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  • 1. Abramsson-Zetterberg, Lilianne
    et al.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, p. 86-89Article in journal (Refereed)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 2. Aspenstrom-Fagerlund, Bitte
    et al.
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Oleic acid increases intestinal absorption of the BCRP/ABCG2 substrate, mitoxantrone, in mice2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 237, no 2, p. 133-139Article in journal (Refereed)
    Abstract [en]

    The efflux transporter breast cancer resistance protein (BCRP/ABCG2) decrease intestinal absorption of many food toxicants. Oleic acid increases absorption of the specific BCRP substrate mitoxantrone (MXR), and also BCRP gene expression in human intestinal Caco-2 cells, suggesting that oleic acid affect the BCRP function. Here, we investigated the effect of oleic acid on intestinal absorption of MXR in mice. Mice were orally dosed with 2.4 g oleic acid/kg b.w. and 1 mg MXR/kg b.w., and sacrificed 30, 60, 90 or 120 min after exposure, or were exposed to 0.6, 2.4 or 4.8 g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 90 min after exposure. Mice were also treated with Ko143 together with MXR and sacrificed after 60 min, as a positive control of BCRP-mediated effects on MXR absorption. Absorption of MXR increased after exposure to oleic acid at all doses, and also after exposure to Ko143. Intestinal BCRP gene expression tended to increase 120 min after oleic acid exposure. Our results in mice demonstrate that oleic acid decreases BCRP-mediated efflux, causing increased intestinal MXR absorption in mice. These findings may have implications in humans, concomitantly exposed to oleic acid and food contaminants that, similarly as MXR, are substrates of BCRP.

  • 3.
    Aspenström-Fagerlund, Bitte
    et al.
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Ring, Linda
    Toxicology Division, National Food Administration, P.O. Box 622, SE-75126 Uppsala, Sweden.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Tallkvist, Jonas
    Department of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Box 7028, SE-75007, Uppsala, Sweden.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 237, no 1-3, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.

  • 4. Aspenström-Fagerlund, Bitte
    et al.
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Glynn, Anders W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Oleic acid decreases BCRP mediated efflux of mitoxantrone in Caco-2 cell monolayers2012In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 50, no 10, p. 3635-3645Article in journal (Refereed)
    Abstract [en]

    Breast cancer resistance protein (BCRP) efflux restricts intestinal absorption of substances like heterocyclic amines, mycotoxins and certain human and veterinary drugs. Fat rich meals seem to increase absorption of drugs which are BCRP substrates or inhibitors. We therefore hypothesize that absorption of toxicants normally effluxed by BCRP are increased by fatty acids in food. Transport across and accumulation of H-3-Mitoxantrone (MXR) in Caco-2 cell monolayers were measured after 60 min exposure to emulsions of H-3-MXR (1 mu M) and oleic acid (0.5-5 mM). In addition, BCRP gene expression (RT-PCR) and the amount of BCRP protein (Western blot) were measured in oleic acid exposed Caco-2 cells. Oleic acid increased transport of MXR in a concentration dependent manner and 2 mM oleic acid or higher increased accumulation of MXR in cells, without any signs of cytotoxicity. Gene expression of BCRP was increased after exposure to oleic acid for 6 h, but the amount of BCRP protein was not increased. In conclusion, oleic acid clearly induced BCRP gene expression and reduced BCRP mediated efflux, although the amount of BCRP in cells was not affected. Consequently, effects of fatty acids on BCRP mediated efflux are important to consider in risk assessment of toxicants in food.

  • 5.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Trace Element Changes in Thoracic Aortic Dissection2016In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 169, no 2, p. 159-163Article in journal (Refereed)
    Abstract [en]

    Thoracic aortic dissection is a life-threatening condition with an incompletely understood pathogenesis. Trace elements are essential for the functioning of different processes in the body, including the immune system and associated responses to infection/inflammation. Because inflammation may be part of the pathogenesis of thoracic aortic dissection, we investigated whether trace element changes associated with inflammation occur in serum and tissue samples during the disease. The study included 21 patients undergoing surgery for thoracic aortic dissection, 10 forensic autopsy specimens for tissue controls and 23 healthy blood donors for serum controls. Levels of magnesium (Mg), calcium (Ca), vanadium (V), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd) and mercury (Hg) were measured in the aortic tissue and serum by inductively coupled plasma-mass spectrometry (ICP-MS). In the serum, Ca, V, Cu and Zn decreased, whereas Fe increased. In the tissue, Cu and Zn decreased and Fe tended to increase. The Cu/Zn ratio in the serum, a marker of infection/inflammation, did not change in the patients. Concerning trace element changes in the serum and tissue, our data do not support the hypothesis that inflammation is involved in the pathogenesis of thoracic aortic dissection.

