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  • 1. Abbasi, Arshad Mehmood
    et al.
    Khan, Mir Ajab
    Khan, Nadeem
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Shah, Munir H
    Ethnobotanical survey of medicinally important wild edible fruits species used by tribal communities of Lesser Himalayas-Pakistan2013Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 148, nr 2, s. 528-536Artikel i tidskrift (Refereegranskat)
    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. Aitio, Antero
    et al.
    Bernard, Alfred
    Fowler, Bruce A.
    Nordberg, Gunnar F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Biological Monitoring and Biomarkers2007Ingår i: 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, s. 65-78Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    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.

  • 3. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, s. 164-173Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Alhouayek, Mireille
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi. Catholic Univ Louvain, Brussels, Belgium.
    Gouveia-Figueira, Sandra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Swedish Univ Agr Sci, Umea, Sweden.
    Hammarström, Marie-Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity2018Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 175, nr 6, s. 877-890Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Alhouayek, Mireille
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Rankin, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gouveia-Figueira, Sandra C.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells2019Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, nr 10, s. 1470-1480Artikel i tidskrift (Refereegranskat)
    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.

  • 6.
    Alhouayek, Mireille
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Sorti, René
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 7622Artikel i tidskrift (Refereegranskat)
    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.

  • 7. Allgardsson, Anders
    et al.
    Andersson, C. David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akfur, Christine
    Worek, Franz
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ekström, Fredrik
    An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet2017Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, nr 9, artikel-id 1433Artikel i tidskrift (Refereegranskat)
    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.

  • 8. Anand, Praveen
    et al.
    Whiteside, Garth
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hohmann, Andrea G
    Targeting CB2 receptors and the endocannabinoid system for the treatment of pain2009Ingår i: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 60, nr 1, s. 255-266Artikel i tidskrift (Refereegranskat)
    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.

  • 9. Andersen, Toril
    et al.
    Bleher, Stefan
    Flaten, Goril Eide
    Tho, Ingunn
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Skalko-Basnet, Natasa
    Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy2015Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 13, nr 1, s. 222-236Artikel i tidskrift (Refereegranskat)
    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.

  • 10. Andersen, Toril
    et al.
    Mishchenko, Ekaterina
    Flaten, Gøril Eide
    Ericson Sollid, Johanna U.
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Tho, Ingunn
    Škalko-Basnet, Nataša
    Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes2017Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 15, nr 3, artikel-id 64Artikel i tidskrift (Refereegranskat)
    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.

  • 11. Andersen, Toril
    et al.
    Vanić, Zeljka
    Flaten, Gøril Eide
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Tho, Ingunn
    Skalko-Basnet, Nataša
    Pectosomes and chitosomes as delivery systems for metronidazole: the one-pot preparation method2013Ingår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 5, nr 3, s. 445-456Artikel i tidskrift (Refereegranskat)
    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.

  • 12.
    Andersson, C. David
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Martinez, Nicolas
    Zeller, Dominik
    Allgardsson, Anders
    Koza, Michael M.
    Frick, Bernhard
    Ekström, Fredrik
    Peters, Judith
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering2018Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, nr 36, s. 8516-8525Artikel i tidskrift (Refereegranskat)
    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.

  • 13.
    Andersson, Patrik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van der Burght, Aafje S.A.M.
    van den Berg, Martin
    Tysklind, Mats
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species: ranking scales and species differences2000Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 19, nr 5, s. 1454-1463Artikel i tidskrift (Refereegranskat)
    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.

  • 14. Aplander, Karolina
    et al.
    Marttila, Marko
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Manner, Sophie
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Sterner, Olov
    Ellervik, Ulf
    Molecular wipes: application to epidemic keratoconjuctivitis2011Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 19, s. 6670-6675Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    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]2008Ingår i: Duodecim, ISSN 0012-7183, Vol. 124, s. 1899--1907Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 16. Aureliano, M.
    et al.
    Ohlin, C. Andre
    Decavanadate in vitro and in vivo effects: facts and opinions2014Ingår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 137, s. 123-130Artikel i tidskrift (Refereegranskat)
    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.

  • 17. Aureliano, Manuel
    et al.
    Fraqueza, Gil
    Ohlin, C. Andre
    Ion pumps as biological targets for decavanadate2013Ingår i: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 42, nr 33, s. 11770-11777Artikel i tidskrift (Refereegranskat)
    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.

