salicin-7-sulfate: A new salicinoid from willow and implications for herbal medicine. Fitoterapia. 2018 Feb 12;: Authors: Noleto-Dias C, Ward JL, Bellisai A, Lomax C, Beale MH Abstract Willow (Salix sp.) is a historically well-known herbal medicine that provided the lead compound (salicin) for the discovery of aspirin, one of the most successful plant derived drugs in human medicine. During a metabolomics screen of 86 Salix species contained in the UK National Willow Collection, we have discovered, isolated and fully characterised a new natural salicinoid - salicin-7-sulfate. This molecule may have important human pharmacological actions that need to be considered in determining the efficacy and safety of willow herbal medicines. PMID: 29447984 [PubMed - as supplied by publisher]

Fc-Glycosylation in Human IgG1 and IgG3 Is Similar for Both Total and Anti-Red-Blood Cell Anti-K Antibodies.

Fri, 16/02/2018 - 13:44
Related Articles Fc-Glycosylation in Human IgG1 and IgG3 Is Similar for Both Total and Anti-Red-Blood Cell Anti-K Antibodies. Front Immunol. 2018;9:129 Authors: Sonneveld ME, Koeleman CAM, Plomp HR, Wuhrer M, van der Schoot CE, Vidarsson G Abstract After albumin, immunoglobulin G (IgG) are the most abundant proteins in human serum, with IgG1 and IgG3 being the most abundant subclasses directed against protein antigens. The quality of the IgG-Fc-glycosylation has important functional consequences, which have been found to be skewed toward low fucosylation in some antigen-specific immune responses. This increases the affinity to IgG1-Fc-receptor (FcγR)IIIa/b and thereby directly affects downstream effector functions and disease severity. To date, antigen-specific IgG-glycosylation have not been analyzed for IgG3. Here, we analyzed 30 pregnant women with anti-K alloantibodies from a prospective screening cohort and compared the type of Fc-tail glycosylation of total serum- and antigen-specific IgG1 and IgG3 using mass spectrometry. Total serum IgG1 and IgG3 Fc-glycoprofiles were highly similar. Fc glycosylation of antigen-specific IgG varied greatly between individuals, but correlated significantly with each other for IgG1 and IgG3, except for bisection. However, although the magnitude of changes in fucosylation and galactosylation were similar for both subclasses, this was not the case for sialylation levels, which were significantly higher for both total and anti-K IgG3. We found that the combination of relative IgG1 and IgG3 Fc-glycosylation levels did not improve the prediction of anti-K mediated disease over IgG1 alone. In conclusion, Fc-glycosylation profiles of serum- and antigen-specific IgG1 and IgG3 are highly similar. PMID: 29445378 [PubMed]

Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect.

Fri, 16/02/2018 - 13:44
Related Articles Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect. Cell Death Dis. 2018 Feb 14;9(2):226 Authors: Secker PF, Beneke S, Schlichenmaier N, Delp J, Gutbier S, Leist M, Dietrich DR Abstract Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin. Canagliflozin inhibited the glutamate dehydrogenase (GDH) and mitochondrial electron transport chain (ETC) complex I at clinically relevant concentrations. This dual inhibition specifically prevented replenishment of tricarboxylic acid cycle metabolites by glutamine (anaplerosis) and thus altered amino acid pools by increasing compensatory transamination reactions. Consequently, canagliflozin caused a characteristic intracellular accumulation of glutamine, glutamate and alanine in confluent, quiescent RPTEC/TERT1. Canagliflozin, but none of the classical ETC inhibitors, induced cytotoxicity at particularly low concentrations in proliferating RPTEC/TERT1, serving as model for proximal tubule regeneration in situ. This finding is testimony of the strong dependence of proliferating cells on glutamine anaplerosis via GDH. Our discovery of canagliflozin-mediated simultaneous inhibition of GDH and ETC complex I in renal cells at clinically relevant concentrations, and their particular susceptibility to necrotic cell death during proliferation, provides a mechanistic rationale for the adverse effects observed especially in patients with preexisting chronic kidney disease or previous kidney injury characterized by sustained regenerative tubular epithelial cell proliferation. PMID: 29445145 [PubMed - in process]

Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue.

