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Related Articles UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. FASEB J. 2015 Mar 5; Authors: Wanders D, Burk DH, Cortez CC, Van NT, Stone KP, Baker M, Mendoza T, Mynatt RL, Gettys TW Abstract Dietary methionine restriction (MR) by 80% increases energy expenditure (EE), reduces adiposity, and improves insulin sensitivity. We propose that the MR-induced increase in EE limits fat deposition by increasing sympathetic nervous system-dependent remodeling of white adipose tissue and increasing uncoupling protein 1 (UCP1) expression in both white and brown adipose tissue. In independent assessments of the role of UCP1 as a mediator of MR's effects on EE and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1(-/-) mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25% in WT mice. In contrast, MR failed to increase EE or reduce adiposity in Ucp1(-/-) mice. However, MR was able to increase overall insulin sensitivity by 2.2-fold in both genotypes. Housing temperatures used to minimize (28°C) or increase (23°C) sympathetic nervous system activity revealed temperature-independent effects of the diet on EE. Metabolomics analysis showed that genotypic and dietary effects on white adipose tissue remodeling resulted in profound increases in fatty acid metabolism within this tissue. These findings establish that UCP1 is required for the MR-induced increase in EE but not insulin sensitivity and suggest that diet-induced improvements in insulin sensitivity are not strictly derived from dietary effects on energy balance.-Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., Mendoza, T., Mynatt, R. L., Gettys, T. W. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. PMID: 25742717 [PubMed - as supplied by publisher]

Related Articles The Human Toxome Project. ALTEX. 2015 Mar 4; Authors: Bouhifd M, Andersen ME, Baghdikian C, Boekelheide K, Crofton KM, Fornace Jr AJ, Kleensang A, Li H, Livi C, Maertens A, McMullen PD, Rosenberg M, Thomas R, Vantangoli M, Yager JD, Zhao L, Hartung T Abstract The Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectroscopy-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies. PMID: 25742299 [PubMed - as supplied by publisher]

Related Articles Health effects from swimming training in chlorinated pools and the corresponding metabolic stress pathways. PLoS One. 2015;10(3):e0119241 Authors: Li JH, Wang ZH, Zhu XJ, Deng ZH, Cai CX, Qiu LQ, Chen W, Lin YJ Abstract Chlorination is the most popular method for disinfecting swimming pool water; however, although pathogens are being killed, many toxic compounds, called disinfection by-products (DBPs), are formed. Numerous epidemiological publications have associated the chlorination of pools with dysfunctions of the respiratory system and with some other diseases. However, the findings concerning these associations are not always consistent and have not been confirmed by toxicological studies. Therefore, the health effects from swimming in chlorinated pools and the corresponding stress reactions in organisms are unclear. In this study, we show that although the growth and behaviors of experimental rats were not affected, their health, training effects and metabolic profiles were significantly affected by a 12-week swimming training program in chlorinated water identical to that of public pools. Interestingly, the eyes and skin are the organs that are more directly affected than the lungs by the irritants in chlorinated water; instead of chlorination, training intensity, training frequency and choking on water may be the primary factors for lung damage induced by swimming. Among the five major organs (the heart, liver, spleen, lungs and kidneys), the liver is the most likely target of DBPs. Through metabolomics analysis, the corresponding metabolic stress pathways and a defensive system focusing on taurine were presented, based on which the corresponding countermeasures can be developed for swimming athletes and for others who spend a lot of time in chlorinated swimming pools. PMID: 25742134 [PubMed - in process]

Related Articles The role of metabolomics in osteoarthritis for early diagnosis, monitoring prognosis and treatment. Eklem Hastalik Cerrahisi. 2015 Apr;26(1):1 Authors: Atik OŞ PMID: 25741911 [PubMed - in process]