  • 18. Beckett, William S.
    et al.
    Nordberg, Gunnar F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Clarkson, Thomas W.
    Routes of Exposure, Dose, and Metabolism of Metals2007Ingår i: 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, s. 39-64Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    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.

  • 19. Becking, George C.
    et al.
    Nordberg, Monica
    Nordberg, Gunnar F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Essential Metals: Assessing Risks from Deficiency and Toxicity2007Ingår i: 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, s. 163-176Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    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.

  • 20. Bengtsson-Palme, Johan
    et al.
    Angelin, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Huss, Mikael
    Kjellqvist, Sanela
    Kristiansson, Erik
    Palmgren, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Larsson, D. G. Joakim
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    The Human Gut Microbiome as a Transporter of Antibiotic Resistance Genes between Continents2015Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, nr 10, s. 6551-6560Artikel i tidskrift (Refereegranskat)
    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.

  • 21.
    Bergdahl, Ingvar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Biomonitoring of metals: Analysis, non-linearity, possible artefacts, and genetics2012Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, s. S12-S12Artikel i tidskrift (Refereegranskat)
  • 22.
    Bergh, Johan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Graffmo, Karin Sixtensdotter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jonsson, P. Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 14, s. 4489-4494Artikel i tidskrift (Refereegranskat)
    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.

  • 23. Berglund, Bjorn
    et al.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lindgren, Per-Eric
    Urban wastewater effluent increases antibiotic resistance gene concentrations in a receiving northern european river2015Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 34, nr 1, s. 192-196Artikel i tidskrift (Refereegranskat)
    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

  • 24.
    Berglund, Åsa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Responses to reduced industrial metal emissions: An ecotoxicological study on Pied Flycatcher (Ficedula hypoleuca, Aves)2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Metaller är grundämnen som inte kan bildas eller förstöras av människan. De förekommer i mineraler i berggrunden och finns överallt på jorden. Människans användning av metaller har dock medfört att de återfinns i högre halter i miljön än de annars skulle gjort.

    Trots att metallerna kan spridas och transporteras långa sträckor med luftmassorna, är det främst kring källorna, såsom metallindustrier, man kan hitta metaller i tillräckligt höga halter för att orsaka skada på växter och djur. I denna avhandling presenteras undersökningar av hur svartvit flugsnappare (Ficedula hypoleuca) påverkas kring två metallindustrier i norra Sverige. Det ena är en numera nedlagd blygruva med anrikningsverk i Laisvall, där vi studerade populationer av svartvit flugsnappare före och efter att industrin stängdes. Det andra är smältverket Rönnskärsverken, utanför Skelleftehamn, som varit i drift sedan 1930-talet. I föroreningsgradienten från smältverket studerades effekter av 20 års kraftigt minskade metallutsläpp till luften som följd av förbättrade reningstekniker.

    Resultaten kring industrierna visar att fåglarna svarade olika på de minskade metallutsläppen. Kring blygruvan minskade halterna av bly i flugsnapparungar med samma takt som nedfallen (mätt i mossa) och bytesdjuren (myror). Däremot, kring smältverket, var fåglarna fortfarande exponerade för höga halter av de giftiga ämnena arsenik, kadmium, kvicksilver och bly, på i princip samma nivåer som 20 år tidigare, trots att utsläppen minskat med 93 – 98%. Orsaken till detta tros vara skillnader på föroreningsgraden i markens översta lager, mårskiktet. Vi kunde visa att flugsnapparna kring smältverket främst fick i sig metallerna från marken, som efter flera årtionden med utsläpp från industrin innehöll mycket höga metallhalter. Detta kan förklara att fåglarna trots att utsläppen var låga, fortfarande var utsatta för stor metallexponering. Det snabba svaret på minskad metallspridning (bly och zink) som flugsnapparna vid blygruvan visade, antar vi berodde på att mindre mäng metaller fanns i marken. Trots minskningen var metallhalterna i fåglarna vid gruvområdet fortfarande tillräckligt höga för att, liksom vid smältverket, påverka fåglarnas hälsa. De uppvisade bl.a. låga blodvärden och tecken på oxidativ stress. Vidare var ungdödligheten förhöjd, vilket ledde till lägre häckningsframgång.

