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  • 1. Abbasi, Arshad Mehmood
    et al.
    Khan, Mir Ajab
    Khan, Nadeem
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Shah, Munir H
    Ethnobotanical survey of medicinally important wild edible fruits species used by tribal communities of Lesser Himalayas-Pakistan2013In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 148, no 2, p. 528-536Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Present survey was conducted to explore ethnomedicinal uses and cultural importance of wild edible fruits species by the inhabitants of Lesser Himalayas-Pakistan. Materials and methods: Information was obtained through informed consent semi-structured interviews, questionnaires, market survey, focus group conversation, unceremonious dialogue and village walks with key informants. Cultural significance of each species was calculated based on use report by participants at each study site. Results: A total of 35 wild edible fruits belonging to 21 genera and 17 families were used for the treatment of various ailments and consumed. Rosaceae was found dominating family with (8 spp.), followed by Moraceae (6 spp.), Rhamnaceae (5 spp.), Palmae and Vitaceae (2 spp. each) and remaining families were represented by one species each. Fruits (48%) were found highly utilized plant parts, followed by leaves (34%), bark, flowers and seeds (4% each), branches, latex and roots (2% each). Water was used as a medium for preparation while milk, ghee, oil, egg and butter are used for application. Modes of preparation were fall into seven categories like fresh parts eaten raw (38%), powder (24%), decoction (20%), extract (12 %), paste (4%), juice and latex (2% each). Based on cultural important index (CI) Morus nigra was found most significant species within top ten fruit plants followed by Morus alba, Olea ferruginea, Berberis lycium, Pyrus pashia, Ficus carica, Ficus palmata, Ziziphus mauritiana, Diospyros lotus and Ziziphus nummularia. Conclusions: Traditional uses of wild edible plant depend mainly on socio-economic factors rather than climatic conditions or wealth of flora. Use reports and citation demonstrated that there is a common cultural heritage regarding the gathered food plants. Further investigation is required for Antioxidant study, essential and toxic components, pharmacological applications; dietary requirements and biotechnological techniques to improve yields.

    (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 2.
    Aggett, Peter
    et al.
    Lancashire School of Health and Postgraduate Medicine, University of Central Lancashire, Preston, United Kingdom.
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Nordberg, Monica
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Essential metals: assessing risks from deficiency and toxicity2022In: Handbook on the toxicology of metals: volume I: general considerations / [ed] Gunnar F. Nordberg; Max Costa, London: Academic Press, 2022, 5, p. 385-406Chapter in book (Refereed)
    Abstract [en]

    Recommendations aimed at protecting the public from toxicity of essential elements including essential metals have usually been developed separately from those recommendations aimed at protection from deficiency. Because of the uncertainties involved in the evaluations, these recommendations have sometimes been in conflict, emphasizing the need for a new approach, including a balanced consideration of nutritional and toxicological data. In developing these new principles of evaluation, some basic concepts based on interindividual variability in sensitivity to deficiency and toxicity must be considered. Such variation translates into one interval of (low) daily intakes, at which there is a risk of developing deficiency, and another interval of (high) dietary intakes at which toxicity may occur. In most instances, there is a third set of intakes in between, which represents the acceptable range of oral intake (AROI), in which no adverse effects occur. This range determined from a homeostatic or biologically based (BBM) approach, which is discussed here, would be expected to apply to the general population. It must be noted, however, that this range would not protect all persons from adverse effects: this applies to those with genetically determined sensitivity, who may require higher intakes to avoid deficiency or lower intakes to avoid toxicity than those defined by the AROI. Nonetheless, AROI could be derived to protect 95% of the general human population from minimal adverse effects of deficiency or toxicity arising from inadequate and excessive intakes. As such the correspondence of these values to current Health-Based Guidance Values (HBGVs) and reference intakes of essential metals (EMs), and the roles of the BBM/Homeostatic Approach in Risk Assessment of EMs are of important public health interest.

  • 3. Aitio, Antero
    et al.
    Bernard, Alfred
    Fowler, Bruce A.
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    Biological Monitoring and Biomarkers2007In: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, p. 65-78Chapter in book (Other academic)
    Abstract [en]

    Biomonitoring was developed for the assessment of the health risks from exposure to metals at work, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used to assess exposure from the environment. Biomonitoring and assessment of external exposure are complementing activities, where the exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis, which is very poorly developed for biomonitoring. Biomonitoring, on the other hand, provides information on exposure from all sources, and via all absorption routes, and also considers accumulation of the chemical in the body. Biomonitoring using exposure biomarkers thus considers interindividual differences in the absorption, whereas use of effect biomarkers also considers interindividual differences in sensitivity. Few effect biomarkers, however, have been validated. Biomarkers of susceptibility have so far not been adapted for use in metal toxicology. The major challenges of biomonitoring are the development of monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible meaningful biomonitoring of metals with a short half-time; development of exposure biomarker guidance values specific to individual species of different metals; expansion of the repertoire of validated effect biomarkers; and validation and application to effect monitoring of the "omic" technologies.

  • 4. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, p. 164-173Article in journal (Refereed)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 5.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Catholic Univ Louvain, Brussels, Belgium.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Univ Agr Sci, Umea, Sweden.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity2018In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 175, no 6, p. 877-890Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFN gamma (10 ng.mL(-1)). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS IFN gamma disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1 alpha mRNA expression. CYP1B1 induction is inhibited by the NF-kappa B inhibitor ammonium pyrrolidinedithiocarbamate (100 mu M) but not by the HIF1 alpha inhibitor 3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole (50 mu M). Inhibition of CYP1B1 with the selective inhibitor 2,4,3,5-tetramethoxystilbene (100 nM) partly reverses the effects of IFN gamma on epithelial permeability. CONCLUSIONS AND IMPLICATIONS These data suggest that increased expression of CYP1B1 is involved in the effects of IFN gamma on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFN gamma and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.

  • 6.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rankin, Linda
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gouveia-Figueira, Sandra C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells2019In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, no 10, p. 1470-1480Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Endocannabinoids and related N-acylethanolamines (NAEs) are involved in regulation of gut function, but relatively little is known as to whether inflammatory cytokines such as IFN affect their levels. We have investigated this in vitro using cultures of T84 colon cancer cells.

    Experimental approach: T84 cells, when cultured in monolayers, differentiate to form adult colonic crypt-like cells with excellent permeability barrier properties. The integrity of the permeability barrier in these monolayers was measured using transepithelial electrical resistance (TEER). NAE levels were determined by ultra-performance liquid chromatography-tandem mass spectrometric analysis. Expression of the enzymes involved in NAE and 2-arachidonoylglycerol (2-AG) turnover were assessed with qPCR.

    Key results: IFN treatment for 8 or 24h increased levels of both endocannabinoids (anandamide and 2-AG) and the related NAEs. The treatment did not affect the rate of hydrolysis of either anandamide or palmitoylethanolamide by intact cells, and in both cases, fatty acid amide hydrolase (FAAH) rather than NAE-hydrolysing acid amidase (NAAA) was mainly responsible for the hydrolysis of these NAEs. IFN treatment reduced the TEER of the cells in a manner that was not prevented by inhibition of either FAAH or NAAA but was partially reversed by apical administration of the NAE palmitoylethanolamide.

