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: 20 min 19 sec ago

The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation.

Sat, 12/05/2018 - 12:28
Related Articles The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation. Nat Commun. 2018 May 10;9(1):1851 Authors: Muri J, Heer S, Matsushita M, Pohlmeier L, Tortola L, Fuhrer T, Conrad M, Zamboni N, Kisielow J, Kopf M Abstract The thioredoxin-1 (Trx1) system is an important contributor to cellular redox balance and is a sensor of energy and glucose metabolism. Here we show critical c-Myc-dependent activation of the Trx1 system during thymocyte and peripheral T-cell proliferation, but repression during T-cell quiescence. Deletion of thioredoxin reductase-1 (Txnrd1) prevents expansion the CD4-CD8- thymocyte population, whereas Txnrd1 deletion in CD4+CD8+ thymocytes does not affect further maturation and peripheral homeostasis of αβT cells. However, Txnrd1 is critical for expansion of the activated T-cell population during viral and parasite infection. Metabolomics show that TrxR1 is essential for the last step of nucleotide biosynthesis by donating reducing equivalents to ribonucleotide reductase. Impaired availability of 2'-deoxyribonucleotides induces the DNA damage response and cell cycle arrest of Txnrd1-deficient T cells. These results uncover a pivotal function of the Trx1 system in metabolic reprogramming of thymic and peripheral T cells and provide a rationale for targeting Txnrd1 in T-cell leukemia. PMID: 29749372 [PubMed - in process]

Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice.

Sat, 12/05/2018 - 12:28
Related Articles Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice. Phytother Res. 2018 May 11;: Authors: Amiri M, Nourian A, Khoshkam M, Ramazani A Abstract Due to the challenges in the control, prevention, and eradication of parasitic diseases like malaria, there is an urgent need to discover new therapeutic agents. Plant-derived medicines may open new ways in the field of antiplasmodial therapy. This study is aimed to investigate the toxicity and in vivo antiplasmodial activity of apigenin, a dietary flavonoid. Apigenin cytotoxicity was investigated on Huh7 cell line, brine shrimp (Artemia salina) larva, and human red blood cells. In vivo toxicity of apigenin was assessed by metabolomics approaches. Apigenin exhibited significant suppression of parasitemia in a dose-dependent manner; it suppressed Plasmodium berghei growth by 69.74%, 50.3%, and 49.23% at concentrations of 70, 35, and 15 mg/kg/day, respectively. The IC50 value for apigenin after 24 hr exposure to Huh7 cells was 225 μg/ml. Apigenin did not show noticeable toxicity on A. salina and also on the membrane integrity of red blood cells. After 24 hr exposure of mice to apigenin, alterations were seen in the metabolism of glucocorticoids and mineralocorticoids, bile acid metabolism (alternative pathway), sulfur metabolism, bile acid metabolism, metabolism of estrogens and androgens, cholesterol catabolism, and biosynthesis of cholesterol. These findings indicate that apigenin has potential in vivo antiplasmodial activity against P. berghei infected mice with high selectivity against malaria, but it can disrupt some metabolic pathways in mice. PMID: 29748995 [PubMed - as supplied by publisher]

Software Tools and Approaches for Compound Identification of LC-MS/MS Data in Metabolomics.

Sat, 12/05/2018 - 12:28
Related Articles Software Tools and Approaches for Compound Identification of LC-MS/MS Data in Metabolomics. Metabolites. 2018 May 10;8(2): Authors: Blaženović I, Kind T, Ji J, Fiehn O Abstract The annotation of small molecules remains a major challenge in untargeted mass spectrometry-based metabolomics. We here critically discuss structured elucidation approaches and software that are designed to help during the annotation of unknown compounds. Only by elucidating unknown metabolites first is it possible to biologically interpret complex systems, to map compounds to pathways and to create reliable predictive metabolic models for translational and clinical research. These strategies include the construction and quality of tandem mass spectral databases such as the coalition of MassBank repositories and investigations of MS/MS matching confidence. We present in silico fragmentation tools such as MS-FINDER, CFM-ID, MetFrag, ChemDistiller and CSI:FingerID that can annotate compounds from existing structure databases and that have been used in the CASMI (critical assessment of small molecule identification) contests. Furthermore, the use of retention time models from liquid chromatography and the utility of collision cross-section modelling from ion mobility experiments are covered. Workflows and published examples of successfully annotated unknown compounds are included. PMID: 29748461 [PubMed]

Omics of Blood Pressure and Hypertension.

