A metabolomic and multivariate statistical process to assess the effects of genotoxins in Saccharomycescerevisiae

Titman, Christopher M.; Downs, Jessica A.; Oliver, Stephen G.; Carmichael, Paul L.; Scott, Andrew D.; Griffin, Julian L.

doi:10.1039/b907754e

Cited by 9 publications

(3 citation statements)

References 27 publications

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“…R 2 is the fraction of variance explained by a component and Q 2 describes the total fraction predicted by a component. A Q 2 value > 0.4 characterizes a model as good and Q 2 > 0.7 characterizes the model as robust [23]. A correlation map was used to detect compounds with a positive correlation to the EC 90 .…”

Section: Methodsmentioning

confidence: 99%

Discovery of potential ovicidal natural products using metabolomics

et al. 2019

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Plant extracts are a potential source of new compounds for nematode control and may be an excellent alternative for the control gastrointestinal nematodes that are resistant to conventional anthelmintics. However, research involving natural products is a complex process. The main challenge is the identification of bioactive compounds. Online analytical techniques with universal detectors, such as high-performance liquid chromatography-mass spectrometry (HPLC-MS), together with metabolomics could enable the fast, accurate evaluation of a massive amount of data, constituting a viable option for the identification of active compounds in plant extracts. This study focused on the evaluation of the ovicidal activity of ethanol extracts from 17 plants collected from the Pantanal wetland in the state of Mato Grosso do Sul, Brazil, against eggs of Haemonchus placei using the egg hatchability test. The ethanol extracts were obtained using accelerated solvent extraction. The data on ovicidal activity, mass spectrometry and metabolomics were evaluated using HPLC-DAD-MS, partial least squares regression analysis (PLS-DA) and a correlation map (univariate correlation analyses) to detect compounds that have a positive correlation with biological activity. Among the ten metabolites with the best correlation coefficients, six were phenylpropanoids, two were triterpene saponins, one was a brevipolide, and one was a flavonoid. Combinations of metabolites with high ovicidal action were also identified, such as phenylpropanoids combined with the triterpene saponins and the flavonoid, flavonoids combined with iridoid and phenylpropanoids, and saponins combined with phenylpropanoid. The positive correlation between classes of compounds in plants belonging to different genera and biological activity (as previously identified in the literature) reinforces the robustness of the statistical data and demonstrates the efficacy of this method for the selection of bioactive compounds without the need for isolation and reevaluation. The proposed method also enables the determination of synergism among the classes, which would be impracticable using traditional methods. The present investigation demonstrates that the metabolomic technique was efficient at detecting secondary metabolites with ovicidal activity against H. placei. Thus, the use of metabolomics can be a tool to accelerate and simplify bioprospecting research with plant extracts in veterinary parasitology.

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Section: Methodsmentioning

confidence: 99%

Discovery of potential ovicidal natural products using metabolomics

et al. 2019

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“…The VIP (variable importance in the projection) values and regression coefficients were calculated to identify the most important molecular variables for the clustering of specific groups. The PLS-DA model was validated by comparison to the classification statistics of models generated after random permutations of the class matrix [82], [83].…”

Section: Methodsmentioning

confidence: 99%

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

et al. 2012

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BackgroundThe identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.Methods and FindingsWe characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.ConclusionsMutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD.

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“…the ability to predict correctly new data. The value of Q 2 ranges from 0 to 1 and typically a Q 2 value of greater than 0.4 is considered as a good model, and those with Q 2 values over 0.7 are robust (Titman et al 2009). In our case, the Q 2 and R 2 were higher than 0.88 in both discrimination.…”

Section: Methodsmentioning

confidence: 99%

Rearrangement of energetic and substrate utilization networks compensate for chronic myocardial creatine kinase deficiency

Dzeja

Hoyer

Tian

et al. 2011

The Journal of Physiology

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Non-technical summary Continuous and vigorous heart work is powered by the energetic grid consisting of mitochondria, miniature ATP-generating fuel cells, and molecular connecting circuits transferring and distributing high-energy phosphoryls. The creatine kinase (CK) phosphotransfer circuit is the major component of the energetic network, coupling mitochondria with ATP utilization sites, and CK deficiency is a hallmark of cardiovascular diseases. Identification of mechanisms that compensate for reduced CK function would foster approaches leading to recovery and repair of injured hearts. Here, using advanced stable isotope metabolic technologies, we demonstrate that genetic CK deficiency induces a shift in heart energy distribution and substrate utilization networks by redirecting phosphotransfer flux through alternative adenylate kinase, glycolytic and guanine nucleotide systems. Such energetic re-wiring, together with increased mitochondrial and glycolytic capacities, defines an adaptive metabolomic phenotype of CK deficiency. These findings advance our understanding of cellular energetic infrastructure and provide new perspectives for regulation of energy distribution in disease states.Abstract Plasticity of the cellular bioenergetic system is fundamental to every organ function, stress adaptation and disease tolerance. Here, remodelling of phosphotransfer and substrate utilization networks in response to chronic creatine kinase (CK) deficiency, a hallmark of cardiovascular disease, has been revealed in transgenic mouse models lacking either cytosolic M-CK (M-CK −/− ) or both M-CK and sarcomeric mitochondrial CK (M-CK/ScCKmit −/− ) isoforms. The dynamic metabolomic signatures of these adaptations have also been defined. Tracking perturbations in metabolic dynamics with 18 O and 13 C isotopes and 31 P NMR and mass spectrometry demonstrate that hearts lacking M-CK have lower phosphocreatine (PCr) turnover but increased glucose-6-phosphate (G-6-P) turnover, glucose utilization and inorganic phosphate compartmentation with normal ATP γ-phosphoryl dynamics. Hearts lacking both M-CK and sarcomeric mitochondrial CK have diminished PCr turnover, total phosphotransfer capacity and intracellular energetic communication but increased dynamics of β-phosphoryls of ADP/ATP, G-6-P and γ-/β-phosphoryls of GTP, indicating redistribution of flux through adenylate kinase (AK), glycolytic and guanine nucleotide phosphotransfer circuits. Higher glycolytic and mitochondrial capacities and increased glucose tolerance contributed to metabolic resilience of M-CK/ScCKmit enzyme-catalysed phosphotransfer networks in supporting the adaptivity and robustness of the cellular energetic system. Abbreviations AK, adenylate kinase; BB-CK, brain-type creatine kinase; CK, creatine kinase; 2-DG, 2-deoxyglucose; 2-DG-6-P, 2-deoxyglucose-6-phosphate; GC-MS, gas chromatography-mass spectroscopy; G ATP , free energy of ATP hydrolysis; G-6-P, glucose-6-phosphate; IPGTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test; M-CK, cytoso...

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A metabolomic and multivariate statistical process to assess the effects of genotoxins in Saccharomycescerevisiae

Cited by 9 publications

References 27 publications

Discovery of potential ovicidal natural products using metabolomics

Discovery of potential ovicidal natural products using metabolomics

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

Rearrangement of energetic and substrate utilization networks compensate for chronic myocardial creatine kinase deficiency

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