Related Articles Phospholipase D affects translocation of NPR1 to the nucleus in Arabidopsis thaliana. Front Plant Sci. 2015;6:59 Authors: Janda M, Šašek V, Chmelařová H, Andrejch J, Nováková M, Hajšlová J, Burketová L, Valentová O Abstract Phytohormone salicylic acid (SA) is a crucial component of plant-induced defense against biotrophic pathogens. Although the key players of the SA pathway are known, there are still gaps in the understanding of the molecular mechanism and the regulation of particular steps. In our previous research, we showed in Arabidopsis suspension cells that n-butanol, which specifically modulates phospholipase D activity, significantly suppresses the transcription of the pathogenesis related (PR-1) gene, which is generally accepted as the SA pathway marker. In the presented study, we have investigated the site of n-butanol action in the SA pathway. We were able to show in Arabidopsis plants treated with SA that n-butanol inhibits the transcription of defense genes (PR-1, WRKY38). Fluorescence microscopy of Arabidopsis thaliana mutants expressing 35S::NPR1-GFP (nonexpressor pathogenesis related 1) revealed significantly decreased nuclear localization of NPR1 in the presence of n-butanol. On the other hand, n-butanol did not decrease the nuclear localization of NPR1 in 35S::npr1C82A-GFP and 35S::npr1C216A-GFP mutants constitutively expressing NPR1 monomers. Mass spectrometric analysis of plant extracts showed that n-butanol significantly changes the metabolic fingerprinting while t-butanol had no effect. We found groups of the plant metabolites, influenced differently by SA and n-butanol treatment. Thus, we proposed several metabolites as markers for n-butanol action. PMID: 25741350 [PubMed]

Related Articles Integration of metabolomics data into metabolic networks. Front Plant Sci. 2015;6:49 Authors: Töpfer N, Kleessen S, Nikoloski Z Abstract Metabolite levels together with their corresponding metabolic fluxes are integrative outcomes of biochemical transformations and regulatory processes and they can be used to characterize the response of biological systems to genetic and/or environmental changes. However, while changes in transcript or to some extent protein levels can usually be traced back to one or several responsible genes, changes in fluxes and particularly changes in metabolite levels do not follow such rationale and are often the outcome of complex interactions of several components. The increasing quality and coverage of metabolomics technologies have fostered the development of computational approaches for integrating metabolic read-outs with large-scale models to predict the physiological state of a system. Constraint-based approaches, relying on the stoichiometry of the considered reactions, provide a modeling framework amenable to analyses of large-scale systems and to the integration of high-throughput data. Here we review the existing approaches that integrate metabolomics data in variants of constrained-based approaches to refine model reconstructions, to constrain flux predictions in metabolic models, and to relate network structural properties to metabolite levels. Finally, we discuss the challenges and perspectives in the developments of constraint-based modeling approaches driven by metabolomics data. PMID: 25741348 [PubMed]

Related Articles The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. Front Microbiol. 2015;6:71 Authors: Nielsen KF, Larsen TO Abstract Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous fungi is much larger than was thought even a decade ago. Fungi harbor many cryptic gene clusters encoding for the biosynthesis of polyketides, non-ribosomal peptides, and terpenoids - which can all undergo extensive modifications by tailoring enzymes - thus potentially providing a large array of products from a single pathway. Elucidating the full chemical profile of a fungal species is a challenging exercise, even with elemental composition provided by high-resolution mass spectrometry (HRMS) used in combination with chemical databases (e.g., AntiBase) to dereplicate known compounds. This has led to a continuous effort to improve chromatographic separation in conjunction with improvement in HRMS detection. Major improvements have also occurred with 2D chromatography, ion-mobility, MS/MS and MS(3), stable isotope labeling feeding experiments, classic UV/Vis, and especially automated data-mining and metabolomics software approaches as the sheer amount of data generated is now the major challenge. This review will focus on the development and implementation of dereplication strategies and will highlight the importance of each stage of the process from sample preparation to chromatographic separation and finally toward both manual and more targeted methods for automated dereplication of fungal natural products using state-of-the art MS instrumentation. PMID: 25741325 [PubMed]