Sat, 12/05/2018 - 12:28
Related Articles Omics of Blood Pressure and Hypertension. Circ Res. 2018 May 11;122(10):1409-1419 Authors: Arnett DK, Claas SA Abstract Essential hypertension is a common, complex disorder affecting ≤1 billion adults globally. Blood pressure is a highly heritable trait, with ≤50% of the variation between individuals accounted for by familial relationships. Despite this strong heritability, determining the genetic architecture of hypertension in humans has proved challenging. Recent technological and methodological developments have given rise to what is now known as omics-a domain of study that includes genomics, as well as epigenomics, transcriptomics, proteomics, and metabolomics. For complex traits like hypertension, which involve multiple pathways and organs, omic approaches offer the advantage of allowing identification of novel hypertensive mechanisms to help further dissect and characterize the disorder's pathophysiology. This review provides a primer on the genomics, transcriptomics, proteomics, and metabolomics of blood pressure and hypertension. We provide an introduction to each approach with examples chosen to illustrate its potential. We conclude with a brief assessment of current methods aimed at integrating multiomic data. A review of the literature found genomic, epigenomic, transcriptomic, proteomic, and metabolomic methods have been applied to dissect the pathophysiology of blood pressure and hypertension. Omic methods and integration of multiomic data represent a potentially fruitful approach to illuminating the complex pathophysiology of hypertension and, ultimately, may point to novel diagnostics and treatments. PMID: 29748366 [PubMed - in process]

Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells.

Sat, 12/05/2018 - 12:28
Related Articles Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells. Genes Dev. 2018 May 10;: Authors: Kim M, Wende H, Walcher J, Küehnemund J, Cheret C, Kempa S, McShane E, Selbach M, Lewin GR, Birchmeier C Abstract Cholesterol is a major constituent of myelin membranes, which insulate axons and allow saltatory conduction. Therefore, Schwann cells, the myelinating glia of the peripheral nervous system, need to produce large amounts of cholesterol. Here, we define a crucial role of the transcription factor Maf in myelination and cholesterol biosynthesis and show that Maf acts downstream from Neuregulin1 (Nrg1). Maf expression is induced when Schwann cells begin myelination. Genetic ablation of Maf resulted in hypomyelination that resembled mice with defective Nrg1 signaling. Importantly, loss of Maf or Nrg1 signaling resulted in a down-regulation of the cholesterol synthesis program, and Maf directly binds to enhancers of cholesterol synthesis genes. Furthermore, we identified the molecular mechanisms by which Nrg1 signaling regulates Maf levels. Transcription of Maf depends on calmodulin-dependent kinases downstream from Nrg1, whereas Nrg1-MAPK signaling stabilizes Maf protein. Our results delineate a novel signaling cascade regulating cholesterol synthesis in myelinating Schwann cells. PMID: 29748249 [PubMed - as supplied by publisher]

Combined untargeted and targeted fingerprinting by comprehensive two-dimensional gas chromatography: revealing fructose-induced changes in mice urinary metabolic signatures.