  • 6.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tallkvist, Jonas
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, S-75007 Uppsala, Sweden..
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Natl Food Agcy, Risk Benefit Assessment Dept, S-75126 Uppsala, Sweden..
    Cholesterol uptake in the mouse aorta increases during Chlamydia pneumoniae infection2017In: Pathogens and Disease, E-ISSN 2049-632X, Vol. 75, no 1, article id ftx004Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae has been suggested as a stimulator of the atherosclerotic process. Mice fed a normal diet were infected intranasally with C. pneumoniae and given one intraperitoneal injection of C-14-cholesterol tracer per day for 12 days. Bacteria were demonstrated in the aorta in the early phase of infection and in lungs and liver throughout the study period of 20 days. C-14-cholesterol was not affected in the heart but increased in the blood, liver and aorta on day 4 when the infection was clinically most severe. Furthermore, on day 20 C-14-cholesterol tended to be increased in the aorta. Accordingly, copper-and zinc levels and expressions of the infection biomarkers Cxcl2 and Ifng increased in the liver on day 4 with a tendency of increased of copper, zinc and Ifng on day 20. In mice where bacteria could be cultivated from the lungs, expressions of cholesterol transporters Abca1 and Idol were both increased in the liver on day 4. The increased levels of C-14-cholesterol in blood and aorta together with increased Abca1 and Idol in the liver during C. pneumoniae infection in mice fed a normal diet suggest that this pathogen may have a role in the initiation of the atherosclerotic process.

  • 7.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tallkvist, Jonas
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Natl Food Agcy, Risk Benefit Assessment Dept, Uppsala, Sweden..
    Iron Homeostasis in Tissues Is Affected during Persistent Chlamydia pneumoniae Infection in Mice2017In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 3642301Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae (C. pneumoniae) may be a mediator in the pathogenesis of atherosclerosis. For its growth C. pneumoniae depends on iron (Fe), but how Fe changes in tissues during persistent infection or affects bacterial replication in tissues is unknown. C. pneumoniae-infected C57BL/6J mice were sacrificed on days 4, 8, 20, and 40. Mice had bacteria in the lungs and liver on all days. Inflammatory markers, chemokine Cxcl2 and interferon-gamma, were not affected in the liver on day 40. The copper (Cu)/zinc (Zn) ratio in serum, another marker of infection/inflammation, increased on day 4 and tended to increase again on day 40. The Fe markers, transferrin receptor (TfR), Hepcidin (Hamp1), and ferroportin 1 (Fpn1), increased in the liver on day 4 and then normalized except for TfR that tended to decrease. TfR responses were similar to Fe in serum that increased on day 4 but tended to decrease thereafter. In the liver, Fe was increased on day 4 and also on day 40. The reappearing increases in Cu/Zn on day 40 concomitant with the increase in liver Fe on day 40, even though TfR tended to decrease, and the fact that viable C. pneumoniae was present in the lungs and liver may indicate the early phase of activation of recurrent infection.

  • 8.
    Frisk, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Darnerud, Per Ola
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sequential trace element changes in serum and blood during a common viral infection in mice2007In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 21, no 1, p. 29-36Article in journal (Refereed)
    Abstract [en]