    Conclusion and implications: IFN treatment mobilized endocannabinoid and related NAE levels in T84 cells. However, blockade of anandamide or NAE hydrolysis was insufficient to negate the deleterious effects of this cytokine upon the permeability barrier of the cell monolayers.

  • 7.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Sorti, René
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 7622Article in journal (Refereed)
    Abstract [en]

    The large pore ion channel pannexin-1 (Panx1) has been reported to play a role in the cellular uptake and release of anandamide (AEA) in the hippocampus. It is not known whether this is a general mechanism or limited to the hippocampus. We have investigated this pharmacologically using T84 colon cancer cells. The cells expressed Panx1 at the mRNA level, and released ATP in a manner that could be reduced by treatment with the Panx1 inhibitors carbenoxolone and mefloquine and the Panxl substrate SR101. However, no significant effects of these compounds upon the uptake or hydrolysis of exogenously applied AEA was seen. Uptake by T84 cells of the other main endocannabinoid 2-arachidonoylglycerol and the AEA homologue palmitoylethanolamide was similarly not affected by carbenoxolone or mefloquine. Total release of tritium from [H-3]AEA-prelabelled T84 cells over 10 min was increased, rather than inhibited by carbenoxolone and mefloquine. Finally, AEA uptake by PC3 prostate cancer and SH-SY5Y neuroblastoma cells, which express functional Panx1 channels, was not inhibited by carbenoxolone. Thus, in contrast to the hippocampus, Panx1 does not appear to play a role in AEA uptake and release from the cells studied under the conditions used.

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  • 8. Allgardsson, Anders
    et al.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Akfur, Christine
    Worek, Franz
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet2017In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 22, no 9, article id 1433Article in journal (Refereed)
    Abstract [en]

    Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.

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  • 9. Anand, Praveen
    et al.
    Whiteside, Garth
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hohmann, Andrea G
    Targeting CB2 receptors and the endocannabinoid system for the treatment of pain2009In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 60, no 1, p. 255-266Article in journal (Refereed)
    Abstract [en]

    The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.

  • 10. Andersen, Toril
    et al.
    Bleher, Stefan
    Flaten, Goril Eide
    Tho, Ingunn
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Skalko-Basnet, Natasa
    Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy2015In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 13, no 1, p. 222-236Article in journal (Refereed)
    Abstract [en]

    Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today's drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.

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  • 11. Andersen, Toril
    et al.
    Mishchenko, Ekaterina
    Flaten, Gøril Eide
    Ericson Sollid, Johanna U.
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Tho, Ingunn
    Škalko-Basnet, Nataša
    Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes2017In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 15, no 3, article id 64Article in journal (Refereed)
    Abstract [en]

    Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.

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  • 12. Andersen, Toril
    et al.
    Vanić, Zeljka
    Flaten, Gøril Eide
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Tho, Ingunn
    Skalko-Basnet, Nataša
    Pectosomes and chitosomes as delivery systems for metronidazole: the one-pot preparation method2013In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 5, no 3, p. 445-456Article in journal (Refereed)
    Abstract [en]

    Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indicate that the polymer is present on the liposomal surface, embedded within inner liposomal bilayers, and entrapped inside the aqueous compartment. The next step in the evaluation of this system is the testing of its mucoadhesiveness.

  • 13.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Martinez, Nicolas
    Zeller, Dominik
    Allgardsson, Anders
    Koza, Michael M.
    Frick, Bernhard
    Ekström, Fredrik
    Peters, Judith
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering2018In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 36, p. 8516-8525Article in journal (Refereed)
    Abstract [en]

    The enzyme acetylcholinesterase (AChE) is essential in humans and animals because it catalyzes the breakdown of the nerve-signaling substance acetylcholine. Small molecules that inhibit the function of AChE are important for their use as drugs in the, for example, symptomatic treatment of Alzheimer's disease. New and improved inhibitors are warranted, mainly because of severe side effects of current drugs. In the present study, we have investigated if and how two enantiomeric inhibitors of AChE influence the overall dynamics of noncovalent complexes, using elastic incoherent neutron scattering. A fruitful combination of univariate models, including a newly developed non-Gaussian model for atomic fluctuations, and multivariate methods (principal component analysis and discriminant analysis) was crucial to analyze the fine details of the data. The study revealed a small but clear increase in the dynamics of the inhibited enzyme compared to that of the noninhibited enzyme and contributed to the fundamental knowledge of the mechanisms of AChE-inhibitor binding valuable for the future development of inhibitors.

  • 14.
    Andersson, Patrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van der Burght, Aafje S.A.M.
    van den Berg, Martin
    Tysklind, Mats
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species: ranking scales and species differences2000In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 19, no 5, p. 1454-1463Article in journal (Refereed)
    Abstract [en]

    Cytochrome P4501A–induced activity of 20 selected polychlorinated biphenyls (PCBs) was evaluated by measuring ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities induced in the hepatocytes of cynomolgus monkeys, male castrated pigs, and chicken embryos. Quantitative structure-activity relationships have been established, including 52 physi-cochemical parameters and different measures of the dose-response curves. Relative effect potencies are predicted for the 154 tetra-to hepta-PCBs and reported for the most potent congeners according to both EC50 and maximal response values. Important physicochemical parameters of the PCBs as related to the modeled activity are parts of their ultraviolet absorption spectra, the Henry's law constant, the ionization potential, and the octanol-water partition coefficient. Interspecies differences were found in terms of varied sensitivity to different structural subgroups of the compounds. The chicken hepatocyte assay showed the most specific structure-activity relationship, with high activity for the non-ortho PCBs, whereas the pig hepatocytes responded even for some di- to tetra-ortho PCBs. An interspecies response, the principal induction potency, is presented for the 41 most potent PCBs. These responses showed strong correlation with the toxic equivalency factors and are likely to be useful in risk assessment of the compounds.

  • 15. Aplander, Karolina
    et al.
    Marttila, Marko
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Manner, Sophie
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sterner, Olov
    Ellervik, Ulf
    Molecular wipes: application to epidemic keratoconjuctivitis2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 19, p. 6670-6675Article in journal (Refereed)
    Abstract [en]

    Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 mu M) and Ad infectivity (IC(50) = 0.7 mu M). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.