Related Articles Molecular toxicity of cerium oxide nanoparticles to the freshwater alga Chlamydomonas reinhardtii is associated with supra-environmental exposure concentrations. Nanotoxicology. 2015 Mar 5;:1-10 Authors: Taylor NS, Merrifield R, Williams TD, Chipman JK, Lead JR, Viant MR Abstract Abstract Ceria nanoparticles (NPs) are widely used as fuel catalysts and consequently are likely to enter the environment. Their potential impacts on. biota at environmentally relevant concentrations, including uptake and toxicity, remain to be elucidated and quantitative data on which to assess risk are sparse. Therefore, a definitive assessment of the molecular and phenotypic effects of ceria NPs was undertaken, using well-characterised mono-dispersed NPs as their toxicity is likely to be higher, enabling a conservative hazard assessment. Unbiased transcriptomics and metabolomics approaches were used to investigate the potential toxicity of tightly constrained 4-5 nm ceria NPs to the unicellular green alga, Chlamydomonas reinhardtii, a sentinel freshwater species. A wide range of exposure concentrations were investigated from predicted environmental levels, to support hazard assessment, to supra-environmental levels to provide insight into molecular toxicity pathways. Ceria NPs were internalised into intracellular vesicles within C. reinhardtii, yet caused no significant effect on algal growth at any exposure concentration. Molecular perturbations were only detected at supra-environmental ceria NP-concentrations, primarily down-regulation of photosynthesis and carbon fixation with associated effects on energy metabolism. For acute exposures to small mono-dispersed particles, it can be concluded there should be little concern regarding their dispersal into the environment for this trophic level. PMID: 25740379 [PubMed - as supplied by publisher]

Related Articles Cyclic Fatty Acids Found in Frying Oils are Detoxified via Classical Drug Metabolic Pathway but also by β-Oxidation and Eliminated as Conjugates in Rats. Lipids. 2015 Mar 5; Authors: Desmarais A, Pujos-Guillot E, Lyan B, Martin JF, Leblanc N, Angers P, Sébédio JL Abstract Cyclic fatty acid monomers (CFAM) are mainly formed during heat treatments, such as frying, of edible oils. These fatty acids are mixtures of disubstituted five- or six-carbon-membered ring structures. Some earlier studies have suggested that some of these molecules could be metabolized and detoxified, but so far, neither the detoxification mechanisms nor the metabolite identifications have been elucidated. The objective of the present study was to identify the metabolites resulting from the metabolism and detoxification of CFAM. A deuterium-labeled CFAM, [9-(2)H]-10-(6-propyl-2-cyclohexenyl)-dodecenoic acid, was synthesized and fed to rats for 3 days, along with a standard chow diet while the control group was fed the same chow diet which did not contain any CFAM. Biological fluids (urine, blood) were collected for both groups of rats and analyzed using an untargeted metabolomic approach by ultra-performance liquid chromatography coupled with mass spectrometry. Two discriminant metabolites and 18 molecules derived from CFAM were identified or tentatively identified in plasma and urine samples, respectively. The structures of the metabolites suggest that CFAM having a six-carbon-membered ring could be detoxified by the classical drug metabolic pathway (phase I and phase II reactions), but our study also indicates that these are substrates for the β-oxidation pathway and eliminated as glucuronide, sulphate, and/or nitrate conjugates. Urine metabolomics investigations without diet effects have indicated a higher excretion of medium-chain acylcarnitines in the D-CFAM diet group, which may indicate an incomplete β-oxidation. PMID: 25739730 [PubMed - as supplied by publisher]