    When trace elements are used as diagnostic tools during disease, it is important to know whether the balance is changed in free or bound elements. Although acute infections are associated with changed trace element balance in serum/plasma, it is not known whether changes occur concomitantly in serum and blood. In the present study the human coxsackievirus B3 (CB3), here adapted to Balb/c mice, was used to study whether infection alters the normal physiological trace element balance in blood and serum. Virus was quantitatively measured in two target organs (pancreas and liver) of this infection by reverse transcription polymerase chain reaction (RT-PCR), showing high concentrations of virus proving ongoing infection. Concentrations of 14 elements were measured in whole blood and serum using inductively coupled plasma mass spectrometry (ICP-MS) on days 3, 6 and 9 of the infection. Free and total thyroxine were measured in serum to prove metabolic changes associated with the infection. The thyroxine decreased, while iron and the Cu/Zn ratio in serum increased as a response to the infection. No clear changes in these elements were observed in blood. Cd and Hg tended to decrease in serum but to increase in blood, indicating accumulation in blood cells. Moreover, Al showed a similar decreasing trend in both serum and blood. A correlation between serum and blood levels was observed at different time points of the disease for 9 of the elements. However, As was the only element indicating correlations between serum and blood during the entire course of the disease.

  • 9. Frisk, Peter
    et al.
    Molin, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tissue uptake of mercury is changed during the course of a common viral infection in mice2008In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 106, no 2, p. 178-184Article in journal (Refereed)
    Abstract [en]

    Mercury (Hg) has been shown to have immunotoxic effects and to influence the severity of infection. However, the impact of infection on the normal Hg homeostasis in different target organs involved in the disease process has not been studied. In this study, Hg was measured through inductively coupled plasma-mass spectrometry (ICP-MS) in the intestine, serum, liver, and brain on days 3, 6, and 9 of coxsackievirus B3 (CVB3) infection in female Balb/c mice. The severity of the infection was assessed from clinical signs of disease and the number of virus particles in infected organs. CVB3 and gene expression of metallothionein 1 (MT1) was measured by reverse transcription-polymerase chain reaction (RT-PCR). Gene expression of MT1 increased and peaked on day 3 in the brain (93%, p<0.01) and liver (19-fold, p<0.01) and on day 6 in the intestine (seven-fold, p<0.01). This peak in MT1 in the liver and brain corresponded to the peak in virus numbers in these tissues. Hg in the intestine and serum tended to decrease on all days of infection. The maximum decrease, in comparison with non-infected mice, occurred in the intestine (78%, p<0.001) on day 9 and in serum (50%, p<0.05) on day 6. However, in the brain, Hg increased by 52% (p<0.05) on day 6. Hg went unchanged in the liver. An infection-induced increase of Hg in the brain but unchanged level in the liver may be due to the peak of virus replication and an associated infection-induced expression of MT1. Moreover, the decrease of Hg in serum and the intestine but a concomitant intestinal increase in MT1 on day 6 may reflect a flux and increased retention of Hg to infected organs such as the brain. The pathophysiological interpretation of these preliminary findings requires further research.

  • 10.
    Frisk, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tallkvist, Jonas
    Gadhasson, Inga-Lill
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Coxsackievirus B3 infection affects metal-binding/transporting proteins and trace elements in the pancreas in mice2007In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 35, no 3, p. e37-e44Article in journal (Refereed)
    Abstract [en]

    Objective: The trigger of juvenile diabetes has been suggested to be an interaction between a virus and trace elements, where enteroviruses, including coxsackievirus B3 (CVB3), have been discussed as potential initiators. The aim of this study was to investigate the effects in the pancreas on gene expressions of metallothionein 1 (MT1), divalent metal transporter 1 (DMT1), and zinc transporter 5 (ZnT-5) and concomitant changes in iron (Fe), copper (Cu), and zinc (Zn) in serum and pancreas of Balb/c mice on days 3, 6, and 9 of CVB3 infection. Methods: Trace elements were measured through inductively coupled plasma-mass spectrometry, and CVB3, MT1, DMT1, and ZnT-5 were measured by reverse transcription/polymerase chain reaction. Results: Virus was found in the pancreas on all days, with a peak on day 3. Infection tended to increase Fe in both serum and the pancreas. The Cu/Zn ratio in the pancreas increased early in the infection because of a great decrease in Zn. In serum, the Cu/Zn ratio was not increased until day 9 of the disease. In the pancreas, MT1 decreased, whereas DMT1 tended to increase on day 6, and ZnT-5 increased progressively during the course of the disease. Conclusions: Virus-induced changes in trace elements, MT1, DMT1, and ZnT-5 in the pancreas may reflect early stages of the development of pancreatitis and prestages of diabetic disease.