  • 16. Arana, Alejandro
    et al.
    Pottegard, Anton
    Kuiper, Josephina G.
    Crellin, Elizabeth
    Reutfors, Johan
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lund, Lars Christian
    Houben, Eline
    Booth, Helen
    Calingaert, Brian
    Kaye, James A.
    Gembert, Karin
    Rothman, Kenneth J.
    Dedman, Daniel
    Kieler, Helle
    Gutierrez, Lia
    Hallas, Jesper
    Perez-Gutthann, Susana
    To what extent are topical tacrolimus or pimecrolimus associated with increased risk of skin cancer and lymphoma?: Longterm results from Joelle study2020In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 29, p. 568-569Article in journal (Other academic)
  • 17.
    Arokoski, Jari
    et al.
    Kuopio University Hospital, Department of surgery and Clinic of rehabilitation, Kuopio, Finland.
    Vuoltenaho, Katriina
    Department of Medicine, Pharmacology, University of Tampere, Tampere, Finland; Tampere University Hospital, Tampere, Finland.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland.
    Moilanern, Eeva
    Department of Medicine, Pharmacology, University of Tampere, Tampere, Finland; Tampere University Hospital, Tampere, Finland.
    Nivelrikon lääkehoito [Medical treatment of osteoarthritis]2008In: Duodecim, ISSN 0012-7183, Vol. 124, p. 1899--1907Article, review/survey (Refereed)
    Abstract [fi]

    teho ei riitä, siirrytään tulehduskipulääkkeisiin niiden haitat huomioiden. Ellei parasetamolilla ja tulehduskipulääkkeillä saada riittävää tehoa nivelrikkokipuun tai niitä ei haittavaikutusten vuoksi ole mahdollista käyttää, kipua voidaan hoitaa opioideilla. Niveleen annettu glukokortikoidi- tai hyaluronaattihoito näyttää lievittävän nivelkipua. Glukosamiini saattaa helpottaa nivelrikon oireita, mutta luotettava tieteellinen näyttö sen tehosta puuttuu edelleen. Kehitteillä on nykyisiin vaikutusmekanismeihin tukeutuvia oireita lievittäviä lääkeaineita, mutta merkittävämpi ja haastavampi pitkän aikavälin tavoite on kehittää rustovaurioita hidastavia lääkkeitä. Potentiaalisia tautiprosessiin vaikuttavia lääkeaineita ovat mm. rustomatriksia hajottavien entsyymien estäjät, typpioksidisynteesin estäjät, sytokiinimodulaattorit ja PPAR-agonistit.

  • 18.
    Audouze, Karine
    et al.
    Université de Paris, T3S, Inserm U1124, Paris, France.
    Zgheib, Elias
    Université de Paris, T3S, Inserm U1124, Paris, France.
    Abass, Khaled
    Thule Institute, University of Arctic, University of Oulu, Oulu, Finland; Department of Pesticides, Menoufia University, Menoufia, Egypt.
    Baig, Asma H.
    Centre for Pollution Research and Policy, Brunel University London, Uxbridge, United Kingdom.
    Forner-Piquer, Isabel
    Centre for Pollution Research and Policy, Brunel University London, Uxbridge, United Kingdom.
    Holbech, Henrik
    Department of Biology, University of Southern Denmark, Odense, Denmark.
    Knapen, Dries
    Zebrafishlab, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.
    Leonards, Pim E. G.
    Department of Environment and Health, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
    Lupu, Diana I.
    Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Palaniswamy, Saranya
    Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
    Rautio, Arja
    Thule Institute, University of Arctic, University of Oulu, Oulu, Finland.
    Sapounidou, Maria
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Martin, Olwenn V.
    Centre for Pollution Research and Policy, Brunel University London, Uxbridge, United Kingdom.
    Evidenced-based approaches to support the development of endocrine-mediated adverse outcome pathways: challenges and opportunities2021In: Frontiers in Toxicology, E-ISSN 2673-3080, Vol. 3, article id 787017Article in journal (Refereed)
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  • 19. Aureliano, M.
    et al.
    Ohlin, C. Andre
    Decavanadate in vitro and in vivo effects: facts and opinions2014In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 137, p. 123-130Article in journal (Refereed)
    Abstract [en]

    This review covers recent advances in the understanding of the in vitro and in vivo effects of decavanadate, (V10O28)(6-), particularly in mitochondria. In vivo toxicological studies involving vanadium rarely account for the fact that under physiological conditions some vanadium may be present in the form of the decavanadate ion, which may behave differently from ortho- and metavanadates. It has for example been demonstrated that vanadium levels in heart or liver mitochondria are increased upon decavanadate exposure. Additionally, in vitro studies have shown that mitochondrial depolarization (IC50, 40 nM) and oxygen consumption (IC50, 99 nM) are strongly affected by decavanadate, which causes reduction of cytochrome b (complex III). We review these recent findings which together suggest that the observed cellular targets, metabolic pathway and toxicological effects differ according to the species of vanadium present. Finally, the toxicological effects of decavanadate depend on several factors such as the mode of administration, exposure time and type of tissue. (C) 2014 Elsevier Inc. All rights reserved.

  • 20. Aureliano, Manuel
    et al.
    Fraqueza, Gil
    Ohlin, C. Andre
    Ion pumps as biological targets for decavanadate2013In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 42, no 33, p. 11770-11777Article in journal (Refereed)
    Abstract [en]

    The putative applications of poly-, oligo-and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e. g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono-and polyoxometalate ions with ion pumps, with particular focus on the interaction of decavanadate with Ca2+-ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca2+-ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore need to cross through the membrane bilayer. In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca2+-ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V-10 (IC50 = 15 mu M) which is quite similar to the majority of the established therapeutic drugs.

  • 21.
    Back, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wåhlander, Håkan
    Hanseus, Katarina
    Bergman, Gunnar
    Naumburg, Estelle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Evidence of support used for drug treatments in pediatric cardiology2021In: Health Science Reports, E-ISSN 2398-8835, Vol. 4, no 2, article id e288Article in journal (Refereed)
    Abstract [en]

    Background and aims: Clinical support systems are widely used in pediatric care. The aim of this study was to assess the support for drug treatments used at pediatric cardiac wards and intensive care units in Sweden.

    Methods: Drug information, such as type of drug, indication, dose, and route of administration, for all in-hospital pediatric cardiac patients, was included in the study. Treatments were classified as either on-label (based on product information) or off-label. Support for off-label treatment was stratified by the use of clinical support systems (the national database on drugs, local, or other clinical experience guidelines).

    Results: In all, 28 patients were included in the study. The total number of drug treatments was 233, encompassing 65 different drugs. Overall, 175 (75%) treatments were off-label. A majority of off-label drug treatments were supported by other sources of information shared by experts. A total of 7% of the drug treatments were used without support.

    Conclusion:  Off-label drug treatment is still common in Swedish pediatric cardiac care. However, the majority of treatments were supported by the experience shared in clinical support systems.

    Key Points:

    • Seventy-five percent of all prescriptions in pediatric cardiology care were off-label.
    • A majority of patients received three or more drug treatments off-label.
    • Use of clinical support systems and guidelines was common, but in 7% of all drug treatments, no support was found for the chosen treatment.
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  • 22.
    Bajraktari, Gani
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Clinic of Cardiology, University Clinical Centre of Kosova, University of Prishtina, Prishtina, Kosovo.
    Bytyci, Ibadete
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Clinic of Cardiology, University Clinical Centre of Kosova, University of Prishtina, Prishtina, Kosovo.
    Bajraktari, Artan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Clinic of Cardiology, University Clinical Centre of Kosova, University of Prishtina, Prishtina, Kosovo.
    Henein, Michael Y.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Non-inferiority of 1 month versus longer dual antiplatelet therapy in patients undergoing PCI with drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials2022In: Therapeutic Advances in Chronic Disease, ISSN 2040-6223, Vol. 13Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this meta-analysis was to evaluate the safety of 1-month dual antiplatelet therapy (DAPT) followed by aspirin or a P2Y12 receptor inhibitor, after percutaneous coronary intervention (PCI) with drug-eluting stents (DES), based on the available evidence.

