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- Mikus, Maria, et al.
(author)
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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
- 2016
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In: Liver international. - : John Wiley & Sons. - 1478-3223 .- 1478-3231. ; 37:1, s. 132-140
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Journal article (peer-reviewed)abstract
- Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
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- Csenki, Leonard, et al.
(author)
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Proof of principle of a generalized fuzzy Hough transform approach to peak alignment of one-dimensional 1H NMR data
- 2007
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In: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 389:3, s. 875-885
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Journal article (peer-reviewed)abstract
- In metabolic profiling, multivariate data analysis techniques are used to interpret one-dimensional (1D) 1H NMR data. Multivariate data analysis techniques require that peaks are characterised by the same variables in every spectrum. This location constraint is essential for correct comparison of the intensities of several NMR spectra. However, variations in physicochemical factors can cause the locations of the peaks to shift. The location prerequisite may thus not be met, and so, to solve this problem, alignment methods have been developed. However, current state-of-the-art algorithms for data alignment cannot resolve the inherent problems encountered when analysing NMR data of biological origin, because they are unable to align peaks when the spatial order of the peaks changes—a commonly occurring phenomenon. In this paper a new algorithm is proposed, based on the Hough transform operating on an image representation of the NMR dataset that is capable of correctly aligning peaks when existing methods fail. The proposed algorithm was compared with current state-of-the-art algorithms operating on a selected plasma dataset to demonstrate its potential. A urine dataset was also processed using the algorithm as a further demonstration. The method is capable of successfully aligning the plasma data but further development is needed to address more challenging applications, for example urine data.
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- Eakins, R, et al.
(author)
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Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome
- 2015
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 16423-
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Journal article (peer-reviewed)abstract
- Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10–15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.
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- Mubanga, M, et al.
(author)
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The gut microbiome and asthma in a Swedish twin study
- 2023
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In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - 1365-2222. ; 53:11, s. 1212-1215
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Journal article (other academic/artistic)
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- Schwieler, L., et al.
(author)
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Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients
- 2016
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 13:1
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Journal article (peer-reviewed)abstract
- Background: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression. Methods: Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22). Results: Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002). Conclusions: This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.
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