    Slutsatsen är att markens innehåll av metaller har stor betydelse för återhämtningsförloppet för svartvit flugsnappare efter minskat metallnedfall, och att en relativt snabb återhämtning kan förväntas i områden med något lägre metallhalter i mårskiktet, medan återhämtning i områden där marken är kraftigt förorenad inte kan förväntas förrän efter flera årtionden, även om nedfallet upphört nästan helt.

  • 25.
    Berglund, Åsa
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Nyholm, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Slow improvements of metal exposure, health- and breeding conditions of pied flycatchers (Ficedula hypoleuca) after decreased industrial heavy metal emissionsManuskript (preprint) (Övrigt vetenskapligt)
    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.

  • 26.
    Bidleman, Terry F.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Melymuk, Lisa
    Forty-five years of foam: a retrospective on air sampling with polyurethane foam2019Ingår i: Bulletin of Environmental Contamination and Toxicology, ISSN 0007-4861, E-ISSN 1432-0800, Vol. 102, nr 4, s. 447-449Artikel i tidskrift (Refereegranskat)
  • 27.
    Björklund, Emmelie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The endocannabinoid system: a translational study from Achilles tendinosis to cyclooxygenase2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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. 

  • 28.
    Björklund, Emmelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Blomqvist, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Joel, Hedlin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Persson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Fowler, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    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 Study2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 7, s. e103479-Artikel i tidskrift (Refereegranskat)
    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.

  • 29.
    Björklund, Emmelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Larsson, Therese N. L.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig O. P.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ketoconazole Inhibits the Cellular Uptake of Anandamide via Inhibition of FAAH at Pharmacologically Relevant Concentrations2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 1, s. e87542-Artikel i tidskrift (Refereegranskat)
    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.

  • 30. 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 helicases2010Ingår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 9, nr 3, s. 237-249Artikel i tidskrift (Refereegranskat)
    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.

  • 31. Bohler, S.
    et al.
    Espín-Pérez, A.
    Gebel, S.
    Bergdahl, Ingvar
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    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 females2018Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 295, s. S159-S160Artikel i tidskrift (Övrigt vetenskapligt)
  • 32. Bolling, Anette Kocbach
    et al.
    Pagels, Joakim
    Yttri, Karl Espen
    Barregard, Lars
    Sallsten, Gerd
    Schwarze, Per E
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik, Energiteknik och termisk processkemi.
    Health effects of residential wood smoke particles: the importance of combustion conditions and physicochemical particle properties2009Ingår i: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 6, artikel-id 29Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 33. Borgå, Olof
    et al.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 Study2019Ingår i: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 36, nr 5, s. 1150-1163Artikel i tidskrift (Refereegranskat)
    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.

  • 34. Borrás Pérez, Maria Victoria
    et al.
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Romer, Tomasz
    Walczak, Mieczyslaw
    Höbel, Nadja
    Zabransky, Markus
    Ten years of clinical experience with biosimilar human growth hormone: a review of safety data2017Ingår i: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 11, s. 1497-1503Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 35.
    Bredenberg, Susanne
    et al.
    Orexo AB, SE-75105 Uppsala, Sweden.
    Dahlgren, Anna
    Orexo AB, SE-75105 Uppsala, Sweden.
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Evaluation of a sieve classification method for characterization of low-dose interactive mixtures2013Ingår i: Pharmaceutical development and technology (Print), ISSN 1083-7450, E-ISSN 1097-9867, Vol. 18, nr 6, s. 1366-1371Artikel i tidskrift (Refereegranskat)
    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.

  • 36. Broms, Gabriella
    et al.
    Kieler, Helle
    Ekbom, Anders
    Gissler, Mika
    Hellgren, Karin
    Leinonen, Maarit K.
    Pedersen, Lars
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Sorensen, Henrik Toft
    Granath, Fredrik
    Infant Infections after Maternal Anti-TNF Treatment in Pregnancy2019Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, s. 10-10Artikel i tidskrift (Övrigt vetenskapligt)
  • 37.
    Brännström, Jon
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Hamberg, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Molander, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Lövheim, Hugo
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Gustafson, Yngve
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Gender disparities in the pharmacological treatment of cardiovascular disease and diabetes mellitus in the very old: an epidemiological, cross-sectional survey2011Ingår i: Drugs & Aging, ISSN 1170-229X, E-ISSN 1179-1969, Vol. 28, nr 12, s. 993-1005Artikel i tidskrift (Refereegranskat)
    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.