    Methods: PubMed, MEDLINE, Embase, Scopus, Google Scholar, CENTRAL, and ClinicalTrials.gov database search identified four RCTs of 26,431 patients who underwent PCI with DES and compared 1-month versus >1-month DAPT. The primary endpoint was major bleeding and co-primary endpoint stent thrombosis, and secondary endpoints included all-cause mortality, cardiovascular death, myocardial infarction (MI), stroke, and major adverse clinical events (MACE).

    Results: Compared with >1-month DAPT, the 1-month DAPT was associated with a similar rate of major bleeding (OR = 0.74, 95%CI: 0.51–1.07, p = 0.11, I2 = 67%), stent thrombosis (OR = 1.10, 95%CI: 0.82–1.47, p = 0.53, I2 = 0.0%), similar risk for all-cause mortality (OR = 0.89, 95%CI: 0.77–1.04, p = 0.14, I2 = 0%), CV death (OR = 0.80, 95% CI: 0.55–1.60, p = 0.24, I2 = 0.0%), MI (OR = 1.02, 95% CI: 0.88–1.19, p = 0.78, I2 = 0.0%), and stroke (OR = 0.76, 95% CI: 0.54–1.08, p = 0.13, I2 = 29%). The risk of MACE was lower (OR = 0.84, 95% CI: 0.73–0.98, p = 0.02, I2 = 39%) in the 1-month DAPT compared with the >1-month DAPT. Only patients with stable CAD had lower risk of MACE with 1-month DAPT (OR = 0.81, 95% CI: 0.67–0.98, p = 0.03, I2 = 21%) compared with >1-month DAPT.

    Conclusion: This meta-analysis proved the non-inferiority of 1-month DAPT followed by aspirin or a P2Y12 receptor inhibitor compared with long-term DAPT in patients undergoing PCI with DES.

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  • 23. Beckett, William S.
    et al.
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    Clarkson, Thomas W.
    Routes of Exposure, Dose, and Metabolism of Metals2007In: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, p. 39-64Chapter in book (Other academic)
    Abstract [en]

    The chapter first describes the main sources of exposure through air, food, and water but also points to unusual sources such as medical implants. Special attention is given to the processes of lung deposition and clearance of inhaled gases, vapors, and particulates, including ultrafine particles. In contrast to the extensive studies in the lung, absorption of metal in the gastrointestinal tract is less well understood. A diagrammatic example is given of the summation of all the absorption processes as they contribute to the total body burden. Since the publication of the first edition, new information has become available on the mechanisms of transport and distribution of metals in the body. In particular, it has been shown that several metals can cross cell membranes by specific carriers and ion channels intended for endogenous substrates. One well-documented example is the chromate oxyanion that is structurally similar to the sulfate anion and thereby gains entrance into the cell by the sulfate carrier. The fecal excretion of several metals occurs as the end result of extensive enterohepatic recirculation. In the case of certain organometallic species, the gut microflora may play a critical role converting the metal to the inorganic form, which is excreted in the feces. The renal accumulation and excretion of metals has also received considerable attention. The renal accumulation of cadmium in the form of its complex with the small molecular weight protein, metallothionein, still remains one of the best-documented mechanisms. Toxicokinetic models continue to be useful in providing a quantitative description of the overall body turnover of metals. They can be useful in establishing dose-response relationships where, for example, the range of half-times of elimination of a metal can contribute to the overall variance in the dose-response relationship. In addition to the observationally based models, pharmacokinetic models can be developed based a priori on physiological and mechanistic considerations. The chapter concludes with a consideration of indicator media that best reflect the dose to the critical organ.

  • 24. Becking, George C.
    et al.
    Nordberg, Monica
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    Essential Metals: Assessing Risks from Deficiency and Toxicity2007In: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, p. 163-176Chapter in book (Other academic)
    Abstract [en]

    Recommendations aimed at protecting the public from toxicity of essential elements have usually been developed separately from those recommendations aimed at protection from deficiency. Because of the uncertainties involved in the evaluations, these recommendations have sometimes been in conflict, emphasizing the need for a new approach, including a balanced consideration of nutritional and toxicological data. In developing these new principles of evaluation, some basic concepts based on interindividual variability in sensitivity to deficiency and toxicity must be considered. Such variation translates into one interval of (low) daily intakes, at which there is risk of developing deficiency, and another interval of (high) dietary intakes at which toxicity may occur. In most instances, there is a third set of intakes in between, which represents the acceptable range of oral intakes (AROI) in which no adverse effects occur. It must be noted, however, that such a range cannot be found that protects all persons from adverse effects. Those persons with genetically determined sensitivity may require higher intakes to avoid deficiency or lower intakes to avoid toxicity than those defined by the AROI. AROI is defined as protecting 95% of an unselected human population from minimal adverse effects of deficiency or toxicity.

  • 25. Bengtsson-Palme, Johan
    et al.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Huss, Mikael
    Kjellqvist, Sanela
    Kristiansson, Erik
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, D. G. Joakim
    Johansson, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 10, p. 6551-6560Article in journal (Refereed)
    Abstract [en]

    Previous studies of antibiotic resistance dissemination by travel have, by targeting only a select number of cultivable bacterial species, omitted most of the human microbiome. Here, we used explorative shotgun metagenomic sequencing to address the abundance of >300 antibiotic resistance genes in fecal specimens from 35 Swedish students taken before and after exchange programs on the Indian peninsula or in Central Africa. All specimens were additionally cultured for extended-spectrum beta-lactamase (ESBL)-producing enterobacteria, and the isolates obtained were genome sequenced. The overall taxonomic diversity and composition of the gut microbiome remained stable before and after travel, but there was an increasing abundance of Proteobacteria in 25/35 students. The relative abundance of antibiotic resistance genes increased, most prominently for genes encoding resistance to sulfonamide (2.6-fold increase), trimethoprim (7.7-fold), and beta-lactams (2.6-fold). Importantly, the increase observed occurred without any antibiotic intake. Of 18 students visiting the Indian peninsula, 12 acquired ESBL-producing Escherichia coli, while none returning from Africa were positive. Despite deep sequencing efforts, the sensitivity of metagenomics was not sufficient to detect acquisition of the low-abundant genes responsible for the observed ESBL phenotype. In conclusion, metagenomic sequencing of the intestinal microbiome of Swedish students returning from exchange programs in Central Africa or the Indian peninsula showed increased abundance of genes encoding resistance to widely used antibiotics.

  • 26.
    Bereketoglu, Ceyhun
    et al.
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Modig, Carina
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Pradhan, Ajay
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stasinopoulou, Sotiria
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Mitsiou, Dimitra J.
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Alexis, Michael N.
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Olsson, Per-Erik
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse2021In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 102, p. 43-55Article in journal (Refereed)
    Abstract [en]

    The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). in vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and β, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated mice were used to study the androgenic effects of TBECHαβ and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαβ affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαβ group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.