Sat, 12/05/2018 - 12:28
Related Articles Combined untargeted and targeted fingerprinting by comprehensive two-dimensional gas chromatography: revealing fructose-induced changes in mice urinary metabolic signatures. Anal Bioanal Chem. 2018 Apr;410(11):2723-2737 Authors: Bressanello D, Liberto E, Collino M, Chiazza F, Mastrocola R, Reichenbach SE, Bicchi C, Cordero C Abstract This study exploits the information potential of comprehensive two-dimensional gas chromatography configured with a parallel dual secondary column-dual detection by mass spectrometry and flame ionization (GC×2GC-MS/FID) to study changes in urinary metabolic signatures of mice subjected to high-fructose diets. Samples are taken from mice fed with normal or fructose-enriched diets provided either in aqueous solution or in solid form and analyzed at three stages of the dietary intervention (1, 6, and 12 weeks). Automated Untargeted and Targeted fingerprinting for 2D data elaboration is adopted for the most inclusive data mining of GC×GC patterns. The UT fingerprinting strategy performs a fully automated peak-region features fingerprinting and combines results from pre-targeted compounds and unknowns across the sample-set. The most informative metabolites, with statistically relevant differences between sample groups, are obtained by unsupervised multivariate analysis (MVA) and cross-validated by multi-factor analysis (MFA) with external standard quantitation by GC-MS. Results indicate coherent clustering of mice urine signatures according to dietary manipulation. Notably, the metabolite fingerprints of mice fed with liquid fructose exhibited greater derangement in fructose, glucose, citric, pyruvic, malic, malonic, gluconic, cis-aconitic, succinic and 2-keto glutaric acids, glycine acyl derivatives (N-carboxy glycine, N-butyrylglycine, N-isovaleroylglycine, N-phenylacetylglycine), and hippuric acid. Untargeted fingerprinting indicates some analytes which were not a priori pre-targeted which provide additional insights: N-acetyl glucosamine, N-acetyl glutamine, malonyl glycine, methyl malonyl glycine, and glutaric acid. Visual features fingerprinting is used to track individual variations during experiments, thereby extending the panorama of possible data elaboration tools. Graphical abstract ᅟ. PMID: 29516133 [PubMed - indexed for MEDLINE]

TRIENNIAL LACTATION SYMPOSIUM/BOLFA:Historical perspectives of lactation biology in the late 20th and early 21st centuries.

Sat, 12/05/2018 - 12:28
Related Articles TRIENNIAL LACTATION SYMPOSIUM/BOLFA:Historical perspectives of lactation biology in the late 20th and early 21st centuries. J Anim Sci. 2017 Dec;95(12):5639-5652 Authors: Collier RJ, Bauman DE Abstract The latter half of the 20th century and the early portion of the 21st century will be recognized as the "Golden Age" of lactation biology. This period corresponded with the rise of systemic, metabolomic, molecular, and genomic biology. It includes the discovery of the structure of DNA and ends with the sequencing of the complete genomes of humans and all major domestic animal species including the dairy cow. This included the ability to identify polymorphisms in the nucleic acid sequence, which can be tied to specific differences in cellular, tissue, and animal performance. Before this period, classical work using endocrine ablation and replacement studies identified the mammary gland as an endocrine-dependent organ. In the early 1960s, the development of RIA and radioreceptor assays permitted the study of the relationship between endocrine patterns and mammary function. The ability to measure nucleic acid content of tissues opened the door to study of the factors regulating mammary growth. The development of high-speed centrifugation in the 1960s allowed separation of specific cell organelles and their membranes. The development of transmission and scanning electron microscopy permitted the study of the relationship between structure and function in the mammary secretory cell. The availability of radiolabeled metabolites provided the opportunity to investigate the metabolic pathways and their regulation. The development of concepts regarding the coordination of metabolism to support lactation integrated our understanding of nutrient partitioning and homeostasis. The ability to produce recombinant molecules and organisms permitted enhancement of lactation in farm animal species and the production of milk containing proteins of value to human medicine. These discoveries and others contributed to vastly increased dairy farm productivity in the United States and worldwide. This review will include the discussion of the centers of excellence and scientists who labored in these fields to produce the harvest of knowledge we enjoy today. PMID: 29293741 [PubMed - indexed for MEDLINE]

Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin.

Sat, 12/05/2018 - 12:28
Related Articles Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin. Clin Cancer Res. 2017 Sep 15;23(18):5639-5647 Authors: Rajeshkumar NV, Yabuuchi S, Pai SG, De Oliveira E, Kamphorst JJ, Rabinowitz JD, Tejero H, Al-Shahrour F, Hidalgo M, Maitra A, Dang CV Abstract Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.Results: Among the agents tested, phenformin showed significant tumor growth inhibition (>30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTENConclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639-47. ©2017 AACR. PMID: 28611197 [PubMed - indexed for MEDLINE]

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase.

