BackgroundSystemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy–based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA.MethodsSerum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation.ResultsUsing PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP.ConclusionsThis study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.
Stroke commonly leads to partial or complete paralysis of one side of the body and there is limited availability of therapists to provide rehabilitation. It is a priority therefore to identify the most effective rehabilitation strategies and/or pharmacotherapies. Motor learning, the essential process underpinning rehabilitation, can be assessed more quickly and robustly than outcomes from rehabilitation. In this paper we describe a proof of concept system that utilises a bespoke video game to measure the critical components of motor learning. We demonstrate that it is sensitive enough to detect how simple changes in therapist instruction significantly change motor performance and learning. Although video games have been shown to aid in rehabilitation, this is the first time video games have been used to derive early response markers, based on the measurement of performance and motor learning, for use in the evaluation of the efficacy of a rehabilitation strategy.
Mercaptopurine (MP) is a cytotoxic thiopurine important for the treatment of cancer and autoimmune diseases. MP and other thiopurine drugs undergo extensive intracellular metabolism, but the mechanisms of action are poorly characterized. In particular, it is unknown how different metabolites contribute to cytotoxicity and incorporation of thiopurine bases into DNA. The aim of this study was to ask whether cytotoxicity results from the incorporation of thioguanosine nucleotides into DNA, an alternative thiopurine metabolite, or a combination of factors. Therefore, we measured the cytotoxicity, metabolism, and incorporation of thioguanosine into DNA in response to MP or MP metabolites. Thiopurine metabolites varied in cytotoxicity, with methyl-thioinosine-mono-phosphate and thioguanosine-tri-phosphate the most toxic, and the methyl-thioguanosine nucleotides the least. We show, using liquid chromatography-tandem mass spectrometry, how different metabolites may perturb biochemical pathways, particularly disrupting guanosine nucleotide homeostasis, that may contribute to the mechanism of action of thiopurines. Although there was no correlation between metabolite cytotoxicity and the levels of 6-methylthioinosine-mono-phosphate or thioguanosine incorporation into DNA as individual factors, a combined analysis suggested that these factors together had a major influence on cytotoxicity. This study emphasizes the importance of enzymes of nucleotide homeostasis, methylation, and demethylation in thiopurine effects. These results will facilitate the development of dynamic biochemical models of thiopurine biochemistry that will improve our understanding of mechanisms of action in relevant target tissues.
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