14 results on '"Glinghammar, Björn"'
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2. Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
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Bonagas, Nadilly, Gustafsson, Nina M. S., Henriksson, Martin, Marttila, Petra, Gustafsson, Robert, Wiita, Elisée, Borhade, Sanjay, Green, Alanna C., Vallin, Karl S. A., Sarno, Antonio, Svensson, Richard, Göktürk, Camilla, Pham, Therese, Jemth, Ann-Sofie, Loseva, Olga, Cookson, Victoria, Kiweler, Nicole, Sandberg, Lars, Rasti, Azita, Unterlass, Judith E., Haraldsson, Martin, Andersson, Yasmin, Scaletti, Emma R., Bengtsson, Christoffer, Paulin, Cynthia B. J., Sanjiv, Kumar, Abdurakhmanov, Eldar, Pudelko, Linda, Kunz, Ben, Desroses, Matthieu, Iliev, Petar, Färnegårdh, Katarina, Krämer, Andreas, Garg, Neeraj, Michel, Maurice, Häggblad, Sara, Jarvius, Malin, Kalderén, Christina, Bögedahl Jensen, Amanda, Almlöf, Ingrid, Karsten, Stella, Zhang, Si Min, Häggblad, Maria, Eriksson, Anders, Liu, Jianping, Glinghammar, Björn, Nekhotiaeva, Natalia, Klingegård, Fredrik, Koolmeister, Tobias, Martens, Ulf, Llona-Minguez, Sabin, Moulson, Ruth, Nordström, Helena, Parrow, Vendela, Dahllund, Leif, Sjöberg, Birger, Vargas, Irene L., Vo, Duy Duc, Wannberg, Johan, Knapp, Stefan, Krokan, Hans E., Arvidsson, Per, Scobie, Martin, Meiser, Johannes, Stenmark, Pål, Warpman Berglund, Ulrika, Homan, Evert J., Helleday, Thomas, Bonagas, Nadilly, Gustafsson, Nina M. S., Henriksson, Martin, Marttila, Petra, Gustafsson, Robert, Wiita, Elisée, Borhade, Sanjay, Green, Alanna C., Vallin, Karl S. A., Sarno, Antonio, Svensson, Richard, Göktürk, Camilla, Pham, Therese, Jemth, Ann-Sofie, Loseva, Olga, Cookson, Victoria, Kiweler, Nicole, Sandberg, Lars, Rasti, Azita, Unterlass, Judith E., Haraldsson, Martin, Andersson, Yasmin, Scaletti, Emma R., Bengtsson, Christoffer, Paulin, Cynthia B. J., Sanjiv, Kumar, Abdurakhmanov, Eldar, Pudelko, Linda, Kunz, Ben, Desroses, Matthieu, Iliev, Petar, Färnegårdh, Katarina, Krämer, Andreas, Garg, Neeraj, Michel, Maurice, Häggblad, Sara, Jarvius, Malin, Kalderén, Christina, Bögedahl Jensen, Amanda, Almlöf, Ingrid, Karsten, Stella, Zhang, Si Min, Häggblad, Maria, Eriksson, Anders, Liu, Jianping, Glinghammar, Björn, Nekhotiaeva, Natalia, Klingegård, Fredrik, Koolmeister, Tobias, Martens, Ulf, Llona-Minguez, Sabin, Moulson, Ruth, Nordström, Helena, Parrow, Vendela, Dahllund, Leif, Sjöberg, Birger, Vargas, Irene L., Vo, Duy Duc, Wannberg, Johan, Knapp, Stefan, Krokan, Hans E., Arvidsson, Per, Scobie, Martin, Meiser, Johannes, Stenmark, Pål, Warpman Berglund, Ulrika, Homan, Evert J., and Helleday, Thomas
- Abstract
The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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- 2022
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3. Proliferative and Molecular Effects of the Dual PPARα/γ Agonist Tesaglitazar in Rat Adipose Tissues: Relevance for Induction of Fibrosarcoma
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Glinghammar, Björn, Berg, Anna-Lena, Bjurström, Sivert, Stockling, Kenneth, Blomgren, Bo, Westerberg, Rolf, Skånberg, Inger, Hellmold, Heike, and Andersson, Ulf
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- 2011
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4. The regulatory role of PGC1α‐related coactivator in response to drug‐induced liver injury
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Buler, Marcin, primary, Naessens, Thomas, additional, Mattsson, Johan, additional, Morias, Yannick, additional, Söderberg, Magnus, additional, Robbins, Philip, additional, Kärrberg, Lillevi, additional, Svensson, Tor S., additional, Thulin, Petra, additional, Glinghammar, Björn, additional, Scarpulla, Richard C., additional, and Andersson, Ulf, additional
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- 2020
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5. The peroxisome proliferator-activated receptor α agonist, AZD4619, induces alanine aminotransferase-1 gene and protein expression in human, but not in rat hepatocytes: Correlation with serum ALT levels
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Thulin, Petra, primary, Bamberg, Krister, additional, Buler, Marcin, additional, Dahl, Björn, additional, and Glinghammar, Björn, additional