Sat, 12/05/2018 - 12:28
Related Articles Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase. Proc Natl Acad Sci U S A. 2017 01 31;114(5):974-979 Authors: Mafu S, Karunanithi PS, Palazzo TA, Harrod BL, Rodriguez SM, Mollhoff IN, O'Brien TE, Tong S, Fiehn O, Tantillo DJ, Bohlmann J, Zerbe P Abstract The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene. PMID: 28096378 [PubMed - indexed for MEDLINE]

The 1H-NMR-based metabolite profile of acute alcohol consumption: A metabolomics intervention study.

Fri, 11/05/2018 - 15:00
The 1H-NMR-based metabolite profile of acute alcohol consumption: A metabolomics intervention study. PLoS One. 2018;13(5):e0196850 Authors: Irwin C, van Reenen M, Mason S, Mienie LJ, Wevers RA, Westerhuis JA, Reinecke CJ Abstract Metabolomics studies of disease conditions related to chronic alcohol consumption provide compelling evidence of several perturbed metabolic pathways underlying the pathophysiology of alcoholism. The objective of the present study was to utilize proton nuclear magnetic resonance (1H-NMR) spectroscopy metabolomics to study the holistic metabolic consequences of acute alcohol consumption in humans. The experimental design was a cross-over intervention study which included a number of substances to be consumed-alcohol, a nicotinamide adenine dinucleotide (NAD) supplement, and a benzoic acid-containing flavoured water vehicle. The experimental subjects-24 healthy, moderate-drinking young men-each provided six hourly-collected urine samples for analysis. Complete data sets were obtained from 20 of the subjects and used for data generation, analysis and interpretation. The results from the NMR approach produced complex spectral data, which could be resolved sufficiently through the application of a combination of univariate and multivariate methods of statistical analysis. The metabolite profiles resulting from acute alcohol consumption indicated that alcohol-induced NAD+ depletion, and the production of an excessive amount of reducing equivalents, greatly perturbed the hepatocyte redox homeostasis, resulting in essentially three major metabolic disturbances-up-regulated lactic acid metabolism, down-regulated purine catabolism and osmoregulation. Of these, the urinary excretion of the osmolyte sorbitol proved to be novel, and suggests hepatocyte swelling due to ethanol influx following acute alcohol consumption. Time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment, thereby also giving methodological significance to this study. The outcomes of this approach have the potential to significantly advance our understanding of the serious impact of the pathophysiological perturbations which arise from the consumption of a single, large dose of alcohol-a simulation of a widespread, and mostly naive, social practice. PMID: 29746531 [PubMed - in process]

Big Data Analytics in Medicine and Healthcare.

Fri, 11/05/2018 - 15:00
Big Data Analytics in Medicine and Healthcare. J Integr Bioinform. 2018 May 10;: Authors: Ristevski B, Chen M Abstract This paper surveys big data with highlighting the big data analytics in medicine and healthcare. Big data characteristics: value, volume, velocity, variety, veracity and variability are described. Big data analytics in medicine and healthcare covers integration and analysis of large amount of complex heterogeneous data such as various - omics data (genomics, epigenomics, transcriptomics, proteomics, metabolomics, interactomics, pharmacogenomics, diseasomics), biomedical data and electronic health records data. We underline the challenging issues about big data privacy and security. Regarding big data characteristics, some directions of using suitable and promising open-source distributed data processing software platform are given. PMID: 29746254 [PubMed - as supplied by publisher]

Molecular insights into the activity and mechanism of cyanide hydratase enzyme associated with cyanide biodegradation by Serratia marcescens.

