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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Article
  • Peer Reviewed
UC Davis Previously Published Works (2006)

Background: Metabolomic studies are targeted at identifying and

quantifying all metabolites in a given biological context. Among the tools used

for metabolomic research, mass spectrometry is one of the most powerful tools.

However, metabolomics by mass spectrometry always reveals a high number of

unknown compounds which complicate in depth mechanistic or biochemical

understanding. In principle, mass spectrometry can be utilized within

strategies of de novo structure elucidation of small molecules, starting with

the computation of the elemental composition of an unknown metabolite using

accurate masses with errors < 5 ppm (parts per million). However even with

very high mass accuracy (< 1 ppm) many chemically possible formulae are

obtained in higher mass regions. In automatic routines an additional orthogonal

filter therefore needs to be applied in order to reduce the number of potential

elemental compositions. This report demonstrates the necessity of isotope

abundance information by mathematical confirmation of the concept. Results:

High mass accuracy (< 1 ppm) alone is not enough to exclude enough

candidates with complex elemental compositions (C, H, N, S, O, P, and

potentially F, Cl, Br and Si). Use of isotopic abundance patterns as a single

further constraint removes > 95% of false candidates. This orthogonal filter

can condense several thousand candidates down to only a small number of

molecular formulas. Example calculations for 10, 5, 3, 1 and 0.1 ppm mass

accuracy are given. Corresponding software scripts can be downloaded from

http:// fiehnlab. ucdavis. edu. A comparison of eight chemical databases

revealed that PubChem and the Dictionary of Natural Products can be recommended

for automatic queries using molecular formulae. Conclusion: More than 1.6

million molecular formulae in the range 0 - 500 Da were generated in an

exhaustive manner under strict observation of mathematical and chemical rules.

Assuming that ion species are fully resolved (either by chromatography or by

high resolution mass spectrometry), we conclude that a mass spectrometer

capable of 3 ppm mass accuracy and 2% error for isotopic abundance patterns

outperforms mass spectrometers with less than 1 ppm mass accuracy or even

hypothetical mass spectrometers with 0.1 ppm mass accuracy that do not include

isotope information in the calculation of molecular formulae.

    Cover page: Metabolomic database annotations via query of elemental compositions: Mass accuracy is insufficient even at less than 1 ppm
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2014)
    Fluoxetine is the only psychopharmacological agent approved for depression by the US Food and Drug Administration for children and is commonly used therapeutically in a variety of neurodevelopmental disorders. Therapeutic response shows high individual variability, and severe side effects have been observed. In the current study we set out to identify biomarkers of response to fluoxetine as well as biomarkers that correlate with impulsivity, a measure of reward delay behavior and potential side effect of the drug, in juvenile male rhesus monkeys. The study group was also genotyped for polymorphisms of monoamine oxidase A (MAOA), a gene that has been associated with psychiatric disorders. We used peripheral metabolite profiling of blood and cerebrospinal fluid (CSF) from animals treated daily with fluoxetine or vehicle for one year. Fluoxetine response metabolite profiles and metabolite/reward delay behavior associations were evaluated using multivariate analysis. Our analyses identified a set of plasma and CSF metabolites that distinguish fluoxetine- from vehicle-treated animals and metabolites that correlate with impulsivity. Some metabolites displayed an interaction between fluoxetine and MAOA genotype. The identified metabolite biomarkers belong to pathways that have important functions in central nervous system physiology. Biomarkers of response to fluoxetine in the normally functioning brain of juvenile nonhuman primates may aid in finding predictors of response to treatment in young psychiatric populations and in progress toward the realization of a precision medicine approach in the area of neurodevelopmental disorders.
      Cover page: Identifying individual differences of fluoxetine response in juvenile rhesus monkeys by metabolite profiling
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2016)
      Ketamine, at sub-anesthetic doses, is reported to rapidly decrease depression symptoms in patients with treatment-resistant major depressive disorder (MDD). Many patients do not respond to currently available antidepressants, (for example, serotonin reuptake inhibitors), making ketamine and its enantiomer, esketamine, potentially attractive options for treatment-resistant MDD. Although mechanisms by which ketamine/esketamine may produce antidepressant effects have been hypothesized on the basis of preclinical data, the neurobiological correlates of the rapid therapeutic response observed in patients receiving treatment have not been established. Here we use a pharmacometabolomics approach to map global metabolic effects of these compounds in treatment-refractory MDD patients upon 2 h from infusion with ketamine (n=33) or its S-enantiomer, esketamine (n=20). The effects of esketamine on metabolism were retested in the same subjects following a second exposure administered 4 days later. Two complementary metabolomics platforms were used to provide broad biochemical coverage. In addition, we investigated whether changes in particular metabolites correlated with treatment outcome. Both drugs altered metabolites related to tryptophan metabolism (for example, indole-3-acetate and methionine) and/or the urea cycle (for example, citrulline, arginine and ornithine) at 2 h post infusion (q<0.25). In addition, we observed changes in glutamate and circulating phospholipids that were significantly associated with decreases in depression severity. These data provide new insights into the mechanism underlying the rapid antidepressant effects of ketamine and esketamine, and constitute some of the first detailed metabolomics mapping for these promising therapies.
        Cover page: Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2013)
        In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment.
          Cover page: Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2022)
          NADK2 encodes the mitochondrial form of nicotinamide adenine dinucleotide (NAD) kinase, which phosphorylates NAD. Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes, such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here, we describe two chemically induced mouse mutations in Nadk2-S326L and S330P-which cause severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on the brain, muscle, liver and spinal cord at the same ages and on plasma at 5 weeks. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNA sequencing and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, as well as those processes that are gene-specific. These findings improve our understanding of the pathophysiology of neuromuscular diseases and describe mouse models that will be useful for future preclinical studies.
            Cover page: Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2015)
            Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10(-5)). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.
              Cover page: Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes
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