  • 11.
    Hammerling, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala Acad Hosp, SE-75185 Uppsala, Sweden..
    Laurila, Jonas Bergman
    Sahlgrens Univ Hosp, Gothia Forum, Sahlgrenska Biobank, Gothenburg, Sweden..
    Grafstrom, Roland
    Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden.;VTT Tech Res Ctr Finland, Knowledge Intens Prod & Serv, Turku, Finland..
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala Acad Hosp, SE-75185 Uppsala, Sweden..
    Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association2016In: Critical reviews in food science and nutrition, ISSN 1040-8398, E-ISSN 1549-7852, Vol. 56, no 4, p. 614-634Article, review/survey (Refereed)
    Abstract [en]

    Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC.

  • 12.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Benyamin, Gad
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Lindh, Ulf
    Department of Oncology, Radiology and Clinical Immunology. Metallbiologisk forskning.
    Fohlman, Jan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Friman, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Trace element changes in the pancreas during viral infection in mice.2003In: Pancreas, ISSN 1536-4828, Vol. 26, no 2, p. 190-6Article in journal (Refereed)
  • 13.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Benyamin, Gad
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Lindh, Ulf
    Department of Oncology, Radiology and Clinical Immunology. Metallbiologisk forskning.
    Friman, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Sequential changes in Fe, Cu, and Zn in target organs during early Coxsackievirus B3 infection in mice.2003In: Biol Trace Elem Res, ISSN 0163-4984, Vol. 91, no 2, p. 111-24Article in journal (Refereed)
  • 14.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Interactions among infections, nutrients and xenobiotics2007In: Critical reviews in food science and nutrition, ISSN 1040-8398, E-ISSN 1549-7852, Vol. 47, no 5, p. 499-519Article, review/survey (Refereed)
    Abstract [en]

    During recent years there have been several incidents in which symptoms of disease have been linked to consumption of food contaminated by chemical substances (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Furthermore, outbreaks of infections in food-producing animals have attracted major attention regarding the safety of consumers, e.g., Bovine Spongiform Encephalitis (BSE) and influenza in chicken. As shown for several xenobiotics in an increasing number of experimental studies, even low-dose xenobiotic exposure may impair immune function over time, as well as microorganism virulence, resulting in more severe infectious diseases and associated complications. Moreover, during ongoing infection, xenobiotic uptake and distribution are often changed resulting in increased toxic insult to the host. The interactions among infectious agents, nutrients, and xenobiotics have thus become a developing concern and new avenue of research in food toxicology as well as in food-borne diseases. From a health perspective, in the risk assessment of xenobiotics in our food and environment, synergistic effects among microorganisms, nutrients, and xenobiotics will have to be considered. Otherwise, such effects may gradually change the disease panorama in society.

  • 15.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Mohamed, Nahla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gadhasson, Inga-Lill
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Virus induces metal-binding proteins and changed trace element balance in the brain during the course of a common human infection (coxsackievirus B3) in mice2007In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 381, no 1-3, p. 88-98Article in journal (Refereed)
    Abstract [en]

    Autopsy of the brain has shown a change in trace element balance in some virus-infected individuals, but it is not known whether this event was a result of the infection. In the present study coxsackievirus B3 (CVB3) adapted to Balb/c mice was used to study whether infection induces gene expression of the metal-binding/transporting proteins metallothionein (MT1 and MT3) and divalent-metal transporter 1 (DMT1) and whether it changes the balance of trace elements in the brain. Virus and MT1, MT3, and DMT1 were quantitatively measured by RT-PCR on days 3, 6 and 9 of the infection. Trace elements (13) were measured in serum and the brain by ICP-MS. High numbers of virus were found in the brain on days 3 and 6, but virus counts were decreased and present only in 50% of the mice on day 9. Gene expression of MT1 tended to increase on all days, whereas that of MT3 only showed a minor and not significant increase on day 3. No clear effect was observed in the expression of DMT1. The increase of MT3 was correlated to the brain concentration of Cu. The Cu/Zn ratio in serum increased as a response to the infection. There was a similar decrease in Cd in serum and the brain. On day 6 of the infection, Hg increased in the brain (p<0.05) and was positively correlated to a concomitant decrease (p<0.05) in serum. Virus numbers in the brain were on day 6 positively correlated (p<0.05) to As concentrations. Enteroviral infections may therefore be an underlying factor regarding the changes in essential as well as potentially toxic trace elements in the brain.