Related Articles Mass spectrometry-based metabolomics: applications to biomarker and metabolic pathway research. Biomed Chromatogr. 2015 Mar 4; Authors: Zhang A, Sun H, Yan G, Wang P, Wang X Abstract Mass spectrometry-based metabolomics has become increasingly popular in molecular medicine. High-definition mass spectrometry (MS), coupled with pattern recognition methods, have been carried out to obtain comprehensive metabolite profiling and metabolic pathway of large biological datasets. This sets the scene for a new and powerful diagnostic approach. Analysis of the key metabolites in body fluids has become an important part of improving disease diagnosis. With technological advances in analytical techniques, the ability to measure low-molecular-weight metabolites in bio-samples provides a powerful platform for identifying metabolites that are uniquely correlated with a specific human disease. MS-based metabolomics can lead to enhanced understanding of disease mechanisms and to new diagnostic markers and has a strong potential to contribute to improving early diagnosis of diseases. This review will highlight the importance and benefit with certain characteristic examples of MS-metabolomics for identifying metabolic pathways and metabolites that accurately screen for potential diagnostic biomarkers of diseases. Copyright © 2015 John Wiley & Sons, Ltd. PMID: 25739660 [PubMed - as supplied by publisher]

Related Articles [Hydrophilic interaction liquid chromatography coupled with mass spectrometry for metabolomic analysis of Escherichia coli]. Se Pu. 2014 Oct;32(10):1084-93 Authors: Wang X, Gao P, Xu G Abstract The zwitterionic hydrophilic interaction liquid chromatography coupled with mass spectrometry (ZIC-HILIC/MS) method was developed and applied for studying the metabolome of Escherichia coli. In this method, the linear ranges of the 52 representative compounds were between 2-6 orders of magnitude. Moreover the lowest limits of detection of most compounds were at ng/mL levels. The analysis for six samples prepared in parallel showed that the method had good reproducibility with more than 85% metabolites with the RSDs of peak area less than 30%. The precision of the method was tested by evaluating the relative recoveries of six internal standards at the low, middle and high concentrations. The results exhibited that the intraday precisions (RSDs) of the six compounds in the same concentrations were less than 20%. The recoveries of most compounds were accepted in the range of 70%-130%. The results of metabolomic analysis of three Escherichia coli strains with genetic modified yfcC gene showed that some small peptides, amino acids, nucleosides, organic acids and phospholipids changed differentially after the yfcC gene modification. These results indicated that the ZIC-HILIC/MS method could detect diverse metabolites and be used for metabolomic analysis purpose with good reproducibility and stability. PMID: 25739269 [PubMed - in process]

Related Articles [Advances of metabolite identification in liquid chromatography-mass spectrometry based metabolomics]. Se Pu. 2014 Oct;32(10):1052-7 Authors: Kong H, Dai W, Xu G Abstract Liquid chromatography-mass spectrometry (LC-MS) based metabolomics has become an important approach in life science research due to its powerful separation and high sensitivity detection. However, because of the lack of an effective mass spectra library for metabolite identification, a vast amount of detected metabolites are unable to be identified. The improvement of the metabolite coverage and the discovery of biomarkers are harmed, leading to the severe loss of chemical and biological information. The metabolite identification has become a major bottleneck in metabolomics studies. This review describes recent advances of metabolite identification based on atmospheric pressure ionization (API)-MS data. In particular, it focuses on the advances in mass spectrometer instruments, assignment of elemental compositions, database and spectral search, computer-aided spectral interpretation, etc. PMID: 25739265 [PubMed - in process]

Related Articles Intake of Hydrolyzed Casein is Associated with Reduced Body Fat Accretion and Enhanced Phase II Metabolism in Obesity Prone C57BL/6J Mice. PLoS One. 2015;10(3):e0118895 Authors: Clausen MR, Zhang X, Yde CC, Ditlev DB, Lillefosse HH, Madsen L, Kristiansen K, Liaset B, Bertram HC Abstract The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets. PMID: 25738501 [PubMed - in process]