Fri, 16/02/2018 - 13:44
Related Articles Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue. J Lipid Res. 2018 Feb 14;: Authors: Gottschall H, Schmoecker C, Hartmann D, Rohwer N, Rund K, Kutzner L, Nolte F, Ostermann AI, Schebb NH, Weylandt KH Abstract Eicosanoids, including prostaglandins and thromboxanes, are broadly bioactive lipid mediators and increase colon tumorigenesis possibly through chronic inflammatory mechanisms. Epidemiological and experimental data suggest that acetylsalicylic acid (ASA) helps prevent colorectal cancer (CRC), possibly through cyclooxygenase (COX)-mediated suppression of eicosanoid - particularly prostaglandin E2 (PGE2) - formation. Recent studies suggest that statins prevent CRC and improve survival after diagnosis. We identified patients on ASA and/or statin treatment undergoing routine colonoscopy and measured eicosanoid levels in colonic mucosa with targeted metabolomics technology (LC-MS/MS). ASA-treated individuals (n=27) had significantly lower tissue eicosanoid levels of most COX-derived metabolites than untreated individuals (n=31). In contrast, COX-derived lipid metabolites tended to be higher in patients with statin treatment (n=7) as compared to those not receiving statins (n=24). This effect was not discernible in subjects treated with ASA and statins (n=11): Individuals treated with both drugs showed a pronounced suppression of COX-derived eicosanoids in colon tissue even compared to subjects treated with ASA alone. Our data from a routine clinical setting support the hypothesis that ASA and statins could inhibit CRC development via lipid mediator modification. Further studies should directly investigate the effect of dual ASA and statin treatment on colon tumorigenesis in humans. PMID: 29444936 [PubMed - as supplied by publisher]

Extended Duration Nocturnal Hemodialysis and Changes in Plasma Metabolite Profiles.

Fri, 16/02/2018 - 13:44
Related Articles Extended Duration Nocturnal Hemodialysis and Changes in Plasma Metabolite Profiles. Clin J Am Soc Nephrol. 2018 Feb 14;: Authors: Kalim S, Wald R, Yan AT, Goldstein MB, Kiaii M, Xu D, Berg AH, Clish C, Thadhani R, Rhee EP, Perl J Abstract BACKGROUND AND OBJECTIVES: In-center, extended duration nocturnal hemodialysis has been associated with variable clinical benefits, but the effect of extended duration hemodialysis on many established uremic solutes and other components of the metabolome is unknown. We determined the magnitude of change in metabolite profiles for patients on extended duration nocturnal hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a 52-week prospective, observational study, we followed 33 patients receiving conventional thrice weekly hemodialysis who converted to nocturnal hemodialysis (7-8 hours per session, three times per week). A separate group of 20 patients who remained on conventional hemodialysis (3-4 hours per session, three times per week) served as a control group. For both groups, we applied liquid chromatography-mass spectrometry-based metabolite profiling on stored plasma samples collected from all participants at baseline and after 1 year. We examined longitudinal changes in 164 metabolites among those who remained on conventional hemodialysis and those who converted to nocturnal hemodialysis using Wilcoxon rank sum tests adjusted for multiple comparisons (false discovery rate <0.05). RESULTS: On average, the nocturnal group had 9.6 hours more dialysis per week than the conventional group. Among 164 metabolites, none changed significantly from baseline to study end in the conventional group. Twenty-nine metabolites changed in the nocturnal group, 21 of which increased from baseline to study end (including all branched-chain amino acids). Eight metabolites decreased after conversion to nocturnal dialysis, including l-carnitine and acetylcarnitine. By contrast, several established uremic retention solutes, including p-cresol sulfate, indoxyl sulfate, and trimethylamine N-oxide, did not change with extended dialysis. CONCLUSIONS: Across a wide array of metabolites examined, extended duration hemodialysis was associated with modest changes in the plasma metabolome, with most differences relating to metabolite increases, despite increased dialysis time. Few metabolites showed reduction with more dialysis, and no change in several established uremic toxins was observed. PMID: 29444900 [PubMed - as supplied by publisher]

Qualitative and quantitative characterization of secondary metabolites and carbohydrates in Bai-Hu-Tang using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and ultraperformance liquid chromatography...