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- 2016
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6. Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts
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Thulin, Petra, Nordahl, Gunnar, Gry, Marcus, Yimer, Getner, Aklillu, Eleni, Makonnen, Eyasu, Aderaye, Getachew, Lindquist, Lars, Mattsson, C. Mikael, Ekblom, Björn, Antoine, Daniel J., Park, B Kevin, Linder, Stig, Harrill, Alison H, Watkins, Paul B., Glinghammar, Björn, Schuppe-Koistinen, Ina, Thulin, Petra, Nordahl, Gunnar, Gry, Marcus, Yimer, Getner, Aklillu, Eleni, Makonnen, Eyasu, Aderaye, Getachew, Lindquist, Lars, Mattsson, C. Mikael, Ekblom, Björn, Antoine, Daniel J., Park, B Kevin, Linder, Stig, Harrill, Alison H, Watkins, Paul B., Glinghammar, Björn, and Schuppe-Koistinen, Ina
- Abstract
BACKGROUND & AIMS: There is a demand for more sensitive, specific and predictive biomarkers for drug-induced liver injury (DILI) than the gold standard used today, alanine aminotransferase (ALT). The aim of this study was to qualify novel DILI biomarkers (keratin-18 markers M65/M30, microRNA-122, glutamate dehydrogenase and alpha-foetoprotein) in human DILI. METHODS: Levels of the novel biomarkers were measured by enzyme-linked immunosorbent assay or real-time quantitative reverse-transcription PCR (qRT-PCR) in two human DILI cohorts: a human volunteer study with acetaminophen and a human immunodeficiency virus (HIV)/tuberculosis (TB) study. RESULTS: In the acetaminophen study, serum M65 and microRNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and microRNA-122 exceeded the increase in ALT. In the HIV/TB study, all the analysed novel biomarkers increased after 1 week of treatment. In contrast to ALT, the novel biomarkers remained stable in a human cohort with exercise-induced muscular injury. CONCLUSIONS: M65 and microRNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity.
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- 2014
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7. Isoform-specific alanine aminotransferase measurement candistinguish hepatic from extrahepatic injury in humans
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Rafter, Ingalill, Gråberg, Truls, Kotronen, Anna, Strömmer, Lovisa, Mattsson, C. Mikael, Kim, Ray W, Ehrenborg, Ewa, Andersson, Håkan B, Yki-Järvinen, Hannele, Schuppe-Koistinen, Ina, Ekblom, Björn, Cotgreave, Ian, Glinghammar, Björn, Rafter, Ingalill, Gråberg, Truls, Kotronen, Anna, Strömmer, Lovisa, Mattsson, C. Mikael, Kim, Ray W, Ehrenborg, Ewa, Andersson, Håkan B, Yki-Järvinen, Hannele, Schuppe-Koistinen, Ina, Ekblom, Björn, Cotgreave, Ian, and Glinghammar, Björn
- Abstract
Serum alanine aminotransferase (ALT) is used asa clinical marker to detect hepatic damage and hepatoxicity.Two isoforms of ALT have been identified, ALT1 and ALT2,which have identical enzymatic capacities and are detectedsimultaneously in human serum/plasma using classical clinicalchemical assays. Differences exist in the expression patterns ofthe ALT1 and ALT2 proteins in different organs which suggestthat changes in the proportion of ALT1 and ALT2 in plasmamay arise and reflect damage to different human organs.However, this has not been previously studied due to the lackof a selective methodology that can quantify both ALT1 andALT2 isoforms in the total ALT activity normally measuredin clinical samples. To the best of our knowledge, our currentstudy reveals for the first time, that under 3 different conditionsof liver damage (non-alcoholic fatty liver disease, hepatitis Cand during liver surgery) the leakage of ALT1 activity intoplasma greatly exceeds that of ALT2, and that the measurementof ALT1 during liver damage is equal to the measurement oftotal ALT activity. By contrast, during skeletal muscle injury,induced in volunteers by physical exertion, the leakage ofALT2 exceeds that of ALT1 and the proportion of circulatingALT isoforms changes accordingly. The ALT isoform changesoccurring in plasma reflect previously demonstrated relativecontents of ALT1 and ALT2 activities in human liver and skeletalmuscle. These data suggest that assessing the percentagecontribution of ALT1 and ALT2 activities to total ALT activityin plasma may distinguish hepatic from extrahepatic injuryusing the same standard analytical platform.