  • 38. Bröms, Gabriella
    et al.
    Kieler, Helle
    Ekbom, Anders
    Hellgren, Karin
    Gissler, Mika
    Lahesmaa-Korpinen, Anna-Maria
    Pedersen, Lars
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Sorensen, Henrik T.
    Granath, Fredrik
    Tnf inhibitor treatment during pregnancy and risk of preterm birth2018Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 27, s. 30-31, artikel-id 60Artikel i tidskrift (Övrigt vetenskapligt)
  • 39.
    Bäckström, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Spontaneous reporting of adverse drug reactions: Possibilities and limitations2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Adverse drug reactions (ADRs) constitute a major problem in society and in drug therapy. They are a common cause of short-term hospitalization, prolonged hospitalization and death. Spontaneous reporting of ADRs remains one the most effective methods for detecting new and serious drug reactions. In Sweden physicians are legally required to report fatal and serious ADRs. We know from previous studies that there is a substantial degree of under-reporting of ADRs also in Sweden.

    Attitudes towards reporting of ADRs among physicians in the northern region of Sweden were investigated using a questionnaire. The most important factor for not reporting ADRs among physicians and general practioners in our region was that the reaction was considered to be well known. However, their attitudes could also allow for a considerable rate of under-reporting.

    The effect on the reporting rate when nurses received instruction and were encouraged to report ADRs was studied. During a 12-month study period, 18 ADR reports with a total number of 22 ADRs were sent in by the nurses participating in the study to test nurses as reporters of ADRs.

    Using the Swedish ADR database, we calculated the risk of agranulocytosis associated with the use of metamizole by using consumption data from the case records of scrutinized patients’ and stored prescriptions. Over the period from 1996 to 1999, ten cases of agranulocytosis during treatment with metamizole were reported to SADRAC. Metamizole was prescribed to 666 (19%) inpatients during the 3-month study period and 112 prescriptions were identified at the participating pharmacies. Thirty-eight percent of them indicated treatment for more than 15 days. Making certain assumptions, the calculated risk of agranulocytosis was one out of every 31 000 inpatients and one out of every 1400 outpatients. The degree of under-reporting of serious ADRs was studied in five hospitals. More than 1300 case records were scrutinized and among these we found 107 cases that according to current rules for ADR reporting, should have been reported. Only fifteen of these were found in the SADRAC database, indicating a under-reporting rate of 86%.The effect on the reporting rate of ADRs was studied in an intervention study in which a small economical inducement was given to those who reported ADRs.

    The effect of a small economical stimulation to increase the reporting rate was studied. From the intervention area we received 62 suspected ADRs compared with 50 from the control area. The increase in the number of reports was 59% compared with an unchanged reporting rate from the control area.

    The physicians in northern Sweden have a relatively good knowledge of the existing rules for ADR reporting. Nurses could play an important role in detecting and reporting suspected ADRs.

    The risk of developing an metamizole induced agranulocytosis is considerably increased if metamizole is given to patients for a longer time than recommended. The rate of reported ADRs is very low, also for serious and fatal reactions. An increase in the reporting rate of suspected ADRs was observed during study period.

  • 40.
    Bäckström, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Ekman, Elizabet
    Regional Pharmacovigilance Unit, Skanes University hospital, CKFL, Lund, Sweden.
    Attitudes among nurses in Sweden and factors for their reporting of adverse drug reactions2011Ingår i: Abstracts 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management Hyatt Regency Chicago: Chicago, Illinois, USA August 14–17, 2011, Wiley , 2011, Vol. 20, s. S202-S203Konferensbidrag (Refereegranskat)
    Abstract [en]

    Background: Adverse drug reactions (ADRs) is a common cause for hospitalization and death. Spontaneous reporting of ADRs remains as one of the cornerstones in post marketing drug safety surveillance. In March 2007 the Medical Product Agency (MPA) in Sweden decided to also accept reports of suspected ADRs from all nurses.

    Objectives: This study was designed to investigate attitudes and factors for reporting adverse drug reactions (ADRs) from nurses within the health care system in Sweden.

    Methods: A questionnaire was distributed to 753 randomly selected nurses in Sweden.

