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  • 1. Abdallah, Qasem M. A.
    et al.
    Phillips, Roger M.
    Johansson, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Cosentino, Laura
    Abdel-Rahman, Hamdy
    Etzad, Jasarat
    Wheelhouse, Richard T.
    Kiakos, Konstantinos
    Bingham, John P.
    Hartley, John A.
    Patterson, Laurence H.
    Pors, Klaus
    Minor structural modifications to alchemix influence mechanism of action and pharmacological activity2012Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 83, nr 11, s. 1514-1522Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

  • 2.
    Chatzakos, Vicky
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Rundlöf, Anna-Klara
    Karolinska Institutet.
    Ahmed, Dilruba
    Karolinska Institutet.
    De Verdier, Petra J.
    Karolinska Institutet.
    Flygare, Jenny
    Karolinska Institutet.
    Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite2012Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 84, nr 5, s. 712-721Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High doses of selenite have been shown to induce cell death in acute myeloid leukemia and lung cancercells. In this study, we combined selenite treatment with modulators of sphingolipid metabolism in thehepatocellular carcinoma cell line Huh7. Treatment with 20 mM of selenite reduced the viability of Huh7cells by half and increased the levels of long chain C14-, C16-, C18- and C18:1- ceramides by two-fold.Inhibition of neutral sphingomyelinase with 3-O-methylsphingosine significantly reduced the cytotoxiceffect of selenite. In line with this result, selenite caused a 2.5-fold increase in the activity of neutralsphingomyelinase. The sphingosine kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophe-nyl)thiazole (SK1-II) sensitized the cells to the cytotoxic effects of selenite. Preincubation with 10 mM ofSK1-II prior to treatment with 10 mM of selenite caused induction of apoptosis and gave rise to a 2.5-foldincrease in C14-, C16-, C18- and C18:1- ceramides. Instead, 50 mM of SK1-II combined with 10 mM ofselenite caused accumulation of cells in G1/S phases, but less apoptosis and accumulation of ceramides.The formation of reactive oxygen species (ROS) after treatment with 10 mM of selenite was maximallyenhanced by 1 mM of SK1-II. Moreover, combined treatment with SK1-II and 10 mM of selenitesynergistically reduced the number of viable Huh7 cells, while the non-tumorigenic hepatocyte cell lineMIHA remained unaffected by the same treatment. These results raise the possibility that a combinationof selenite and SK1 inhibitors could be used to treat liver cancer cells, that are regarded as drug resistant,at doses that are non-toxic to normal liver cells.

  • 3. Imtiaz, Bushra
    et al.
    Tolppanen, Anna-Maija
    Kivipelto, Miia
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). University of Eastern Finland, Finland.
    Soininen, Hilkka
    Future directions in Alzheimer's disease from risk factors to prevention2014Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 88, nr 4, s. 661-670Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The increase in life expectancy has resulted in a high occurrence of dementia and Alzheimer's disease (AD). Research on AD has undergone a paradigm shift from viewing it as a disease of old age to taking a life course perspective. Several vascular, lifestyle, psychological and genetic risk factors influencing this latent period have been recognized and they may act both independently and by potentiating each other. These risk factors have consequently been used to derive risk scores for predicting the likelihood of dementia. Despite population differences, age, low education and vascular risk factors were identified as key factors in all scoring systems. Risk scores can help to identify high-risk individuals who might benefit from different interventions. The European Dementia Prevention Initiative (EDPI), an international collaboration, encourages data sharing between different randomized controlled trials. At the moment, it includes three large ongoing European trials: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), Prevention of Dementia by Intensive Vascular Care (preDIVA), and Multidomain Alzheimer Prevention study (MAPT). Recently EDPI has developed a Healthy Aging through Internet Counseling in Elderly (HATICE) program, which intends to manage modifiable risk factors in an aged population through an easily accessible Internet platform. Thus, the focus of dementia research has shifted from identification of potential risk factors to using this information for developing interventions to prevent or delay the onset of dementia as well as identifying special high-risk populations who could be targeted in intervention trials.

  • 4.
    Lindgren, Maria
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Rosenthal-Aizman, Katri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Saar, Külliki
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Eiríksdóttir, Emelía
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Jiang, Yang
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Sassian, Meeri
    Östlund, Pernilla
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Hällbrink, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide2006Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 71, nr 4, s. 416-425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Here, we present a new approach to overcome the setback of drug resistance by designing a conjugate of a cell-penetrating peptide and the cytostatic agent methotrexate (MTX). Two different peptides, YTA2 and YTA4, were designed and their intracellular delivery efficiency was characterized by fluorescence microscopy and quantified by fluorometry. MTX was conjugated to the transport peptides and the ability of the peptide–MTX conjugates to inhibit dihydrofolate reductase, the target enzyme of MTX, was found to be 15 and 20 times less potent than MTX. In addition, in vitro studies were performed in a drug resistant cell model using the 100-fold MTX resistant breast cancer cells MDA-MB-231. At a concentration of 1 mM, the peptide–MTX conjugates were shown to overcome MTX resistance and kill the cells more efficiently than MTX alone. Estimated EC50’s were determined for MTX, MTXYTA2 and YTA2 to be 18.5, 3.8 and 20 µM, respectively. In summary, cell-penetrating peptide conjugation of MTX is a new way of increasing delivery, and thereby, the potency of already well-characterized therapeutic molecules into drug resistant tumour cells.