Fri, 11/05/2018 - 15:00
Related Articles Molecular insights into the activity and mechanism of cyanide hydratase enzyme associated with cyanide biodegradation by Serratia marcescens. Arch Microbiol. 2018 May 09;: Authors: Kushwaha M, Kumar V, Mahajan R, Bhalla TC, Chatterjee S, Akhter Y Abstract The present study provides molecular insights into the activity and mechanism of cyanide hydratase enzyme associated with degradation of cyanide compounds, using Serratia marcescens RL2b as a model organism. Resting cells harvested after 20 h achieved complete degradation of 12 mmol l- 1 cyanide in approximately 10 h. High-performance liquid chromatography analysis of reaction samples revealed formation of formamide as the only end product, which confirmed the presence of cyanide hydratase activity in S. marcescens RL2b. Comparative structural analysis with the other nitrilase family proteins, which was carried out using a sequence of cyanide hydratase from a phylogenetically related strain S. marcescens WW4, also revealed subtle but significant differences in amino acid residues of the substrate-binding pocket and catalytic triad (Cys-Lys-Glu). PMID: 29744557 [PubMed - as supplied by publisher]

Comparative metabolomics and glycolysis enzyme profiling of embryogenic and nonembryogenic grape cells.

Fri, 11/05/2018 - 15:00
Related Articles Comparative metabolomics and glycolysis enzyme profiling of embryogenic and nonembryogenic grape cells. FEBS Open Bio. 2018 May;8(5):784-798 Authors: Parrilla J, Gaillard C, Verbeke J, Maucourt M, Aleksandrov RA, Thibault F, Fleurat-Lessard P, Gibon Y, Rolin D, Atanassova R Abstract A novel biological model was created for the comparison of grapevine embryogenic cells (EC) and nonembryogenic cells (NEC) sharing a common genetic background but distinct phenotypes, when cultured on their respective most appropriate media. Cytological characterization, 1H-NMR analysis of intracellular metabolites, and glycolytic enzyme activities provided evidence for the marked metabolic differences between EC and NEC. The EC were characterized by a moderate and organized cell proliferation, coupled with a low flux through glycolysis, high capacity of phosphoenolpyruvate carboxylase and glucokinase, and high oxygen consumption. The NEC displayed strong anarchic growth, and their high rate of glycolysis due to the low energetic efficiency of the fermentative metabolism is confirmed by increased enolase capacity and low oxygen consumption. PMID: 29744293 [PubMed]

Role of biobanks in transplantation.

Fri, 11/05/2018 - 15:00
Related Articles Role of biobanks in transplantation. Ann Med Surg (Lond). 2018 Apr;28:30-33 Authors: Hanif Z, Sufiyan N, Patel M, Akhtar MZ Abstract The establishment of bio-banks together with high throughput technologies, such as genomics, transcriptomics and proteomics has opened new frontiers in biomarker discovery and the development of systems biology approaches to identifying key pathways that could be exploited to improve outcomes of solid organ transplantation. One of the major challenges in organ donation has been the lack of access to large scale well characterised material to facilitate projects that aim to characterise injury to donor organs and identify biomarkers. This may have hampered research in the field of organ donation by not allowing researchers to materials of high quality and lower pre-analytical variability. We describe in this manuscript the need for bio-banks in organ donation, research opportunities and the particular challenges in establishing such an initiative. PMID: 29744049 [PubMed]

Pharmacokinetics of Chinese medicines: strategies and perspectives.