    Results: The most important factors in their decision to report as suspected ADRs were the severity, if the drug was newly approved and if the reaction were unusual. The nurses with a shorter professional experience responded to a higher degree than their colleagues that they made other priorities, did not have the time or where unaware/uncertain what and how to report. Almost two - thirds of the responders assessed that they had insufficient pharmacological knowledge. A vast majority (84%) of the responders would prefer a possibility to report a suspected ADR using a web - based formula.

    Conclusions: Nurses in Sweden have a fairly good knowledge about the existing rules for reporting. However, there is room for improvement in some areas. Further education and information is needed.

  • 41. Bøhn, Thomas
    et al.
    Rover, Carina Macagnan
    Semenchuk, Philipp Robert
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Daphnia magna negatively affected by chronic exposure to purified Cry-toxins2016Ingår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 91, s. 130-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cry-toxin genes originating from Bacillus thuringiensis are inserted into genetically modified (GM) plants, often called Bt-plants, to provide insect resistance to pests. Significant amounts of Bt-plant residues, and thus Cry-toxins, will be shed to soil and aquatic environments. We exposed Daphnia magna to purified Cry1Ab and Cry2Aa toxins for the full life-span of the animals. We used single toxins in different doses and combinations of toxins and Roundup, another potential stressor on the rise in agricultural ecosystems. Animals exposed to 4.5 mg/L (ppm) of Cry1Ab, Cry2Aa and the combination of both showed markedly higher mortality, smaller body size and very low juvenile production compared to controls. Animals exposed to 0.75 mg/L also showed a tendency towards increased mortality but with increased early fecundity compared to the controls. Roundup stimulated animals to strong early reproductive output at the cost of later rapid mortality. We conclude that i) purified Cry-toxins in high concentrations are toxic to D. magna, indicating alternative modes-of-action for these Cry-toxins; ii) Cry-toxins act in combination, indicating that 'stacked events' may have stronger effects on non-target organisms; iii) further studies need to be done on combinatorial effects of multiple Cry-toxins and herbicides that co-occur in the environment.

  • 42. Carlsson, Rose-Marie
    et al.
    Blennow, Margareta
    Gothefors, Leif
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vaccination av barn och ungdomar (ingår i Läkemedelsboken 2011-2012)2011Ingår i: Läkemedelsboken 2011-2012 / [ed] Odeberg H et al (red), Uppsala: Läkemedelsverket , 2011, s. 177-191Kapitel i bok, del av antologi (Refereegranskat)
  • 43.
    Cassel, Gudrun
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Cyanide and central nervous system: a study with focus on brain dopamine1993Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The brain is a major target site in acute cyanide intoxication, as indicated by several symptoms and signs. Cyanide inhibits the enzyme cytochrome oxidase. This inhibition causes impaired oxygen utilization in all cells affected, severe metabolic acidosis and inhibited production of energy. In this thesis, some neurotoxic effects of cyanide, in particular, the effects on dopaminergic pathways were studied.

    In a previous study, decreased levels of striatal dopamine and HVA were found after severe cyanide intoxication (5-20 mg/kg i.p.). However, increased striatal dopamine were found in rats showing convulsions after infusion of low doses of cyanide (0.9 mg/kg i.v.), at the optimal dose rate (the dose rate that gives the treshold dose).

    Increased striatal dopamine synthesis was observed in rats after cyanide treatment and in vitro. Furthermore, in rat, as well as in pig striatal tissue, cyanide dose- dependently increased the oxidative deamination of 5-HT (MAO-A) and DA (MAO-A and -B) but not that of PEA (MAO-B). Thus cyanide affects both the synthesis and metabolism of dopamine.

    In rats, sodium cyanide (2.0 mg/kg, i.p.) decreased the striatal dopamine Dj- and D2-receptor binding 1 hour after injection. Increased extracellular levels of striatal dopamine and homovanillic acid were also shown after cyanide (2.0 mg/kg; i.p.). DOPAC and 5-HIAA were slightly decreased. This indicates an increased release or an extracellular leakage of dopamine due to neuronal damage caused by cyanide. Thus the effects of cyanide on dopamine Dj- and D2~receptors could in part be due to cyanide-induced release of dopamine.

