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  • 1.
    McBean, G. J.
    et al.
    School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
    López, M. G.
    Instituto Teófilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
    Wallner, Fredrik K.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Redoxis AB.
    Redox-based therapeutics in neurodegenerative disease2017In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 174, no 12, p. 1750-1770Article in journal (Refereed)
    Abstract [en]

    This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research.

  • 2.
    Wallner, Fredrik K.
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Redoxis AB/ProNoxis AB, Lund, Sweden / Wallner Medicinal Chemistry AB, Göteborg, Sweden.
    Hultquist Hopkins, Malin
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Woodworth, Nina
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Lindvall Bark, Therese
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles2018In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 128, p. 244-251Article in journal (Refereed)
    Abstract [en]

    Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis. This allows for prediction of functions and drug target of a novel drug candidate based on profiles obtained in this study. Results from the study showed that the JAK inhibitors tofacitinib and ruxolitinib formed a robust cluster and were found to have a distinct cytokine profile compared to the other drugs. Another robust cluster included the calcineurin inhibitors cyclosporine A and tacrolimus and the protein kinase inhibitors fostamatinib disodium and sotrastaurin acetate, which caused a strong overall inhibition of the cytokine production. The results of this methodology indicate that cytokine profiles can be used to provide a fingerprint-like identification of a drug as a tool to benchmark novel drugs and to improve descriptions of mode of action.

  • 3.
    Wallner, Fredrik K.
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Redoxis AB, Lund, Sweden.
    Hultqvist Hopkins, Malin
    Redoxis AB, Lund, Sweden.
    Lindvall, Therese
    Redoxis AB, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB, Lund, Sweden.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Cytokine correlation analysis based on drug perturbation2017In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 90, p. 73-79Article in journal (Refereed)
    Abstract [en]

    Cytokines and chemokines play a crucial role in regulating the immune system. Understanding how these molecules are co-regulated is important to understand general immunology, and particularly their role in clinical applications such as development and evaluation of novel drug therapies. Cytokines are today widely used as therapeutic targets and as biomarkers to monitor effects of drug therapies and for prognosis and diagnosis of diseases. Therapies that target a specific cytokine are also likely to affect the production of other cytokines due to their cross-regulatory functions and because the cytokines are produced by common cell types. In this study, we have perturbated the production of 17 different cytokines in a preclinical rat model of autoimmune arthritis, using 55 commercially available immunomodulatory drugs and clinical candidates. The majority of the studied drugs was selected for their anti-inflammatory role and was confirmed to inhibit the production of IL-2 and IFN-γ in this model but was also found to increase the production of other cytokines compared to the untreated control. Correlation analysis identified 58 significant pairwise correlations between the cytokines. The strongest correlations found in this study were between IL-2 and IFN-γ (r=0.87) and between IL-18 and EPO (r=0.84). Cluster analysis identified two robust clusters: (1) IL-7, IL-18 and EPO, and (2) IL-2, IL-17 and IFN-γ. The results show that cytokines are highly co-regulated, which provide valuable information for how a therapeutic drug might affect clusters of cytokines. In addition, a cytokine that is used as a therapeutic biomarker could be combined with its related cytokines into a biomarker panel to improve diagnostic accuracy.

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