  • 16.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Glynn, Anders
    Wikberg, I
    Netzel, E
    Lindh, Ulf
    Department of Oncology, Radiology and Clinical Immunology. Metallbiologisk forskning.
    Metallothionein is induced and trace element balance changed in target organs of a common viral infection.2004In: Toxicology, Vol. 199, no 2-3, p. 241-50Article in journal (Refereed)
  • 17.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Gunnarsson, K
    Persson, R
    Lindh, Ulf
    Department of Oncology, Radiology and Clinical Immunology. Metallbiologisk forskning.
    Stålhandske, T
    Effects of a superantigen-antibody recombinant fusion protein (r-C242 Fab-SEA) on toxicological responses in the anaesthetised rabbit.2003In: Toxicology, Vol. 185, no 1-2, p. 161-74Article in journal (Refereed)
  • 18.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Enheten för metallbiologisk forskning.
    Minqin, Ren
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Watt, Frank
    Selenium and mercury are redistributed to the brain during viral infection in mice2005In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 108, no 1-3, p. 215-224Article in journal (Refereed)
    Abstract [en]

    As part of the general host response to coxsackievirus B3 (CB3) infection, the concentration of essential and nonessential trace elements changes in different target organs of the infection. Essential (e.g., Se) and nonessential (e.g., Hg) trace elements are known to interact and affect inflammatory tissue lesions induced by CB3 infection. However, it is unknown whether these changes involve the brain. In the present study, the brain Hg and Se contents were measured through inductively coupled plasma-mass spectrometry and their distribution investigated by means of nuclear microscopy in the early phase (d 3) of CB3 infection in normally fed female Balb/c mice. Because of the infection, the concentration of Hg (4.07 +/- 0.46 ng/g wet wt) and Se (340 +/- 16 ng/g wet wt) in the brain increased twofold for Hg (8.77 +/- 1.65 ng/g wet wt, p < 0.05) and by 36% for Se (461 +/- 150 ng/g wet wt, ns). Nuclear microscopy of brain sections from mice having elevated Se and Hg concentrations failed to find localized levels of the elements high enough to make detection possible, indicating approximately homogeneous tissue distribution. Although the pathophysiological interpretation of these findings requires further research, the increase of Hg in the brain during infection might have an influence on the pathogenesis of the disease.

  • 19.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Siller, M.
    Stålhandske, T.
    Effects of buprenorphine on body temperature, locomotor activity and cardiovascular function when assessed by telemetric monitoring in rats2008In: Laboratory Animals. Journal of the Laboratory Animal Science Association, ISSN 0023-6772, E-ISSN 1758-1117, Vol. 42, no 2, p. 149-160Article in journal (Refereed)
    Abstract [en]

    Buprenorphine is a potent analgesic commonly used clinically in humans and rodents experiencing severe pain. However, effects of therapeutic doses on locomotor activity and the cardiovascular system have not been studied in conscious animals. The effects of buprenorphine were therefore evaluated in this study using telemetric monitoring in conscious animals. Telemetry transmitters were implanted in the peritoneal cavity of Wistar rats with a pressure catheter in the aorta and electrodes for electrocardiogram (ECG) recording subcutaneously. After a single subcutaneous administration of saline, each rat was administered single subcutaneous doses of 0.006, 0.03 or 0.15 mg/kg body weight (bw) of buprenorphine. During a 10 h period after administration, buprenorphine induced a varying dose-dependent increase in body temperature, heart rate, dP/dt and systolic-diastolic blood pressure, as well as a corresponding decrease in QT time. At high dose, however, QT time was still decreased 24 h post-administration, but no arrhythmias or visual changes were observed in the ECG complex. Body temperature and heart rate increased at the high dose of buprenorphine, even at 20-24 h after administration. Moreover, the high dose of buprenorphine induced a biphasic response in diastolic blood pressure, with an early and pronounced increase that, at 14 h after administration, reversed to a decrease, failing to normalize within 24 h post-dosage. The results indicate that buprenorphine induces long-lasting effects (such as body temperature and cardiovascular effects) in the rat after a single subcutaneous dose at 0.15 mg/kg bw.