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  • 27.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Biomonitoring of metals: Analysis, non-linearity, possible artefacts, and genetics2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S12-S12Article in journal (Refereed)
  • 28.
    Bergdahl, Ingvar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Skerfving, Staffan
    Department of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
    Lead2022In: Handbook on the toxicology of metals: volume II: Specific metals / [ed] Gunnar F. Nordberg; Max Costa, Elsevier, 2022, 5, p. 427-493Chapter in book (Refereed)
    Abstract [en]

    Inorganic lead is the most extensively studied environmental toxin. Today's humans have in the order of 100 times higher lead exposure, compared to prehistoric humans, mainly from food. The exposure was even higher during the 20th century, mainly due to lead addition to gasoline. Today, high exposures occur in many occupations, but also through, for example, contaminated drinking water, traditional drugs, lead paint, and soil and dust in "hotspots" around mines and smelters. Absorbed lead is widely distributed in the body. It accumulates in the skeleton, which, in turn, causes endogenous exposure, especially during pregnancy/lactation and in osteoporosis. Lead passes over the placenta into the fetus, and via breast milk into the infant. The mode(s) of action is not known; different mechanisms might be operating at different concentrations. Toxic effects occur first in the nervous system of fetuses/infants/children, with small cognitive effects already at a mean blood lead concentration (B-Pb) of ≤0.05. μmol/L (≤10. μg/L; which is well below the worldwide mean), without any threshold. Lead effects have also been reported for the cardiovascular system [increase of blood pressure at B-Pb well below 0.5. μmol/L (100. μg/L)], the kidney, post- and prenatal growth, cognition in also adults and elderly, the blood, the immune system, the gastrointestinal tract, and the female and male reproduction. There is important genetic modification of the toxicity. Lead is carcinogenic in animal experiments, but there is only limited evidence in humans.

    The organolead compounds tetraethyl- and tetramethyllead, earlier used in enormous quantities in leaded gasoline, are easily absorbed at inhalation and through the skin and may cause acute encephalopathia.

  • 29.
    Bergh, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jonsson, P. Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, p. 4489-4494Article in journal (Refereed)
    Abstract [en]

    Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

  • 30. Berglund, Bjorn
    et al.
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindgren, Per-Eric
    Urban wastewater effluent increases antibiotic resistance gene concentrations in a receiving northern european river2015In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 34, no 1, p. 192-196Article in journal (Refereed)
    Abstract [en]

    Antibiotic-resistant bacteria are an emerging global problem that threatens to undermine important advances in modern medicine. The environment is likely to play an important role in the dissemination of antibiotic-resistance genes (ARGs) among both environmental and pathogenic bacteria. Wastewater treatment plants (WWTPs) accumulate both chemical and biological waste from the surrounding urban milieu and have therefore been viewed as potential hotspots for dissemination and development of antibiotic resistance. To assess the effect of wastewater effluent on a river that flows through a Swedish city, sediment and water samples were collected from Stangan River, both upstream and downstream of an adjacent WWTP over 3 mo. Seven ARGs and the integrase gene on class 1 integrons were quantified in the collected sediment using real-time polymerase chain reaction (PCR). Liquid chromatography-mass spectrometry was used to assess the abundance of 10 different antibiotics in the water phase of the samples. The results showed an increase in ARGs and integrons downstream of the WWTP. The measured concentrations of antibiotics were low in the water samples from the Stangan River, suggesting that selection for ARGs did not occur in the surface water. Instead, the downstream increase in ARGs is likely to be attributable to accumulation of genes present in the treated effluent discharged from the WWTP. Environ Toxicol Chem 2015;34:192-196. (c) 2014 SETAC

  • 31.
    Berglund, Åsa
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Responses to reduced industrial metal emissions: An ecotoxicological study on Pied Flycatcher (Ficedula hypoleuca, Aves)2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Metals have been used by humans for thousands of years, and this has resulted in increased concentrations in the biosphere. The environment around point-sources, such as mines and smelters, are of particular concern, as metals may accumulate to high concentrations, and potentially reach levels toxic to the local flora and fauna. This thesis focuses on the effects on pied flycatcher populations of two such point-sources, a lead mine and enrichment plant, and a sulfide ore smelter. Mining activities at the lead mine ceased in 2001 and pied flycatcher populations were assessed before and after the closure. At the sulfide ore smelter, pied flycatchers were studied during the 1980s. Since then, the metal emissions to air from the smelter (e.g. arsenic, cadmium, copper, mercury, lead and zinc) have been greatly reduced (by 93 – 99%).

    Pied flycatchers from these two contaminated environments differed in their responses to reduced atmospheric deposition. At the mine site, nestling responses reflected the reduced atmospheric deposition and less lead accumulated in their tissues. However, lead levels were still high enough to cause negative effects on blood status (δ-aminolevulinic acid dehydratase [ALAD], hemoglobin [Hb], hematocrit [ht], and mean cell hemoglobin concentration) and reproduction (reduced clutch size, increased mortality and reduced breeding success), as was observed when the mine was in operation. Along the pollution gradient away from the smelter, nestling concentrations reflected the metal load in the soil pool, accumulating over time, rather than the atmospheric deposition. This resulted in only a minor response to decreased metal deposition (slightly reduced liver lead concentrations at 3.5 – 90 km from the smelter). This suggests that in environments with highly polluted soils, decreased inputs of atmospheric metal deposition have only minor impacts, and recovery from contamination should not be expected within decades.

    The high metal concentrations in the vicinity of the smelter contributed to poorer blood status (ALAD, Hb and ht), induced oxidative damage and defenses, and decreased reproduction (increased mortality and reduced breeding success). There were only minor improvements in blood and reproductive variables at 3.5 km from the smelter.

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  • 32.
    Berglund, Åsa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Nyholm, Erik
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Slow improvements of metal exposure, health- and breeding conditions of pied flycatchers (Ficedula hypoleuca) after decreased industrial heavy metal emissionsManuscript (preprint) (Other academic)
    Abstract [en]

    The environment around metal industries, such as smelters, is often highly contaminated due to continuous deposition of metals. We studied nest box breeding populations of pied flycatchers (Ficedula hypoleuca) in a well-studied pollution gradient from a sulfide ore smelter in Northern Sweden, after reduced aerial metal emissions (by 93 – 99%) from the smelter. The deposition of As, Cd, Cu and Zn (based on moss samples) reflected the reduced emissions fairly well. However, nestling pied flycatchers had similar concentrations of these elements and Hg in tissue (bone, liver and blood) and feces in the 2000s, as in the 1980s, when the emissions were substantially higher. The slow improvement of metal accumulation in birds was explained by a food web transfer of metals mainly from the highly polluted soils, and it was concluded that nestlings reflected the slowly cycling soil pool, rather than the current atmospheric deposition. The exposure to high metal concentrations in the close vicinity of the smelter resulted in inhibited ALAD activities, depressed hemoglobin and hematocrit levels and increased mortality of nestlings. Our results indicate that in metal contaminated environments, the concentration in soils plays an important role for the response of pied flycatchers to reduced atmospheric deposition.