Fri, 11/05/2018 - 15:00
Related Articles Pharmacokinetics of Chinese medicines: strategies and perspectives. Chin Med. 2018;13:24 Authors: Yan R, Yang Y, Chen Y Abstract The modernization and internationalization of Chinese medicines (CMs) are hampered by increasing concerns on the safety and the efficacy. Pharmacokinetic (PK) study is indispensable to establish concentration-activity/toxicity relationship and facilitate target identification and new drug discovery from CMs. To cope with tremendous challenges rooted from chemical complexity of CMs, the classic PK strategies have evolved rapidly from PK study focusing on marker/main drug components to PK-PD correlation study adopting metabolomics approaches to characterize associations between disposition of global drug-related components and host metabolic network shifts. However, the majority of PK studies of CMs have adopted the approaches tailored for western medicines and focused on the systemic exposures of drug-related components, most of which were found to be too low to account for the holistic benefits of CMs. With an area under concentration-time curve- or activity-weighted approach, integral PK attempts to understand the PK-PD relevance with the integrated PK profile of multiple co-existing structural analogs (prototyes/metabolites). Cellular PK-PD complements traditional PK-PD when drug targets localize inside the cells, instead of at the surface of cell membrane or extracellular space. Considering the validated clinical benefits of CMs, reverse pharmacology-based reverse PK strategy was proposed to facilitate target identification and new drug discovery. Recently, gut microbiota have demonstrated multifaceted roles in drug efficacy/toxicity. In traditional oral intake, the presystemic interactions of CMs with gut microbiota seem inevitable, which can contribute to the holistic benefits of CMs through biotransforming CMs components, acting as the peripheral target, and regulating host drug disposition. Hence, we propose a global PK-PD approach which includes the presystemic interaction of CMs with gut microbiota and combines omics with physiologically based pharmacokinetic modeling to offer a comprehensive understanding of the PK-PD relationship of CMs. Moreover, validated clinical benefits of CMs and poor translational potential of animal PK data urge more research efforts in human PK study. PMID: 29743935 [PubMed]

Metabolic fingerprinting of joint tissue of collagen-induced arthritis (CIA) rat: In vitro, high resolution NMR (nuclear magnetic resonance) spectroscopy based analysis.

Fri, 11/05/2018 - 15:00
Related Articles Metabolic fingerprinting of joint tissue of collagen-induced arthritis (CIA) rat: In vitro, high resolution NMR (nuclear magnetic resonance) spectroscopy based analysis. EXCLI J. 2018;17:257-272 Authors: Srivastava NK, Sharma S, Sharma R, Sinha N, Mandal SK, Sharma D Abstract Rheumatoid arthritis (RA) is a systemic autoimmune disease whose major characteristics persistent joint inflammation that results in joint destruction and failure of the function. Collagen-induced arthritis (CIA) rat is an autoimmune disease model and in many ways shares features with RA. The CIA is associated with systemic manifestations, including alterations in the metabolism. Nuclear magnetic resonance (NMR) spectroscopy-based metabolomics has been successfully applied to the perchloric acid extract of the joint tissue of CIA rat and control rat for the analysis of aqueous metabolites. GPC (Glycerophosphocholine), carnitine, acetate, and creatinine were important discriminators of CIA rats as compared to control rats. Level of lactate (significance; p = 0.004), alanine (p = 0.025), BCA (Branched-chain amino acids) (p = 0.006) and creatinine (p = 0.023) was significantly higher in CIA rats as compared to control rats. Choline (p = 0.038) and GPC (p = 0.009) were significantly reduced in CIA rats as compared to control rats. Choline to GPC correlation was good and negative (Pearson correlation = -0.63) for CIA rats as well as for control rats (Pearson correlation = -0.79). All these analyses collectively considered as metabolic fingerprinting of the joint tissue of CIA rat as compared to control rat. The metabolic fingerprinting of joint tissue of CIA rats was different as compared to control rats. The metabolic fingerprinting reflects inflammatory disease activity in CIA rats with synovitis, demonstrating that underlying inflammatory process drives significant changes in metabolism that can be measured in the joint tissue. Therefore, the outcome of this study may be helpful for understanding the mechanism of metabolic processes in RA. This may be also helpful for the development of advanced diagnostic methods and therapy for RA. PMID: 29743863 [PubMed]

NMR-Based Plasma Metabolomics at Set Intervals in Newborn Dairy Calves with Severe Sepsis.