  • 20.
    Ilbäck, Nils-Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siller, Max
    Stålhandske, Torbjörn
    Evaluation of cardiovascular effects of caffeine using telemetric monitoring in the conscious rat2007In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 45, no 5, p. 834-842Article in journal (Refereed)
    Abstract [en]

    Caffeine (1,3,7 trimethylxanthine) affects the cardiovascular system, with potential toxic effects ranging from a moderate increase in heart rate to more severe cardiac arrhythmias. Telemetry transmitters were implanted in Wistar rats in the peritoneal cavity with a pressure catheter in the aorta and electrodes for electrocardiogram (ECG) recording subcutaneously. After a single oral administration of saline, each rat was administered single oral doses of 5, 15 and 45 mg/kg b.w. of caffeine. Caffeine was found to induce, to various degrees, a dose-dependent early increase in spontaneous physical activity, heart rate, dp/dt and systolic–diastolic blood pressure. No arrhythmias or visual changes were observed in the ECG complex. High doses induced more strong responses and of longer duration. The increase in systolic blood pressure at the median dose remained in the rats until 20 h after administration. However, the highest dose of caffeine (45 mg/kg b.w.) induced a biphasic response, with an early and pronounced increase in body temperature, spontaneous physical activity, systolic and diastolic blood pressure that later decreased, except for the systolic blood pressure. The results show that the dose level for long-lasting signs of intoxication to develop in the rat, in terms of effects on spontaneous physical activity, body temperature and cardiovascular function, was reached after a single oral dose of caffeine at 45 mg/kg b.w.

  • 21.
    Lundgren, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Darnerud, Per Ola
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    The flame-retardant BDE-99 dose-dependently affects viral replication in CVB3-infected mice2013In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 91, no 10, p. 1434-1438Article in journal (Refereed)
    Abstract [en]

    The flame retardant component 2,2',4,4',5-penta-BDE (BDE-99) is found in the environment and in human tissues and fluids. In mice the common human coxsackievirus B3 (CVB3) infection has been shown to change the tissue distribution of BDE-99. We now investigate how CVB3 infection in mice affects liver uptake of C-14 at two doses of radiolabelled BDE-99, and whether increased tissue levels are related to changed virus replication and gene expression of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1). Mice were infected on day 0, orally treated either with 200 mu g or 20 mg C-14-BDE-99/kg bw on day 1, and euthanised on day 3. Serum and liver levels of C-14-BDE-99, as well as virus levels and gene expressions of MCP-1 in the liver, were measured. In non-infected mice, there was a dose-dependent uptake of BDE-99 in both liver and serum, and in infected animals the liver BDE-99 levels was further increased. When comparing infected mice exposed to the two BDE-99 doses, the higher BDE dose resulted in increased virus amounts in the liver, and decreased infection-induced expression of MCP-1. Consequently, a high enough dose/tissue concentration of BDE-99 may result in a disturbed mobilisation of immune cells into infected tissues that could explain higher virus titres and a possibly altered clinical course of the disease. Moreover, the fact that CVB3 infection increased the BDE-99 levels in liver but not in serum may impair the risk assessment of polybrominated diphenyl ethers (PBDEs) in subclinical and clinically infected individuals, as serum levels is the common marker of exposure. 

  • 22.
    Nyström-Rosander, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindqvist, Olle
    Thelin, Stefan
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Trace element changes in sclerotic heart valves from patients are expressed in their blood2004In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 17, no 2, p. 121-128Article in journal (Refereed)
    Abstract [en]