    Because of reported changes in intracellular calcium in cyanide-treated animals, the effects of cyanide on inositol phospholipid breakdown was studied. Cyanide seemed not to affect the inositol phospholipid breakdown in vitro.

    The effects of cyanide on the synthesis and metabolism of brain GAB A were also examined. A decreased activity of both GAD and GAB A-T were found in the rat brain tissue. The reduced activity of GAB A-T, but not that of GAD returned to the control value after adding PLP in the incubation media. The cyanide-produced reduction of GABA levels will increase the susceptibility to convulsions, and could partly be due to GAD inhibition.

    In conclusion, cyanide affects the central nervous system in a complex manner. Some effects are probably direct. The main part, however, appears to be secondary, e.g. hypoxia, seizures, changes in calcium levels or transmitter release produced by cyanide.

  • 44.
    Chatzittofis, A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Boström, A.
    Öberg, K.
    Flanagan, J.
    Schioth, H.
    Arver, S.
    Jokinen, J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Testosterone, luteinizing hormone levels and methylation status in men with hypersexual disorders2019Ingår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S135-S135Artikel i tidskrift (Övrigt vetenskapligt)
  • 45. Chen, Xiao
    et al.
    Zhu, Guoying
    Wang, Zhongqiu
    Liang, Yihuai
    Chen, Bo
    He, Ping
    Nordberg, Monica
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nordberg, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Ding, Xiaoqiang
    Jin, Taiyi
    The association between dietary cadmium exposure and renal dysfunction - the benchmark dose estimation of reference levels: the ChinaCad study2018Ingår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 38, nr 10, s. 1365-1373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tolerable dietary intake of cadmium was recommended at provisional tolerable monthly intake of 25gkg(-1) body weight. However, several studies indicated that this tolerable level should be re-evaluated for sufficient health protection. In this study, we show the reference levels of dietary cadmium intake for renal dysfunction by using a benchmark dose (BMD) approach. A total of 790 subjects (302 men and 488 women) living in control and cadmium-polluted areas were included. The dietary cadmium intake was estimated by a food survey. Blood cadmium, urinary cadmium and renal function markers (microalbuminuria, N-acetyl--d-glucosaminidase [NAG] and its isoform B [NAGB], (2)-microglobulin and retinol binding protein) in urine were measured. We calculated the 95% lower confidence bounds of BMD (BMDLs) of cumulative cadmium intake. In control and two polluted areas, the median cumulative cadmium intake was 0.5, 2.1 and 11.1g. The odds ratio of the intermediate (1.0-3.0g), second highest (3.0-11.0g) and the highest cumulative cadmium intake (>11.0g) compared with the lowest cumulative cadmium intake (<1.0g) were 2.8 (95% CI: 1.4-5.8), 8.1 (95% CI: 3.8-17.2) and 11.4 (95% CI: 6.5-26.4) for urinary NAG and 6.6 (95% CI: 3.2-13.8), 14.8 (95% CI: 6.8-32.2) and 22.5 (95% CI: 10.7-47.5) for urinary NAGB. The BMDLs of cumulative cadmium intake were 1.1-1.2g (benchmark response [BMR]=5%) for urinary NAG, and were 0.7-0.9g (BMR=5%) for urinary NAGB, and were 1.3-1.4g (BMR=5%) for urinary (2)-microglobulin. The BMDLs of cumulative cadmium intake in a Chinese population were lower than the critical standard previously reported. Further evaluations are needed for sufficient health protection. Several studies indicated that the tolerable dietary intake of cadmium should be re-evaluated for sufficient health protection. In this study, we show the reference levels of dietary cadmium intake for renal dysfunction by using benchmark dose (BMD) approach. The lowest BMD lower bound confidence limits of cumulative cadmium intake were 0.7-0.9g (benchmark response=5%). The BMD lower bound confidence limits of cumulative cadmium intake were lower than the critical standard previously reported. Further evaluations are needed for sufficient health protection.