Fri, 11/05/2018 - 15:00
Related Articles NMR-Based Plasma Metabolomics at Set Intervals in Newborn Dairy Calves with Severe Sepsis. Mediators Inflamm. 2018;2018:8016510 Authors: Basoglu A, Sen I, Meoni G, Tenori L, Naseri A Abstract The aim of this first study was to reveal the new potential biomarkers by a metabolomics approach in severe septic calves. Sepsis is a common cause of morbidity and mortality in newborn dairy calves. The main challenges with the use of biomarkers of sepsis in domestic animals are their availability, cost, and time required to obtain a result. Metabolomics may offer the potential to identify biomarkers that define calf sepsis in terms of combined clinical, physiological, and pathobiological abnormalities. To our knowledge, this is the first study presenting an NMR- (nuclear magnetic resonance-) based plasma metabolomics at set intervals in neonatal septic calves. Twenty neonatal dairy calves with severe sepsis and ten healthy calves were used. Hematological and biochemical health profiles were gathered in plasma samples at set intervals. Similarly, NMR spectra were acquired. All diseased animals (except one) died after 72 hours. Clinical and laboratory results were in accordance with those of severe septic animals. Multivariate analysis on NMR plasma spectra proved to be an excellent tool for faster identification of calves with severe sepsis from healthy animals. The NMR-based metabolomic profile may contribute to the better understanding of severe sepsis in newborn calves. PMID: 29743812 [PubMed - in process]

Untargeted metabolomic on urine samples after α-lipoic acid and/or eicosapentaenoic acid supplementation in healthy overweight/obese women.

Fri, 11/05/2018 - 15:00
Related Articles Untargeted metabolomic on urine samples after α-lipoic acid and/or eicosapentaenoic acid supplementation in healthy overweight/obese women. Lipids Health Dis. 2018 May 09;17(1):103 Authors: Romo-Hualde A, Huerta AE, González-Navarro CJ, Ramos-López O, Moreno-Aliaga MJ, Martínez JA Abstract BACKGROUND: Eicosapentaenoic acid (EPA) and α-lipoic acid (α-LA) have been investigated for their beneficial effects on obesity and cardiovascular risk factors. In the current research, the goal was to evaluate metabolomic changes following the dietary supplementation of these two lipids, alone or combined in healthy overweight/obese sedentary women following an energy-restricted diet. For this purpose, an untargeted metabolomics approach was conducted on urine samples using liquid chromatography coupled with time of flight mass spectrometry (HPLC-TOF-MS). METHODS: This is a short-term double blind placebo-controlled study with a parallel nutritional design that lasted 10 weeks. Participants were assigned to one of the 4 experimental groups [Control, EPA (1.3 g/d), α-LA (0.3 g/d) and EPA+α-LA (1.3 g/d + 0.3 g/d)]. All intervention groups followed an energy-restricted diet of 30% less than total energy expenditure. Clinically relevant biochemical measurements were analyzed. Urine samples (24 h) were collected at baseline and after 10 weeks. Untargeted metabolomic analysis on urine samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were performed for the pattern recognition and characteristic metabolites identification. RESULTS: Urine samples were scattered in the PCA scores plots in response to the supplementation with α-LA. Totally, 28 putative discriminant metabolites in positive ionization, and 6 in negative ionization were identified among groups clearly differentiated according to the α-LA administration. Remarkably is the presence of an ascorbate intermediate metabolite (one of the isomers of trihydroxy-dioxohexanoate, or dihydroxy-oxohexanedionate) in the groups supplemented with α-LA. This fact might be associated with antioxidant properties of both α-LA and ascorbic acid. Correlations between phenotypical parameters and putative metabolites of provided additional information on whether there is a direct or inverse relationship between them. Especially interesting are the negative correlation between ascorbate intermediate metabolite and asymmetric dimethylarginine (ADMA) and the positive one between superoxide dismutase (SOD) and α-LA supplementation. CONCLUSIONS: This metabolomic approach supports that the beneficial effects of α-LA administration on body weight reduction may be partly explained by the antioxidant properties of this organosulfur carboxylic acid mediated by isomers of trihydroxy-dioxohexanoate, or dihydroxy-oxohexanedionate. TRIAL REGISTRATION: Clinicaltrials.gov NCT01138774 . PMID: 29743087 [PubMed - in process]

Barrett's oesophagus: Current controversies.