    The pathogenesis of some heart diseases has been associated with changes in the balance of certain trace elements. However, whether blood trace element changes exist that are related to changes in the cardiovascular system are, in most cases, unknown. In this study, blood trace element levels were analysed in 46 patients with non-rheumatic aortic valve sclerosis that were previously shown to have a disturbed trace element balance in their valve tissue, including 11/15 elements. Results showed significant changes of blood levels of 8/15 trace elements in these patients when compared with blood levels in 46 healthy controls. Of these elements, Cd and Mg were the only elements that increased in both blood and valves. Cu and Se were increased in blood but decreased in valves, whereas Co and Zn were decreased in blood but increased in valves. Several elements (As, Ca, Fe, Pb, and V) were unchanged in blood although changed in valves. Although Mn and Hg showed changes in blood, this was not evident in the valves. Al and Ag were the only elements that did not change in both blood and valves. Significant covariation in blood and valve levels was only observed for Al and Pb. The recorded pattern of trace element changes indicates a complex competition/exchange between body compartments in this disease, where the increased blood Cu/Zn ratio suggests an ongoing infectious/inflammatory process.

  • 23.
    Nyström-Rosander, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hjelm, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Thelin, Stefan
    Lindqvist, Olle
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Interactions between Chlamydia pneumoniae and trace elements: a possible link to aortic valve sclerosis2003In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 91, no 2, p. 97-110Article in journal (Refereed)
    Abstract [en]

    An association between Chlamydia pneumoniae and atherosclerotic cardiovascular diseases has been suggested. However, other factors may interact in the pathogenesis of valve sclerosis. Therefore, trace elements important for C. pneumoniae growth and host defense and markers of C. pneumoniae infection were studied in sclerotic valves and serum. Forty-six patients undergoing surgical valve replacement due to advanced aortic sclerosis were prospectively studied. Valves from 15 forensic cases with no heart valve disease and plasma from 46 healthy volunteers served as controls. C. pneumoniae was detected in 16/46 (34.8 %) sclerotic valves and in 0/15 forensic controls. IgG and IgA antibodies to C. pneumoniae were present in 54.3% and 26.1 % patients, respectively. In the patients' valves, iron, magnesium, and zinc each correlated to calcium, a marker of the histopathological severity of disease. Patients showed 10- to 70-fold increases of these trace elements in valves and an increased copper/zinc ratio in serum. In a majority of aortic sclerosis patients, one of several markers of C. pneumoniae infection were detected and all patients had a disturbed trace element balance in valves and serum suggestive of active immune process and infection. The pattern of trace element changes was essentially similar regardless of positive makers of C. pneumoniae, suggesting a similar etiopathogenesis in both subgroups. The 20-fold increase in iron, essential for C. pneumoniae growth, in sclerotic valves suggests a new possible link to this infection in aortic sclerosis.

  • 24.
    Nyström-Rosander, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lindquist, Olle
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Trace element changes in sclerotic heart valves from patients undergoing aortic valve surgery.2002In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 88, no 1, p. 9-24Article in journal (Other academic)
    Abstract [en]

    Several trace elements are essential nutrients for an optimal functioning of organs and tissues, including the immune system and the heart. The pathogenesis of some heart diseases has been associated with changes in the balance of certain trace elements. The etiology of nonrheumatic aortic valve sclerosis is unknown, however. A prospective study was performed on trace element changes in the sclerotic valves of 46 patients undergoing surgical aortic valve replacement because of aortic stenosis. Valves from 15 individual forensic cases without known cardiac disease served as controls. The contents of 15 trace elements (Al, As, Cd, Ca, Co, Cu, Fe, Pb, Mg, Mn, Hg, Se, Ag, V, and Zn) were measured by inductively coupled plasma - mass spectrometry (ICP-MS) of aortic valve tissue from both patients and forensic autopsy controls. Some trace elements showed similar concentrations in sclerotic and control valves (Al, Ag, Hg, Mn), whereas a few were moderately changed in the sclerotic as compared with the control valves, including an increase in Cd by 52% (p < 0.05) and decreases in Se by 14% (p < 0.05), in V by 42% (p < 0,001), and in Cu by 45% (p < 0.001). However, there were pronounced increases (p < 0.001) in the concentrations of As (5-fold), Ca (70-fold), Co(10-fold), Fe (20-fold), Pb (8-fold), Mg (20-fold), and Zn (10-fold) in the sclerotic valves. Thus, sclerotic aortic valve disease is associated with a pronounced imbalance in several trace elements of well-known importance for cardiovascular and immune function as well as in trace elements with hitherto unknown significance.

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