Fri, 16/02/2018 - 13:44
Related Articles Qualitative and quantitative characterization of secondary metabolites and carbohydrates in Bai-Hu-Tang using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and ultraperformance liquid chromatography coupled with photodiode array detector. J Food Drug Anal. 2017 Oct;25(4):946-959 Authors: Zhong WF, Tong WS, Zhou SS, Yip KM, Li SL, Zhao ZZ, Xu J, Chen HB Abstract Bai-Hu-Tang (BHT), a classic traditional Chinese medicine (TCM) formula used for clearing heat and promoting body fluid, consists of four traditional Chinese medicines, i.e., Gypsum Fibrosum (Shigao), Anemarrhenae Rhizoma (Zhimu), Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (Zhigancao), and nonglutinous rice (Jingmi). The chemical composition of BHT still remains largely elusive thus far. To qualitatively and quantitatively characterize secondary metabolites and carbohydrates in BHT, here a combination of analytical approaches using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and ultraperformance liquid chromatography coupled with photodiode array detector was developed and validated. A total of 42 secondary metabolites in BHT were tentatively or definitely identified, of which 10 major chemicals were quantified by the extracting ion mode of quadrupole time-of-flight mass spectrometry. Meanwhile, polysaccharides, oligosaccharides, and monosaccharides in BHT were also characterized via sample pretreatment followed by sugar composition analysis. The quantitative results indicated that the determined chemicals accounted for 35.76% of the total extract of BHT, which demonstrated that the study could be instrumental in chemical dissection and quality control of BHT. The research deliverables not only laid the root for further chemical and biological evaluation of BHT, but also provided a comprehensive analytical strategy for chemical characterization of secondary metabolites and carbohydrates in traditional Chinese medicine formulas. PMID: 28987372 [PubMed - indexed for MEDLINE]

OLS Client and OLS Dialog: Open Source Tools to Annotate Public Omics Datasets.

Fri, 16/02/2018 - 13:44
Related Articles OLS Client and OLS Dialog: Open Source Tools to Annotate Public Omics Datasets. Proteomics. 2017 Oct;17(19): Authors: Perez-Riverol Y, Ternent T, Koch M, Barsnes H, Vrousgou O, Jupp S, Vizcaíno JA Abstract The availability of user-friendly software to annotate biological datasets and experimental details is becoming essential in data management practices, both in local storage systems and in public databases. The Ontology Lookup Service (OLS, http://www.ebi.ac.uk/ols) is a popular centralized service to query, browse and navigate biomedical ontologies and controlled vocabularies. Recently, the OLS framework has been completely redeveloped (version 3.0), including enhancements in the data model, like the added support for Web Ontology Language based ontologies, among many other improvements. However, the new OLS is not backwards compatible and new software tools are needed to enable access to this widely used framework now that the previous version is no longer available. We here present the OLS Client as a free, open-source Java library to retrieve information from the new version of the OLS. It enables rapid tool creation by providing a robust, pluggable programming interface and common data model to programmatically access the OLS. The library has already been integrated and is routinely used by several bioinformatics resources and related data annotation tools. Secondly, we also introduce an updated version of the OLS Dialog (version 2.0), a Java graphical user interface that can be easily plugged into Java desktop applications to access the OLS. The software and related documentation are freely available at https://github.com/PRIDE-Utilities/ols-client and https://github.com/PRIDE-Toolsuite/ols-dialog. PMID: 28792687 [PubMed - indexed for MEDLINE]

Potentiation of the bioavailability of blueberry phenolic compounds by co-ingested grape phenolic compounds in mice, revealed by targeted metabolomic profiling in plasma and feces.

Fri, 16/02/2018 - 13:44
Related Articles Potentiation of the bioavailability of blueberry phenolic compounds by co-ingested grape phenolic compounds in mice, revealed by targeted metabolomic profiling in plasma and feces. Food Funct. 2016 Aug 10;7(8):3421-30 Authors: Dudonné S, Dal-Pan A, Dubé P, Varin TV, Calon F, Desjardins Y Abstract The low bioavailability of dietary phenolic compounds, resulting from poor absorption and high rates of metabolism and excretion, is a concern as it can limit their potential beneficial effects on health. Targeted metabolomic profiling in plasma and feces of mice supplemented for 15 days with a blueberry extract, a grape extract or their combination revealed significantly increased plasma concentrations (3-5 fold) of blueberry phenolic metabolites in the presence of a co-ingested grape extract, associated with an equivalent decrease in their appearance in feces. Additionally, the repeated daily administration of the blueberry-grape combination significantly increased plasma phenolic concentrations (2-3-fold) compared to animals receiving only a single acute dose, with no such increase being observed with individual extracts. These findings highlight a positive interaction between blueberry and grape constituents, in which the grape extract enhanced the absorption of blueberry phenolic compounds. This study provides for the first time in vivo evidence of such an interaction occurring between co-ingested phenolic compounds from fruit extracts leading to their improved bioavailability. PMID: 27443888 [PubMed - indexed for MEDLINE]

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