Related Articles Preprocessing of NMR metabolomics data. Scand J Clin Lab Invest. 2015 May;75(3):193-203 Authors: Euceda LR, Giskeødegård GF, Bathen TF Abstract Abstract Metabolomics involves the large scale analysis of metabolites and thus, provides information regarding cellular processes in a biological sample. Independently of the analytical technique used, a vast amount of data is always acquired when carrying out metabolomics studies; this results in complex datasets with large amounts of variables. This type of data requires multivariate statistical analysis for its proper biological interpretation. Prior to multivariate analysis, preprocessing of the data must be carried out to remove unwanted variation such as instrumental or experimental artifacts. This review aims to outline the steps in the preprocessing of NMR metabolomics data and describe some of the methods to perform these. Since using different preprocessing methods may produce different results, it is important that an appropriate pipeline exists for the selection of the optimal combination of methods in the preprocessing workflow. PMID: 25738209 [PubMed - in process]

2004 Oct 22 [updated 2024 Feb 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024.ABSTRACTCLINICAL CHARACTERISTICS: Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, swallow and phonation disorders, sleep disorders including apnea, migraine, entrapment and peripheral neuropathies, inflammation from mast cell activation disorders, anxiety disorders, and urogynecologic disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications.DIAGNOSIS/TESTING: The diagnosis of hEDS is established in an adult proband based on 2017 international clinical diagnostic criteria. Currently, no underlying genetic, epigenetic, or metabolomic etiology has been identified for hEDS.MANAGEMENT: Treatment of manifestations: Tailored treatment with exercise to increase core and extremity muscle strength and tone, proprioception, and joint stability; braces and splints to improve alignment and control; occupational therapy for assistive devices (e.g., wide-grip writing utensils, home and work ergonomics); physical therapy for assistive devices (e.g., wheelchair or scooter, suitable mattress, soft neck collar); pain management tailored to cause and symptoms; platelet disorders may respond to tranexamic or mefenamic acid; nutrition advice for micronutrient deficiencies; gastritis, gastroparesis, and gastroesophageal reflux disease may require intensive pharmacotherapy; therapies for other gastrointestinal, cardiovascular, ocular, neurologic, and urogynecologic manifestations; orthodontic, maxillofacial, and ENT management for narrow palate, crowded teeth, temporomandibular joint laxity and dysfunction, and disorders of swallow and phonation; standard treatment of periodontal disease; avoidance of triggers for mast cell activation disorder and pharmacotherapy or monoclonal biologic therapy as needed; counseling and pharmacotherapy for neurobehavioral and psychiatric manifestations.Surveillance: Assess for joint manifestations, pain, disability, bleeding issues, functional bowel disorders, autonomic dysfunction, oral health needs, phonation and respiratory issues, sleep issues, vision issues, headaches and other neurologic manifestations, inflammatory disease, neurobehavioral and psychiatric manifestations, and urogynecologic manifestations annually or at each visit. Dual-energy x-ray absorptiometry in those with height loss greater than one inch, atypical/low trauma fractures, or radiographs suggestive of osteopenia. Follow-up echocardiography in those with aortic root dilatation.Agents/circumstances to avoid: High-impact activity may increase the risk of acute subluxation/dislocation and acute and chronic pain. Chiropractic adjustment and yoga are not contraindicated but like all other physical treatments must be performed in ways that avoid iatrogenic subluxations or dislocations. Autonomic concerns, gastrointestinal disorders, and intolerances may preclude use of medications or their excipients (e.g., common analgesics in someone with slow gastrointestinal transit, vasodilator in a person with orthostatic intolerance).Pregnancy management: Preconceptual (e.g., musculoskeletal health and medication use), antenatal (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum (e.g., birth choices, mobility in labor, anesthesia), and postpartum (e.g., wound healing, pelvic health, newborn/infant care) issues should all be addressed.GENETIC COUNSELING: Hypermobile EDS is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members. Most individuals diagnosed with hEDS have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin manifestations despite the absence of serious complications. Each child of an individual with hEDS has a 50% chance of inheriting hEDS. Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible.PMID:20301456 | Bookshelf:NBK1279