  • 33. Betari, Nibal
    et al.
    Sahlholm, Kristoffer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain.
    Morato, Xavier
    Godoy-Marin, Hector
    Jauregui, Olga
    Teigen, Knut
    Ciruela, Francisco
    Haavik, Jan
    Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole-In Vitro and In Vivo Investigations2020In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 11, article id 593416Article in journal (Refereed)
    Abstract [en]

    Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism.

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  • 34. Betari, Nibal
    et al.
    Teigen, Knut
    Sahlholm, Kristoffer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Haavik, Jan
    Synthetic corticosteroids as tryptophan hydroxylase stabilizers2021In: Future Medicinal Chemistry, ISSN 1756-8919, E-ISSN 1756-8927, Vol. 13, no 17, p. 1465-1474Article in journal (Refereed)
    Abstract [en]

    Background: Clinically, corticosteroids are used mainly for their immune-modulatory properties but are also known to influence mood. Despite evidence of a role in regulating tryptophan hydroxylases (TPH), key enzymes in serotonin biosynthesis, a direct action of corticosteroids on these enzymes has not been systematically investigated.

    Methodology & results: Corticosteroid effects on TPHs were tested using an in vitro assay. The compound with the strongest modulatory effect, beclomethasone dipropionate, activated TPH1 and TPH2 with low micromolar potency. Thermostability assays suggested a stabilizing mechanism, and computational docking indicated that beclomethasone dipropionate interacts with the TPH active site.

    Conclusion: Beclomethasone dipropionate is a stabilizer of TPHs, acting as a pharmacological chaperone. Our findings may inspire further development of steroid scaffolds as putative antidepressant drugs.

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  • 35.
    Bidleman, Terry F.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Melymuk, Lisa
    Forty-five years of foam: a retrospective on air sampling with polyurethane foam2019In: Bulletin of Environmental Contamination and Toxicology, ISSN 0007-4861, E-ISSN 1432-0800, Vol. 102, no 4, p. 447-449Article in journal (Refereed)
  • 36.
    Bjorkli, Christiana
    et al.
    Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway.
    Hemler, Mary
    Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway.
    Julian, Joshua B.
    Princeton Neuroscience Institute, Princeton University, NJ, Princeton, United States.
    Sandvig, Axel
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway; Department of Clinical Neurosciences, Division of Neuro Head and Neck, Umeå University Hospital, Umeå, Sweden.
    Sandvig, Ioanna
    Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway.
    Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 913971Article in journal (Refereed)
    Abstract [en]

    All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.

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  • 37.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The endocannabinoid system: a translational study from Achilles tendinosis to cyclooxygenase2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The endogenous cannabinoids anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) exert their effect by activating cannabinoid receptors (CB). These receptors mediate a broad range of physiological functions such as beneficial effects in pain and inflammation, although little is known about the expression of CB receptors in human pain conditions. AEA and 2-AG are short- lived molecules due to their rapid cellular accumulation and metabolism. The enzymes primarily responsible for their degradation are fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MGL) for 2-AG. Inhibition of endocannabinoid metabolism is a potential approach for drug development, and there is a need for the identification of novel compounds with inhibitory effects upon FAAH and MGL.

    In Paper I of this thesis, the expression of CB1 receptors in human Achilles tendon was examined. We found expression of CB1 receptors in tenocytes, blood vessel wall as well as in the perineurium of the nerve. A semi-quantitative analysis showed an increase of CB1 receptors in painful human Achilles tendinosis.

    In papers II and III, termination of AEA signalling was investigated via inhibition of FAAH. In Paper II, Flu-AM1, an analogue of flurbiprofen, was investigated. The compound inhibited both FAAH and the oxygenation of 2-AG by cyclooxygenase-2. In Paper III the antifungal compound ketoconazole was shown to inhibit the cellular uptake of AEA in HepG2, CaCo-2 and C6 cell lines in a manner consistent with inhibition of FAAH.

    The role of FAAH in gating the cellular accumulation of AEA was investigated in Paper IV. FAAH has been shown to control the concentration gradient of AEA across the plasmamembrane in RBL2H3 cells, whereas no such effect is seen in other FAAH-expressing cell lines. To determine whether this effect is assay dependent or due to intrinsic differences between the cell lines, we assayed four cell lines with different levels of FAAH expression using the same methodology. We found that the sensitivity of FAAH uptake inhibition was not dependent on the expression level of FAAH, suggesting that factors other than FAAH are important for uptake.

    Paper V is focused on the inhibition of MGL. Prior to this study no selective inhibitors of the enzyme had been described. Thus, we screened a number of compounds for their inhibitory effect on MGL. Troglitazone was found to be an inhibitor of MGL, although its potency was dependent upon the enzyme assay used. 

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    The endocannabinoid system: A translational study from Achilles tendinosis to cyclooxygenase
  • 38.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Blomqvist, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Joel, Hedlin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, p. e103479-Article in journal (Refereed)
    Abstract [en]

    Background:

    The endocannabinoid ligand anandamide (AEA) is removed from the extracellular space by a process ofcellular uptake followed by metabolism. In many cells, such as the RBL-2H3 cell line, inhibition of FAAH activity reduces theobserved uptake, indicating that the enzyme regulates uptake by controlling the intra- : extracellular AEA concentrationgradient. However, in other FAAH-expressing cells, no such effect is seen. It is not clear, however, whether these differencesare methodological in nature or due to properties of the cells themselves. In consequence, we have reinvestigated the roleof FAAH in gating the uptake of AEA.Methodology/Principal Findings: The effects of FAAH inhibition upon AEA uptake were investigated in four cell lines: AT1rat prostate cancer, RBL-2H3 rat basophilic leukaemia, rat C6 glioma and mouse P19 embryonic carcinoma cells. SemiquantitativePCR for the cells and for a rat brain lysate confirmed the expression of FAAH. No obvious expression of atranscript with the expected molecular weight of FLAT was seen. FAAH expression differed between cells, but all four couldaccumulate AEA in a manner inhibitable by the selective FAAH inhibitor URB597. However, there was a difference in thesensitivities seen in the reduction of uptake for a given degree of FAAH inhibition produced by a reversible FAAH inhibitor,with C6 cells being more sensitive than RBL-2H3 cells, despite rather similar expression levels and activities of FAAH. Thefour cell lines all expressed FABP5, and AEA uptake was reduced in the presence of the FABP5 inhibitor SB-FI-26, suggestingthat the different sensitivities to FAAH inhibition for C6 and RBL2H3 cells is not due to differences at the level of FABP-5.Conclusions/Significance: When assayed using the same methodology, different FAAH-expressing cells display differentsensitivities of uptake to FAAH inhibition.