  • 5. Lundgren, B
    et al.
    Andersson, K
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    DePierre, J W
    Effects of dietary treatment with 11 dicarboxylic acids, diethylcarboxylic esters and fatty acids on peroxisomal fatty acid beta-oxidation, epoxide hydrolases and lauric acid omega-hydroxylation in mouse liver.1992Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 43, nr 4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    C57B1/6 male mice were exposed through their diet to 11 dicarboxylic acids, carboxylic acids and diethyldicarboxylesters for 10 days. For the diacids and diethylesters this treatment resulted in a chain length-dependent induction of lauryl-CoA oxidase and cyanide-insensitive palmitoyl-CoA oxidation activities. A chain length of 12 carbon atoms or more seemed to be necessary for induction of these two activities. In addition, the same chain length dependence was observed for induction of lauric acid omega + omega-1 hydroxylase activity and increase in the protein content of the mitochondrial fraction. Treatment with two "natural" fatty acids, i.e. lauric and palmitic acid gave no effect at all on these various parameters. In no case was induction of cytosolic and mitochondrial epoxide hydrolase activities observed. Instead, a slight decrease in these activities was observed after administration of diacids with a chain length of 4-8 carbon atoms, whereas microsomal epoxide hydrolase activity was concurrently induced.

  • 6.
    Lundgren, B
    et al.
    Stockholms universitet.
    Meijer, J
    DePierre, J W
    Induction of cytosolic and microsomal epoxide hydrolases and proliferation of peroxisomes and mitochondria in mouse liver after dietary exposure to p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid.1987Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 36, nr 6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of dietary exposure to 0.125% (w/w) p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid or 2,4,5-trichlorophenoxyacetic acid on the content of peroxisomes and levels of certain xenobiotic-metabolizing enzymes in mouse liver have been investigated. In agreement with the literature on rat liver 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid were found to cause extensive proliferation of peroxisomes (as judged by the total levels of "mitochondrial" protein, carnitine acetyltransferase, cyanide-insensitive palmitoyl-CoA oxidation and catalase) in mouse liver. On the other hand, exposure to p-chlorophenoxyacetic acid did not significantly affect any of these parameters. As with certain other peroxisome proliferators, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid increased total cytochrome oxidase activity as well. In addition, dietary exposure to 2,4-dichlorophenoxyacetic acid and to 2,4,5-trichlorophenoxyacetic acid resulted in increases in the activities of cytosolic and microsomal epoxide hydrolases in mouse liver and generally less pronounced increases in the total cytosolic glutathione transferase activity and microsomal content of cytochrome P-450. In the case of cytochrome P-450, this process can be said to be a true induction (i.e. the amount of enzyme protein is increased), because the assay procedure for cytochrome P-450 measures holoenzyme amount. Immunoquantitation demonstrated that this was also the case for the changes in cytosolic epoxide hydrolase. The dramatic differences in proliferation of peroxisomes and induction of xenobiotic-metabolizing enzymes seen here with compounds differing relatively little in structure may indicate that a receptor mechanism of some kind is involved.

  • 7. Minami, S. Sakura
    et al.
    Shen, Vivian
    Le, David
    Krabbe, Grietje
    Asgarov, Rustam
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. Gladstone Institute of Neurological Diseases, United States.
    Perez-Celajes, Liberty
    Lee, Chih-Hung
    Li, Jinhe
    Donnelly-Roberts, Diana
    Gan, Li
    Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with alpha 7 nicotinic acetylcholine receptor agonists2015Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 97, nr 4, s. 454-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific alpha 7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or alpha 7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective alpha 7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-kappa B in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNF alpha levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the alpha 7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

  • 8. Permadi, H
    et al.
    Lundgren, B
    Andersson, K
    DePierre, J W
    Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver.1992Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 44, nr 6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial protein content, microsomal contents of cytochromes P450 and b5, NADPH-cytochrome P450 reductase activity [measured as NADPH-cytochrome c reductase (EC 1.6.2.3)], microsomal and cytosolic epoxide hydrolase (EC 3.3.2.3) activities, cytosolic DT-diaphorase (EC 1.6.99.2), glutathione transferase (EC 2.5.1.18), glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities, and levels of thiobarbituric acid-reactive material (as an indicator of lipid peroxidation) in the mitochondrial subfraction. The most dramatic changes observed were a 5-9-fold increase in mitochondrial protein, a 3-6-fold increase in the microsomal content of cytochrome P450, a 3-10-fold increase in cytosolic DT-diaphorase activity, an approximately 2-fold increase in cytosolic epoxide hydrolase activity and as much as a 60% decrease in the level of thiobarbituric acid-reactive compounds in the mitochondrial fraction. Smaller increases in microsomal epoxide hydrolase activity and decreases in cytosolic glutathione peroxidase activity were also observed. Of the perfluoro fatty acids tested, perfluorooctanoic acid caused the largest changes in the parameters examined here. Dietary exposure of mice to a 0.02% dose of this substance for 10 days results in a maximal or near-maximal effect in most cases.

  • 9.
    Sato, Masaaki
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Monash University, Australia.
    Evans, Bronwyn A.
    Sandström, Anna L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Chia, Ling Yeong
    Mukaida, Saori
    Bui, San
    Anh, Nguyen
    Lim, Linzi
    Tan, Christina Y. R.
    Baltos, Jo-Anne
    White, Paul J.
    May, Lauren T.
    Hutchinson, Dana S.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    alpha(1A)-Adrenoceptors activate mTOR signalling and glucose uptake in cardiomyocytes2018Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 148, s. 27-40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the am-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised alpha(1A)-AR signalling in CHO-K1 cells co-expressing the human alpha(1A)-AR and GLUT4 (CHO alpha(1A)GLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ga2* mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the alpha(1A)-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another alpha(1A)-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHO alpha(1A)GLUT4myc cells, siRNA directed against rictor but not raptor suppressed alpha(1A)-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by alpha(1A)-AR agonists. Our findings identify a novel link between the alpha(1A)-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of alpha(1A)-AR selective agonists as tools in the treatment of cardiac dysfunction.

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