  • 46. Chung, Sui Chu
    et al.
    Hammarsten, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Granfors, Torvald
    Egevad, Lars
    Mancini, Giacomo
    Lutz, Beat
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer2009Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, nr 1, s. 174-182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the light of findings indicating that cannabinoids can affect the proliferation of a number of cancer cell types and that cannabinoid receptor expression is higher in prostate cancer cell lines than in non-malignant cells, we investigated whether the level of cannabinoid 1 receptor immunoreactivity (CB(1)IR) in prostate cancer tissues is associated with disease severity and outcome. Formalin-fixed paraffin-embedded non-malignant and tumour tissue samples from patients who were diagnosed with prostate cancer at a transurethral resection for voiding problems were used. CB(1)IR, which was scored in a total of 399 cases, was associated with the epithelial cell membranes, with little staining in the stroma. Patients with a tumour CB(1)IR score greater or equal to the median (2) had a significantly higher proportion of Gleason scores 8-10, metastases at diagnosis, tumour size and rate of cell proliferation at diagnosis than patients with a score<2. For 269 cases, tumour CB(1)IR was measured for patients who only received palliative therapy at the end stages of the disease, allowing the influence of CB(1)IR upon the disease outcome to be determined. Receiver operating characteristic (ROC) curves showed an area under the curve of 0.67 (95% confidence limits 0.59-0.74) for CB(1)IR in the tumour. CB(1)IR in non-malignant tissue was not associated with disease outcome. A tumour CB(1)IR score >or=2 was associated with a significantly lower disease specific survival. A Cox proportional hazards regression indicated that the tumour CB(1)IR score and the Gleason score were independent prognostic variables. It is concluded that a high tumour CB(1)IR score is associated with prostate cancer severity and outcome.

  • 47.
    Cipriano, Mariateresa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Björklund, Emmelie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Wilson, Alan A.
    Congiu, Cenzo
    Onnis, Valentina
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen2013Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 720, nr 1-3, s. 383-390Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH/cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl) amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [H-3]anandamide by rat brain homogenates with IC50 values of 044 and 0.74 mu M. The corresponding values for flurbiprofen and naproxen were 29 and > 100 mu M, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K-slope(i) and K-intercept(i) values of 0.21 and 1.4 mu M, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol > COX-1 vs. arachidonic acid > COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than Flu-AM 1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low micromolar concentrations inhibited the FAAH-driven uptake of [H-3]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [F-18]DOPP to brain FAAH. It is concluded that Flu-AM 1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.

  • 48.
    Cipriano, Mariateresa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Häggström, Jenny
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Hammarsten, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65798-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.

    Methodology/Principal Findings: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.

    Conclusions/Significance: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative.

  • 49. Cisneros, Jose Antonio
    et al.
    Vandevoorde, Severine
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ortega-Gutierrez, Silvia
    Paris, Clement
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Lopez-Rodriguez, Maria L
    Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis-comparison with effects upon fatty acid amide hydrolase2007Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, nr 20, s. 5012-5023Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) were synthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid an-tide hydrolase activities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits that mimic the glycerol fragment. This series has allowed us to carry out the first systematic structure activity relationship study on inhibition of 2-AG hydrolysis. The most promising compounds were oxiran-2-ylmethyl (5Z,8Z,l 11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2-ylmethyl (5Z,8Z,11Z,14z)-icosa5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 mu M, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26,mu M, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 mu M, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolytic activity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.

  • 50.
    Claeson, Anna-Sara
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Andersson, Linus
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance2017Ingår i: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 60, s. 92-98Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Chemical intolerance (CI) is a widespread occupational and public health problem characterized by symptoms that reportedly result from low-levels of chemical exposure. The mechanisms behind CI are unknown, however modifications of the chemical senses (rather than toxic processes) have been suggested as key components. The aim of this study was to investigate whether individuals with self-reported CI report more sensory irritation during masked acrolein exposure compared to controls without CI. Methods: Individuals with CI (n = 18) and controls without CI (n = 19) were exposed in an exposure chamber. Each participant took part in two exposure conditions – one with heptane (the masking compound), and one with heptane and acrolein at a dose below previously reported sensory irritation thresholds. The exposures lasted for 60 min. Symptoms and confidence ratings were measured continuously throughout the exposure as were measurements of electrodermal activity and self-reported tear-film break-up time. Participants were blind to exposure condition. Results: Individuals with CI, compared with controls reported greater sensory irritation in the eyes, nose and throat when exposed to acrolein masked with heptane. There was no difference during exposure to heptane. Conclusions: Masked exposure to acrolein at a concentration below the previously reported detection threshold is perceived as more irritating by individuals with CI compared with controls. The results indicate that there is altered trigeminal reactivity in those with CI compared to controls.

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