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  • 1.
    Burström, Lage
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Björ, Bodil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Carlsson, Daniel
    Hjalmarsson, Ulla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Nilsson, Tohr
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Rödin, Ingemar
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Wahlström, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hälsoundersökning bland arbetande inom gruvnäring i Barentsregionen: Deskriptiva data från basenkäten, Aitik Boliden november 20122014Report (Other academic)
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  • 2. Cheng, Ran
    et al.
    Mori, Wakana
    Ma, Longle
    Alhouayek, Mireille
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hatori, Akiko
    Zhang, Yiding
    Ogasawara, Daisuke
    Yuan, Gengyang
    Chen, Zhen
    Zhang, Xiaofei
    Shi, Hang
    Yamasaki, Tomoteru
    Xie, Lin
    Kumata, Katsushi
    Fujinaga, Masayuki
    Nagai, Yuji
    Minamimoto, Takafumi
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wang, Lu
    Du, Yunfei
    Ondrechen, Mary Jo
    Vasdev, Neil
    Cravatt, Benjamin F.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Zhang, Ming-Rong
    Liang, Steven H.
    In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2278-2291Article in journal (Refereed)
    Abstract [en]

    Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-11-carbonylation and spirocyclic iodonium ylide (SCIDY) radio fluorination. The lead compound [C-11]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.

  • 3. Deplano, Alessandro
    et al.
    Morgillo, Carmine Marco
    Demurtas, Monica
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hashemian, Sanaz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Cabiddu, Maria G.
    Novellino, Ettore
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Catalanotti, Bruno
    Onnis, Valentina
    Novel propanamides as fatty acid amide hydrolase inhibitors2017In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, p. 523-542Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.

  • 4.
    Gouveia-Figueira, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlsson, Jessica
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Deplano, Alessandro
    Hashemian, Sanaz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fredriksson Sundbom, Marcus
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Congiu, Cenzo
    Onnis, Valentina
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor2015In: PLoS ONE, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139212Article in journal (Refereed)
    Abstract [en]

    Background Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. Methodology/Principal Findings COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon gamma-stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manner, with IC50 values in the absence of a preincubation phase of: (R)-Flu-AM1, COX-1 (arachidonic acid) 6 mu M; COX-2 (arachidonic acid) 20 mu M; COX-2 (2-AG) 1 mu M; (S)-Flu-AM1, COX-1 (arachidonic acid) 3 mu M; COX-2 (arachidonic acid) 10 mu M; COX-2 (2-AG) 0.7 mu M. The compounds showed no enantiomeric selectivity in their FAAH inhibitory properties. (R)-Flu-AM1 (10 mu M) greatly inhibited the production of prostaglandin D2 and E2 in both unstimulated and lipopolysaccharide + interferon.-stimulated RAW 264.7 macrophage cells. Levels of 2-AG were not affected either by (R)-Flu-AM1 or by 10 mu M flurbiprofen, either alone or in combination with the FAAH inhibitor URB597 (1 mu M). Conclusions/Significance Both enantiomers of Flu-AM1 are more potent inhibitors of 2-AG compared to arachidonic acid oxygenation by COX-2. Inhibition of COX in lipopolysaccharide + interferon.-stimulated RAW 264.7 cells is insufficient to affect 2-AG levels despite the large induction of COX-2 produced by this treatment.

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  • 5.
    Gunnarsson, David
    et al.
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Svensson, Mona
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Nordberg, Gunnar
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Pronounced induction of testicular PGF2alpha and suppression of testosterone by cadmium: prevention by zinc2004In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 200, no 1, p. 49-58Article in journal (Refereed)
    Abstract [en]

    In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(PGF) production, adult male Sprague–Dawley rats were exposed to CdCl2 by subcutaneous injections. Dose–response as well as temporal–response experiments were performed, and PGF levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 μmol/kg) caused a dramatic elevation of testicular PGF, which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 μmol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF synthesis (22.3-fold) detected after exposure to 20 μmol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

  • 6.
    Karlsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Morgillo, Carmine M.
    Deplano, Alessandro
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Novellino, Ettore
    Congiu, Cenzo
    Onnis, Valentina
    Catalanotti, Bruno
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142711Article in journal (Refereed)
    Abstract [en]

    Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAH(T488A)-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)-and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 mu M, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 mu M) was more potent than the (R)-enantiomer (IC50 5.7 mu M). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.

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  • 7.
    Lagerkvist, Birgitta Json
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Bernard, Alfred
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Pulmonary Medicine.
    Bergström, Erik
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Holmstrom, Karin
    Karp, Kjell
    Lundstrom, Nils-Goran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Segerstedt, Bo
    Svensson, Mona
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Nordberg, Gunnar
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
    Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance.2004In: Environ Health Perspect, ISSN 0091-6765, Vol. 112, no 17, p. 1768-71Article in journal (Refereed)
  • 8.
    Liljelind, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wahlström, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Utvärdering av en mätmetod för objektiv skattning av exponeringstiden vid hand-arm-vibrationer2014Report (Other academic)
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  • 9.
    Nordberg, Gunnar F
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lundström, Nils-Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hagenbjörk-Gustafsson, Annika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lagerkvist, Birgitta J-Son
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nilsson, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Nilsson, Leif
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Bernard, Alfred
    Dumont, Xavier
    Bertilsson, Helen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Eriksson, Kåre
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lung function in volunteers before and after exposure to trichloramine in indoor pool environments and asthma in a cohort of pool workers2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 5, p. e000973-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Exposure to trichloramine (NCl(3)) in indoor swimming-pool environments is known to cause mucous membrane irritation, but if it gives rise to changes in lung function or asthma in adults is not known. (1) We determined lung function in volunteers before and after exposure to indoor pool environments. (2) We studied the occurrence of respiratory symptoms and asthma in a cohort of pool workers.

    DESIGN/METHODS/PARTICIPANTS: (1) We studied two groups of volunteers, 37 previously non-exposed healthy persons and 14 pool workers, who performed exercise for 2 h in an indoor pool environment. NCl(3) in air was measured during pool exposures and in 10 other pool environments. Filtered air exposures were used as controls. Lung function and biomarkers of pulmonary epithelial integrity were measured before and after exposure. (2) We mailed a questionnaire to 1741 persons who indicated in the Swedish census 1990 that they worked at indoor swimming-pools.

    RESULTS: (1) In previously non-exposed volunteers, statistically significant decreases in FEV(1) (forced expiratory volume) and FEV(%) (p=0.01 and 0.05, respectively) were found after exposure to pool air (0.23 mg/m(3) of NCl(3)). In pool workers, a statistically significant decrease in FEV(%) (p=0.003) was seen (but no significant change of FEV(1))(.) In the 10 other pool environments the median NCl(3) concentration was 0.18 mg/m(3). (2) Our nested case/control study in pool workers found an OR for asthma of 2.31 (95% CI 0.79 to 6.74) among those with the highest exposure. Exposure-related acute mucous membrane and respiratory symptoms were also found.

    CONCLUSIONS: This is the first study in adults showing statistically significant decreases in lung function after exposure to NCl(3). An increased OR for asthma among highly exposed pool workers did not reach statistical significance, but the combined evidence supports the notion that current workroom exposures may contribute to asthma development. Further research on sensitive groups is warranted.

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  • 10.
    Sunduru, Naresh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Marwaha, Sania
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors2017In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 32, no 1, p. 513-521Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b] pyri-din-2-yl) phenyl) acetamide, 4g, with an IC50 of 2.6 mu M as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b] pyridin-2-yl)phenyl) acetamide, 4i, with an IC50 of 0.35 mu M.

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