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- 2012
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8. Toxicity with LXR agonists – Problem solving activities for mechanistic understanding
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Andersson, Patrik, Kenne, Kerstin, Glinghammar, Björn, Pointon, Amy V., Åkerblad, Peter, Lutz, Mareike, Hovdal, Daniel, Maxvall, Ingela, Lindstedt, Eva-Lotte, Andersson, Patrik, Kenne, Kerstin, Glinghammar, Björn, Pointon, Amy V., Åkerblad, Peter, Lutz, Mareike, Hovdal, Daniel, Maxvall, Ingela, and Lindstedt, Eva-Lotte
- Abstract
Several lines of evidence points toward the potential positive effects of LXR (Liver X Receptor) modulators for effective and safe therapy of cardiovascular diseases (CVDs). LXR is a dimeric nuclear hormone receptor that exists as a combination of RXR and one of two subtypes LXR alpha or beta, which act as cholesterol sensors. LXR alpha is highly expressed in the liver, intestine and adipose tissue while LXR beta is ubiquitously expressed. Activation of LXR up-regulates several genes involved in reverse cholesterol transport (RCT), including ABC transporters. This results in increased efflux of cholesterol from macrophages in atherosclerotic vascular lesions to the circulation and further on to other tissues to ultimately be excreted into the faeces. These effects together with systemic and local anti-inflammatory properties of LXR modulation are likely to contribute to decreased atherosclerosis. The positive effects of LXR activation on RCT and cholesterol balance must be obtained without negative lipid effects, since LXR also activates lipogenic genes. Other types of toxicity and approaches to better understand the mechanism(s) behind these will be presented. Copyright © 2012 Published by Elsevier Ireland Ltd.
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- 2012
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9. Isoform-specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans
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RAFTER, INGALILL, primary, GRÅBERG, TRULS, additional, KOTRONEN, ANNA, additional, STRÖMMER, LOVISA, additional, MATTSON, C. MIKAEL, additional, KIM, RAY W., additional, EHRENBORG, EWA, additional, ANDERSSON, HÅKAN B., additional, YKI-JÄRVINEN, HANNELE, additional, SCHUPPE-KOISTINEN, INA, additional, EKBLOM, BJÖRN, additional, COTGREAVE, IAN, additional, and GLINGHAMMAR, BJÖRN, additional
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- 2012
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10. Toxicological aspects of bile acids and human fecal water on cultured human colon carcinoma cells
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Glinghammar, Björn and Glinghammar, Björn
- Abstract
Colorectal tumorigenesis involves activation of mutations in proto-oncogenes, such as ras and c-myc, as well as mutations that inactivate tumor suppressor genes including the APC and the p53 gene. These genetic events, in turn, lead to epigenetic changes in signal transduction pathways, which regulate processes such as cell proliferation, differentiation and apoptosis. There exists also a large body of evidence from animal carcinogenesis studies and human epidemiology that a high fat intake drastically affects tumor incidence in the colon. However, there has been little understanding of how the dietary factors and genetic/epigentic events interact. It is, generally believed that this interaction is at least in part mediated by events occurring in the lumen of the large bowel. Bile acids have been suggested to mediate the tumor promoter effect of a high fat diet. The mechanism of bile acid induced tumor promoter activity is poorly understood. The aim of this thesis was to understand more about bile acids cellular effects, in the context of their tumor promoter activity, and to study the mechanisms behind the observed effects. By using cultured human colonic cell lines, we showed that dihydroxy bile acids induced the transcription factor AP-1, while other luminal components like cholesterol and long-chain fatty acids were without effect. The bile acid, deoxycholic acid (DCA) induced cell proliferation at the same concentrations as it induced AP-1. Incubation of the extracellular fluid of feces (human fecal water), which is the stool water in contact with the epithelial cells in vivo, resulted in activation of AP-1 and induction of cell proliferation which varied between different samples. Our attention then moved to, COX-2, another early response gene which has been shown to play an important role in colon tumorigenesis. We showed that dihydroxy bile acids and human fecal waters induced COX-2 promoter activity. This resulted in an increase in COX-2 protein expression.
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- 2001
11. PPARδ increases expression of the human apolipoprotein A-II gene in human liver cells
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Thulin, Petra, primary, Glinghammar, Björn, additional, Skogsberg, Josefin, additional, Lundell, Kerstin, additional, and Ehrenborg, Ewa, additional
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- 2008
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12. Differential expression of peroxisomal proliferator activated receptors α and δ in skeletal muscle in response to changes in diet and exercise
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Kannisto, Katja, primary, Chibalin, Alexander, additional, Glinghammar, Björn, additional, Zierath, Juleen, additional, Hamsten, Anders, additional, and Ehrenborg, Ewa, additional
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- 2006
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13. Detection of the mitochondrial and catalytically active alanine aminotransferase in human tissues and plasma.