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    Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study
  • 39.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Larsson, Therese N. L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig O. P.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ketoconazole Inhibits the Cellular Uptake of Anandamide via Inhibition of FAAH at Pharmacologically Relevant Concentrations2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 1, p. e87542-Article in journal (Refereed)
    Abstract [en]

    Background: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 mu M, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 mu M. Conclusions/Significance: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

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  • 40.
    Blomqvist, Lennart K.
    et al.
    Department of Imaging and Physiology, Karolinska University Hospital, Stockholm, Sweden; Research Group Leader Radiology, Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nordberg, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, Brumunddal, Norway; Inland Norway University Applied Science, Elverum, Norway.
    Gadolinium2022In: Handbook on the toxicology of metals: volume II: Specific metals / [ed] Gunnar F. Nordberg; Max Costa, Elsevier, 2022, 5, p. 267-274Chapter in book (Refereed)
    Abstract [en]

    Gadolinium (Gd) belongs to the rare-earth elements. Depending on the temperature, Gd is either ferromagnetic or paramagnetic. Gadolinium obtained its name from Johan Gadolin, the Finnish chemist who discovered gadolinite, a mineral that contains gadolinium. The specific properties of Gd make it suitable for certain applications in nuclear reactors as well as in medicine being the base for a chelate administered to patients as a contrast agent in magnetic resonance imaging. Such Gd chelates have been used for more than 30 years. During the past decades, there has been increasing knowledge about the potentially harmful effects of Gd chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially life-threatening disease, nephrogenic systemic fibrosis. Precautions, restricting the use of Gd chelates in persons with severely impaired renal function have drastically decreased the occurrence of nephrogenic systemic fibrosis in the last decade. There has also been an increasing awareness of the fact that there is Gd deposition in the body even in patients without renal dysfunction and that this deposition is related partly to the cumulative number of doses given but also the chemical structure of the chelate. In this chapter, the physical and chemical properties of Gd and its related chelates, methods for detection, industrial and medical applications, human exposures, toxicity as well as a further description of potential side effects related to injection of Gd chelates are described.

  • 41. Bochman, Matthew L
    et al.
    Sabouri, Nasim
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA .
    Zakian, Virginia A
    Unwinding the functions of the Pif1 family helicases2010In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 9, no 3, p. 237-249Article in journal (Refereed)
    Abstract [en]

    Helicases are ubiquitous enzymes found in all organisms that are necessary for all (or virtually all) aspects of nucleic acid metabolism. The Pif1 helicase family is a group of 5'-->3' directed, ATP-dependent, super family IB helicases found in nearly all eukaryotes. Here, we review the discovery, evolution, and what is currently known about these enzymes in Saccharomyces cerevisiae (ScPif1 and ScRrm3), Schizosaccharomyces pombe (SpPfh1), Trypanosoma brucei (TbPIF1, 2, 5, and 8), mice (mPif1), and humans (hPif1). Pif1 helicases variously affect telomeric, ribosomal, and mitochondrial DNA replication, as well as Okazaki fragment maturation, and in at least some cases affect these processes by using their helicase activity to disrupt stable nucleoprotein complexes. While the functions of these enzymes vary within and between organisms, it is evident that Pif1 family helicases are crucial for both nuclear and mitochondrial genome maintenance.

  • 42. Bohler, S.
    et al.
    Espín-Pérez, A.
    Gebel, S.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palli, D.
    Rantakokko, P.
    Kiviranta, H.
    Kyrtopoulos, S.
    Balling, R.
    Kleinjans, J. C. S.
    Genes associated with Parkinson's disease respond to increasing polychlorinated biphenyl levels in the blood of healthy females2018In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 295, p. S159-S160Article in journal (Other academic)
  • 43. Bolling, Anette Kocbach
    et al.
    Pagels, Joakim
    Yttri, Karl Espen
    Barregard, Lars
    Sallsten, Gerd
    Schwarze, Per E
    Boman, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics, Energy Technology and Thermal Process Chemistry.
    Health effects of residential wood smoke particles: the importance of combustion conditions and physicochemical particle properties2009In: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 6, article id 29Article, review/survey (Refereed)
    Abstract [en]

    Background: Residential wood combustion is now recognized as a major particle source in many developed countries, and the number of studies investigating the negative health effects associated with wood smoke exposure is currently increasing. The combustion appliances in use today provide highly variable combustion conditions resulting in large variations in the physicochemical characteristics of the emitted particles. These differences in physicochemical properties are likely to influence the biological effects induced by the wood smoke particles.

    Outline: The focus of this review is to discuss the present knowledge on physicochemical properties of wood smoke particles from different combustion conditions in relation to wood smoke-induced health effects. In addition, the human wood smoke exposure in developed countries is explored in order to identify the particle characteristics that are relevant for experimental studies of wood smoke-induced health effects. Finally, recent experimental studies regarding wood smoke exposure are discussed with respect to the applied combustion conditions and particle properties.

    Conclusion: Overall, the reviewed literature regarding the physicochemical properties of wood smoke particles provides a relatively clear picture of how these properties vary with the combustion conditions, whereas particle emissions from specific classes of combustion appliances are less well characterised. The major gaps in knowledge concern; (i) characterisation of the atmospheric transformations of wood smoke particles, (ii) characterisation of the physicochemical properties of wood smoke particles in ambient and indoor environments, and (iii) identification of the physicochemical properties that influence the biological effects of wood smoke particles.

  • 44. Borgå, Olof
    et al.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bjermo, Helena
    Lilienberg, Elsa
    Heldring, Nina
    Loman, Niklas
    Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study2019In: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 36, no 5, p. 1150-1163Article in journal (Refereed)
    Abstract [en]

    Introduction: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).

    Methods: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.

    Results: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration–time curve to infinite time (AUCinf), respectively.

    Conclusion: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150–275 mg/m2dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.

    Trial Registration: EudraCT no: 2004-001821-54.

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  • 45. Borrás Pérez, Maria Victoria
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Romer, Tomasz
    Walczak, Mieczyslaw
    Höbel, Nadja
    Zabransky, Markus
    Ten years of clinical experience with biosimilar human growth hormone: a review of safety data2017In: Drug Design, Development and Therapy, E-ISSN 1177-8881, Vol. 11, p. 1497-1503Article, review/survey (Refereed)
    Abstract [en]

    Safety concerns for recombinant human growth hormone (rhGH) treatments include impact on cancer risk, impact on glucose homeostasis, and the formation of antibodies to endogenous/exogenous GH. Omnitrope (R) (biosimilar rhGH) was approved by the European Medicines Agency in 2006, with approval granted on the basis of comparable quality, safety, and efficacy to the reference medicine (Genotropin (R)). Additional concerns that may exist in relation to biosimilar rhGH include safety in indications granted on the basis of extrapolation and the impact of changing to biosimilar rhGH from other rhGH treatments. A substantial data set is available to fully understand the safety profile of biosimilar rhGH, which includes data from its clinical development studies and 10 years of post-approval experience. As of June 2016, 106,941,419 patient days (292,790 patient-years) experience has been gathered for biosimilar rhGH. Based on the available data, there have been no unexpected or unique adverse events related to biosimilar rhGH treatment. There is no increased risk of cancer, adverse glucose homeostasis, or immunogenic response with biosimilar rhGH compared with the reference medicine and other rhGH products. The immunogenicity of biosimilar rhGH is also similar to that of the reference and other rhGH products. Physicians should be reassured that rhGH products have a good safety record when used for approved indications and at recommended doses, and that the safety profile of biosimilar rhGH is in keeping with that of other rhGH products.

