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  • 1. Dammeyer, Pascal
    et al.
    Hellberg, Victoria
    Wallin, Inger
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Shoshan, Maria
    Ehrsson, Hans
    Arner, Elias S. J.
    Kirkegaard, Mette
    Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 5, p. 448-454Article in journal (Refereed)
    Abstract [en]

    Conclusion: Inhibition of thioredoxin reductase (TrxR) may be a contributing factor in cisplatin- induced ototoxicity. Direct exposure of organ of Corti to cisplatin and oxaliplatin gives equal loss of hair cells. Objectives: Platinum- containing drugs are known to target the anti- oxidant selenoprotein TrxR in cancer cells. Two such anti- cancer, platinum- containing drugs, cisplatin and oxaliplatin, have different side effects. Only cisplatin induces hearing loss, i.e. has an ototoxic side effect that is not seen after treatment with oxaliplatin. The objective of this study was to evaluate if TrxR is a target in the cochlea. Loss of outer hair cells was also compared when cisplatin and oxaliplatin were administered directly to the organ of Corti. Methods: Organ of Corti cell culture was used for direct exposure to cisplatin and oxaliplatin. Hair cells were evaluated and the level of TrxR was assessed. Immunohistochemical staining for TrxR was performed. An animal model was used to evaluate the effect on TrxR after treatment with cisplatin and oxaliplatin in vivo. Results: Direct exposure of cochlear organotypic cultures to either cisplatin or oxaliplatin induced comparable levels of outer hair cell loss and inhibition of TrxR, demonstrating that both drugs are similarly ototoxic provided that the cochlea becomes directly exposed.

  • 2.
    Katsu-Jimenez, Yurika
    et al.
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Vazquez-Calvo, Carmela
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Maffezzini, Camilla
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Peng, Xiaoxiao
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Coastal Int Holdings Ltd, Strateg Investment Dept, Shenzhen, Peoples R China.
    Freyer, Christoph
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Wredenberg, Anna
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Gimenez-Cassina, Alfredo
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Univ Autonoma Madrid, Dept Mol Biol, Ctr Biol Mol Severo Ochoa, Madrid, Spain.
    Wedell, Anna
    Karolinska Inst, Dept Mol Med & Surg, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate2019In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 4, p. 709-723Article in journal (Refereed)
    Abstract [en]

    Thioredoxin-interacting protein (TXNIP) is an -arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes -cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.

  • 3. Wang, Xin
    et al.
    Stafford, William
    Mazurkiewicz, Magdalena
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Brjnic, Slavica
    Zhang, Xiaonan
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Arner, Elias S. J.
    D'Arcy, Padraig
    Linder, Stig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    The 19S Deubiquitinase Inhibitor b-AP15 Is Enriched in Cells and Elicits Rapid Commitment to Cell Death2014In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 85, no 6, p. 932-945Article in journal (Refereed)
    Abstract [en]

    b-AP15 [(3E, 5E)-3,5-bis[(4-nitrophenyl) methylidene]-1-(prop-2enoyl) piperidin-4-one] is a small molecule inhibitor of the ubiquitin specific peptidase (USP) 14/ubiquitin carboxyl-terminal hydrolase (UCH) L5 deubiquitinases of the 19S proteasome that shows antitumor activity in a number of tumor models, including multiple myeloma. b-AP15 contains an alpha,beta-unsaturated carbonyl unit that is likely to react with intracellular nucleophiles such as cysteine thiolates by Michael addition. We found that binding of b-AP15 to USP14 is partially reversible, and that inhibition of proteasome function is reversible in cells. Despite reversible binding, tumor cells are rapidly committed to apoptosis/cell death after exposure to b-AP15. We show that b-AP15 is rapidly taken up from the medium and enriched in cells. Enrichment provides an explanation of the stronger potency of the compound in cellular assays compared with in vitro biochemical assays. Cellular uptake was impaired by 30-minute pretreatment of cells with low concentrations of N-ethylmaleimide (10 mu M), suggesting that enrichment was thiol dependent. We report that in addition to inhibition of deubiquitinases, b-AP15 inhibits the selenoprotein thioredoxin reductase (TrxR). Whereas proteasome inhibition was closely associated with cell death induction, inhibition of TrxR was not. TrxR inhibition is, however, likely to contribute to triggering of oxidative stress observed with b-AP15. Furthermore, we present structure-activity, in vivo pharmacokinetic, and hepatocyte metabolism data for b-AP15. We conclude that the strong enrichment of b-AP15 in cells and a rapid commitment to apoptosis/cell death are factors that likely contribute to the strong antitumor activity of this compound.

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