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Related Articles Barrett's oesophagus: Current controversies. World J Gastroenterol. 2017 Jul 28;23(28):5051-5067 Authors: Amadi C, Gatenby P Abstract Oesophageal adenocarcinoma is rapidly increasing in Western countries. This tumour frequently presents late in its course with metastatic disease and has a very poor prognosis. Barrett's oesophagus is an acquired condition whereby the native squamous mucosa of the lower oesophagus is replaced by columnar epithelium following prolonged gastro-oesophageal reflux and is the recognised precursor lesion for oesophageal adenocarcinoma. There are multiple national and society guidelines regarding screening, surveillance and management of Barrett's oesophagus, however all are limited regarding a clear evidence base for a well-demonstrated benefit and cost-effectiveness of surveillance, and robust risk stratification for patients to best use resources. Currently the accepted risk factors upon which surveillance intervals and interventions are based are Barrett's segment length and histological interpretation of the systematic biopsies. Further patient risk factors including other demographic features, smoking, gender, obesity, ethnicity, patient age, biomarkers and endoscopic adjuncts remain under consideration and are discussed in full. Recent evidence has been published to support earlier endoscopic intervention by means of ablation of the metaplastic Barrett's segment when the earliest signs of dysplasia are detected. Further work should concentrate on establishing better risk stratification and primary and secondary preventative strategies to reduce the risk of adenocarcinoma of the oesophagus. PMID: 28811703 [PubMed - indexed for MEDLINE]

Cardioprotective effects and mechanism of Radix Salviae miltiorrhizae and Lignum Dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury.

Fri, 11/05/2018 - 15:00
Related Articles Cardioprotective effects and mechanism of Radix Salviae miltiorrhizae and Lignum Dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury. Mol Med Rep. 2017 Aug;16(2):1759-1770 Authors: Mu F, Duan J, Bian H, Yin Y, Zhu Y, Wei G, Guan Y, Wang Y, Guo C, Wen A, Yang Y, Xi M Abstract Radix Salviae miltiorrhizae (SM) and Lignum Dalbergiae odoriferae (DO) are traditional Chinese medicinal herbs used to treat ischemic heart disease and other cardiovascular diseases; however, to the best of our knowledge, there are currently few studies regarding their effects. The present study aimed to investigate the cardioprotective effects of SM and DO during myocardial ischemia/reperfusion (MI/R) injury in rats, and explore the molecular mechanisms that underlie their actions. In the present study, Sprague‑Dawley rats were pretreated with SM, the aqueous extract of DO (DOA) and the volatile oil of DO (DOO), either as a monotherapy or in combination for 7 days. Subsequently, the rats were subjected to 30 min of ischemia followed by 180 min of reperfusion. Traditional pharmacodynamic evaluation and metabonomics based on gas chromatography/time‑of‑flight mass spectrometry were used to identify the therapeutic effects of these traditional Chinese medicines. The results revealed that SM, DOA and DOO monotherapies ameliorated cardiac function, and this effect was strengthened further when used in combined therapies. Among the combined treatments, SM + DOO exhibited the greatest potential (P<0.05) to improve electrocardiogram results and heart rate, reduce the heart weight index and myocardial infarct size, and decrease the levels of creatine kinase‑MB and lactate dehydrogenase. In addition, metabonomics‑based findings, including the principal component analysis and partial least squares discriminant analysis score plot of the metabolic state in rat serum, provided confirmation for the aforementioned results, verifying that SM + DOO exerted synergistic therapeutic efficacies to exhibit a greater effect on rats with MI/R injury when compared with the other pretreatment groups. Furthermore, the most effective duration of SM + DOO treatment was 30 min and the least effective duration was 180 min. Treatment with SM + DOO also significantly (P<0.01) reduced the number of terminal deoxynucleotidyl transferase‑mediated dUTP nick end‑labeling‑positive cells, tumor necrosis factor‑α andinterleukin‑6 expression, and malondialdehyde content, and increased the serum and tissue activity of superoxide dismutase. These results indicated that the combined effects of SM + DOO may be more effective compared with the single pretreatments against MI/R injury in rats. This effect may be achieved partly through anti‑apoptotic, antioxidant and anti‑inflammatory activities. Therefore, SM + DOO may be considered an effective and promising novel strategy for the prophylaxis and treatment of ischemic heart disease. PMID: 28656200 [PubMed - indexed for MEDLINE]

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