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Glinghammar B, Rafter I, Lindström AK, Hedberg JJ, Andersson HB, Lindblom P, Berg AL, and Cotgreave I
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- Adolescent, Adult, Aged, Aged, 80 and over, Alanine Transaminase metabolism, Cells, Cultured, Female, Hepatocytes metabolism, Humans, Male, Middle Aged, Plasma chemistry, Plasma metabolism, Recombinant Proteins metabolism, Serum metabolism, Substrate Specificity, Young Adult, Alanine Transaminase analysis, Alanine Transaminase blood, Liver metabolism, Mitochondria metabolism, Muscle, Skeletal metabolism
- Abstract
Serum alanine aminotransferase (ALT) is used as a clinical marker of hepatotoxicity. Three forms of human ALT have been identified, ALT1 and 2 and an alternative splice variant of ALT2 (herein called ALT2_2). The standard ALT activity assay does not discriminate between ALT from different organs, or the isoforms measured in the plasma. Here, we show that ALT1 and 2 possess similar enzymatic activity for alanine and pyruvate but with different Km and kcat values, while recombinant ALT2_2 protein does not possess any enzymatic activity. Isolation of organelles from cultured human skeletal muscle cells, showed localisation of ALT2 to the mitochondrial fraction and endoplasmatic reticulum (ER), but not to the cytosol. In human hepatocytes, on the other hand, ALT1 was only localised to the cytosol and ER, with no detection in mitochondria. ALT2 was not detected in cultured human hepatocytes, liver extract or tissue using Western blotting or immunohistochemistry. The islet of Langerhans and cardiomyocytes were other examples of cells with high expression of catalytic ALT2. A clinical method for selective measurement of ALT1 and 2 in human plasma is described, and both ALT1 and 2 were immunoprecipitated from human plasma and structurally detected using Western blotting techniques.
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- 2009
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14. Differential expression of peroxisomal proliferator activated receptors alpha and delta in skeletal muscle in response to changes in diet and exercise.
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Kannisto K, Chibalin A, Glinghammar B, Zierath JR, Hamsten A, and Ehrenborg E
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- Adipose Tissue metabolism, Aging physiology, Animals, Blood Chemical Analysis, Dietary Fats, Female, Insulin Resistance physiology, Metabolic Syndrome metabolism, Molecular Sequence Data, Muscle, Skeletal cytology, PPAR alpha genetics, PPAR delta genetics, Protein Isoforms genetics, Protein Kinases genetics, Protein Kinases metabolism, RNA, Messenger metabolism, Rats, Rats, Wistar, Diet, Muscle, Skeletal physiology, PPAR alpha metabolism, PPAR delta metabolism, Physical Conditioning, Animal, Protein Isoforms metabolism
- Abstract
Peroxisome proliferator-activated receptors (PPARs) alpha, delta and gamma are nuclear transcription factors that control key genes involved in fatty acid metabolism and energy homeostasis. Little is known about PPAR activation in vivo and the existence of overlapping functions between PPARalpha, -delta and -gamma. As skeletal muscle is an important site for insulin action and acts as a significant sensor for life-style-induced influences in whole-body energy metabolism, we investigated the expression of PPARalpha, -delta and -gamma in rat skeletal muscle in response to exercise after four- and twelve-weeks of high-fat feeding, respectively. PPARalpha mRNA expression in skeletal muscle increased in parallel with other signs of developing metabolic syndrome such as increased visceral fat pad volymes, plasma free fatty acids and muscle triglyceride concentrations. PPARalpha mRNA expression was up-regulated 3-fold after four weeks of high-fat feeding (p<0.01). Exercise reversed the high-fat induced increase in PPARalpha expression in young lean rats (p<0.05), but did not change the PPARalpha, -delta and -gamma expression in the skeletal muscle in the normal nutritional state. The increase in PPARalpha expression declined during a longer term of high-fat feeding. In contrast, exercise increased PPARdelta mRNA and protein expression 3- to 6-fold in skeletal muscle after longer-term high-fat feeding (p<0.05). This effect was accompanied by a reduction in skeletal muscle fat content. These findings suggest that parallel activation of PPARalpha and -delta expression in skeletal muscle may be an important adaptive mechanism in response to increased fatty acid loads in young, lean animals, protecting them from insulin resistance, whereas exercise might be needed to mediate the same positive effects in older animals.
- Published
- 2006
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