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  • 46.
    Bredenberg, Susanne
    et al.
    Orexo AB, SE-75105 Uppsala, Sweden.
    Dahlgren, Anna
    Orexo AB, SE-75105 Uppsala, Sweden.
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Evaluation of a sieve classification method for characterization of low-dose interactive mixtures2013In: Pharmaceutical development and technology (Print), ISSN 1083-7450, E-ISSN 1097-9867, Vol. 18, no 6, p. 1366-1371Article in journal (Refereed)
    Abstract [en]

    This study investigated a sieve classification method for evaluating carrier materials and particle size fractions, which could be a valuable tool in the early development of pharmaceutical dosage forms containing low-dose interactive mixtures. When developing new products based on interactive mixtures, it is essential to ensure that the drug particles are successfully deagglomerated and have adhered to the carrier particles. In this study, the effect on the demixing potential (DP) of low-dose interactive mixtures was assessed for various carrier particle sizes and surface textures. The model drug used was sodium salicylate and the tested carriers were lactose, mannitol, and isomalt. The results showed that the lowest DPs, i.e. the most mechanically stable mixtures, were obtained with lactose. Furthermore, for interactive mixtures, small carrier particles and/or a narrow carrier particle size range are essential for obtaining a low DP and high homogeneity. Calculation of the DP provided a reliable estimate of the quality of the low-dose interactive mixtures used in this study.

  • 47. Broms, Gabriella
    et al.
    Kieler, Helle
    Ekbom, Anders
    Gissler, Mika
    Hellgren, Karin
    Leinonen, Maarit K.
    Pedersen, Lars
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Sorensen, Henrik Toft
    Granath, Fredrik
    Infant Infections after Maternal Anti-TNF Treatment in Pregnancy2019In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, p. 10-10Article in journal (Other academic)
  • 48.
    Brännström, Jon
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Molander, Lena
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gender disparities in the pharmacological treatment of cardiovascular disease and diabetes mellitus in the very old: an epidemiological, cross-sectional survey2011In: Drugs & Aging, ISSN 1170-229X, E-ISSN 1179-1969, Vol. 28, no 12, p. 993-1005Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There are many reports of disparities in health and medical care both between women and men and between various age groups. In most cases, men receive better treatment than women and young and middle-aged people are privileged compared with the old and the very old. Cardiovascular morbidity and diabetes mellitus are common, increase with age and are often treated extensively with drugs, many of which are known to have significant adverse effects.

    OBJECTIVE: The aim of the study was to analyse gender differences in the pharmacological treatment of cardiovascular disease and diabetes among very old people.

    METHODS: The study took the form of an epidemiological, cross-sectional survey. A structured interview was administered during one or more home visits, and data were further retrieved from medical charts and interviews with relatives, healthcare staff and other carers. Home-dwelling people as well as people living in institutional care in six municipalities in the county of Västerbotten, Sweden, in 2005-7 were included in the study. Half of all people aged 85 years, all of those aged 90 years and all of those aged ≥95 years living in the selected municipalities were selected for inclusion in the study. In total, 467 people were included in the present analysis. The main study outcome measures were medical diagnoses and drug use.

    RESULTS: In total, women were prescribed a larger number of drugs than men (mean 7.2 vs 5.4, p < 0.001). Multiple logistic regression models adjusted for age and other background variables as well as relevant medical diagnoses (hypertension, heart failure) showed strong associations between female sex and prescriptions of thiazide diuretics (odds ratio [OR] 4.4; 95% CI 1.8, 10.8; p = 0.001), potassium-sparing diuretics (OR 3.5; 95% CI 1.4, 8.7; p = 0.006) and diuretics as a whole (OR 1.8; 95% CI 1.1, 2.9; p = 0.021). A similar model, adjusted for angina pectoris, showed that female sex was associated with prescription of short-acting nitroglycerin (OR 3.7; 95% CI 1.6, 8.9; p = 0.003). However, more men had been offered coronary artery surgery (p = 0.001). Of the participants diagnosed with diabetes, 55% of the women and 85% of the men used oral antihyperglycaemic drugs (p = 0.020), whereas no gender difference was seen in prescriptions of insulin.

    CONCLUSIONS: Significant gender disparities in the prescription of several drugs, such as diuretics, nitroglycerin and oral antihyperglycaemic drugs, were observed in this study of very old people. In most cases, women were prescribed more drugs than men. Men more often had undergone coronary artery surgery. These disparities could only in part be explained by differences in diagnoses and symptoms.

  • 49. Bröms, Gabriella
    et al.
    Kieler, Helle
    Ekbom, Anders
    Gissler, Mika
    Hellgren, Karin
    Leinonen, Maarit K.
    Pedersen, Lars
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Sorensen, Henrik Toft
    Granath, Fredrik
    Paediatric infections in the first 3 years of life after maternal anti-TNF treatment during pregnancy2020In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 52, no 5, p. 843-854Article in journal (Refereed)
    Abstract [en]

    Background: Most anti‐tumour necrosis factor (anti‐TNF) agents are transferred across the placenta and may increase paediatric susceptibility to infections.

    Aims: To assess the risk of paediatric infections after maternal anti‐TNF treatment.

    Methods: Population‐based cohort study in Denmark, Finland and Sweden 2006‐2013 in which 1027 children born to women with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease, treated with anti‐TNF, and 9346 children to women with nonbiologic systemic treatment, were compared to 1 617 886 children of the general population. Children were followed for 3 years.

    Results: Adjusted by maternal age, parity, smoking, body mass index, country and calendar year, the incidence rate ratios with 95% confidence interval (CI) for hospital admissions for infection in the first year were 1.43 (1.23‐1.67) for anti‐TNF and 1.14 (1.07‐1.21) for non‐biologic systemic treatment, and 1.29 (1.11‐1.50) and 1.09 (1.02‐1.15), respectively, when additionally adjusting for adverse birth outcomes. There was a slight increase in antibiotic prescriptions in the second year for anti‐TNF, 1.19 (1.11‐1.29), and for non‐biologic systemic treatment, 1.10 (1.07‐1.13). There was no difference among anti‐TNF agents, treatment in the third trimester, or between mono/combination therapy with non‐biologic systemic treatment.

    Conclusions: Both anti‐TNF and non‐biologic systemic treatment were associated with an increased risk of paediatric infections. However, reassuringly, the increased risks were present regardless of treatment in the third trimester, with combination of treatments, and were not persistent across the first 3 years of life. Our findings may indicate a true risk, but could also be due to unadjusted confounding by disease severity and healthcare‐seeking behaviour. This may in turn shift the risk‐benefit equation towards continuation of treatment even in the third trimester.

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  • 50. Bröms, Gabriella
    et al.
    Kieler, Helle
    Ekbom, Anders
    Hellgren, Karin
    Gissler, Mika
    Lahesmaa-Korpinen, Anna-Maria
    Pedersen, Lars
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Sorensen, Henrik T.
    Granath, Fredrik
    Tnf inhibitor treatment during pregnancy and risk of preterm birth2018In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 27, p. 30-31, article id 60Article in journal (Other academic)
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