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  • 251.
    Stafberg, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jessica, Karlsson
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Christopher, Fowler
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The mRNA expression of endocannabinoid-related enzymes in rat prostate AT-1 cells following exposure to lactate and interleukin-6Manuscript (preprint) (Other academic)
    Abstract [en]

    The endocannabinoid system is dysregulated in prostate cancer but the mechanisms responsible for this dysregulation are not known. We hypothesise that the dysregulation is secondary to factors in the tumour microenvironment. In this study we investigated the effects of lactic acid induced low pH and interleukin-6 (IL-6) treatment upon the expression of endocannabinoid related enzymes and the functional effects upon anandamide degradation and cell viability in Dunning R3327 rat prostate AT-1 cancer cells. Cells were exposed for 3 h at 37 °C to Krebs-Ringer-HEPES/bicarbonate buffer at either pH 7.4 or at pH 6.6 (due to the presence of 40 mM lactic acid), and to 0, 25 or 100 ng/ml of IL-6. Neither low pH (pH 6.6) nor IL-6 induced any changes in the mRNA levels of the anandamide metabolic enzymes. However, the expression of the 2- arachidonoylglycerol-synthesizing enzyme DAGLα was increased by low pH and the expression of CB2 receptor mRNA was decreased at the low pH. The DAGL inhibitor orlistat increased extracellular LDH levels after 24 h of incubation of AT-1 cells, suggesting a higher frequency of cell death. It is concluded that under the conditions used, exposure to lactate and IL-6 do not affect the expression of the anandamide metabolic enzymes in AT-1 cells, but do modify the expression of an enzyme involved in the synthesis of 2-arachidonoylglycerol. 

  • 252. Stone, Jana E
    et al.
    Kumar, Dinesh
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Binz, Sara K
    Inase, Aki
    Iwai, Shigenori
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Burgers, Peter M
    Kunkel, Thomas A
    Lesion bypass by S. cerevisiae Pol ζ alone2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 826-834Article in journal (Refereed)
    Abstract [en]

    DNA polymerase zeta (Pol ζ) participates in translesion synthesis (TLS) of DNA adducts that stall replication fork progression. Previous studies have led to the suggestion that the primary role of Pol ζ in TLS is to extend primers created when another DNA polymerase inserts nucleotides opposite lesions. Here we test the non-exclusive possibility that Pol ζ can sometimes perform TLS in the absence of any other polymerase. To do so, we quantified the efficiency with which S. cerevisiae Pol ζ bypasses abasic sites, cis-syn cyclobutane pyrimidine dimers and (6-4) photoproducts. In reactions containing dNTP concentrations that mimic those induced by DNA damage, a Pol ζ derivative with phenylalanine substituted for leucine 979 at the polymerase active site bypasses all three lesions at efficiencies between 27 and 73%. Wild-type Pol ζ also bypasses these lesions, with efficiencies that are lower and depend on the sequence context in which the lesion resides. The results are consistent with the hypothesis that, in addition to extending aberrant termini created by other DNA polymerases, Pol ζ has the potential to be the sole DNA polymerase involved in TLS.

  • 253.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    The discovery of antiviral compounds targeting adenovirus and herpes simplex virus: assessment of synthetic compounds and natural products2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is a need for new antiviral drugs. Especially for the treatment of adenovirus infections, since no approved anti-adenoviral drugs are available. Adenovirus infections in healthy persons are most often associated with respiratory disease, diarrhea and infections of the eye. These infections can be severe, but are most often self-limiting. However, in immunocompromised patients, adenovirus infections are associated with morbidity and high mortality rates. These patients are mainly stem cell or bone marrow transplantation recipients, however solid organ transplantation recipients or AIDS patients may be at risk as well. In addition, children are at higher risk to develop disseminated disease.

    Due to the need for effective anti-adenoviral drugs, we have developed a cell based screening assay, using a replication-competent GFP expressing adenovirus vector based on adenovirus type 11 (RCAd11GFP). This assay facilitates the screening of chemical libraries for antiviral activity. Using this assay, we have screened 9800 small molecules for anti-adenoviral activity with low toxicity. One compound, designated Benzavir-1, was identified with activity against representative types of all adenovirus species. In addition, Benzavir-1 was more potent than cidofovir, which is the antiviral drug used for treatment of adenovirus disease. By structure-activity relationships analysis (SAR), the potency of Benzavir-1 was improved. Hence, the improved compound is designated Benzavir-2. To assess the antiviral specificity, the activity of Benzavir-1 and -2 on both types of herpes simplex virus (HSV) was evaluated. Benzavir-2 displayed better efficacy than Benzavir-1 and had an activity comparable to acyclovir, which is the original antiviral drug used for therapy of herpes virus infections. In addition, Benzavir-2 was active against acyclovir-resistant clinical isolates of both HSV types.

    To expand our search for compounds with antiviral activity, we turned to the natural products. An ethyl acetate extract library was established, with extracts derived from actinobacteria isolated from sediments of the Arctic Sea. Using our screening assay, several extracts with anti-adenoviral activity and low toxicity were identified. By activity-guided fractionation of the extracts, the active compounds could be isolated. However, several compounds had previously been characterized with antiviral activity. Nonetheless, one compound had uncharacterized antiviral activity and this compound was identified as a butenolide. Additional butenolide analogues were found and we proposed a biosynthetic pathway for the production of these compounds. The antiviral activity was characterized and substantial differences in their toxic potential were observed. One of the most potent butenolide analogues had minimal toxicity and is an attractive starting point for further optimization of the anti-adenoviral activity.

    This thesis describes the discovery of novel antiviral compounds that targets adenovirus and HSV infections, with the emphasis on adenovirus infections. The discoveries in this thesis may lead to the development of new antiviral drugs for clinical use. 

  • 254. Strapáčová, Simona
    et al.
    Brenerová, Petra
    Krčmář, Pavel
    Andersson, Patrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van Ede, Karin, I
    van Duursen, Majorie B. M.
    van den Berg, Martin
    Vondráček, Jan
    Machala, Miroslav
    Relative effective potencies of dioxin-like compounds in rodent and human lung cell models2018In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 404–405, p. 33-41Article in journal (Refereed)
    Abstract [en]

    Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.

  • 255.
    Strålberg, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Kassem, Ali
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Kasprzykowski, Franciszek
    Abrahamson, Magnus
    Grubb, Anders
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vitro and in vivo by cysteine proteinase inhibitors2017In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, no 5, p. 1233-1243Article in journal (Refereed)
    Abstract [en]

    Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginylleucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-kappa B ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors. Adult mice were injected locally with LPS and then treated with E-64 and osteoclast formation assessed by the number of cathepsin K+ multinucleated cells. Cystatin C inhibited LPS-induced osteoclast formation time and concentration dependently (IC50 = 0.3 mu M). The effect was associated with decreased mRNA and protein expression of tartrate-resistant acid phosphatase (TRAP) and cathepsin K and of the osteoclastogenic transcription factors c-Fos and NFATc1. LPS-induced osteoclast formation on bone slices was also inhibited by cystatin C, resulting in decreased pit formation and release of bone matrix proteins. Similar data were obtained with E-64 and Z-RLVG-CHN2. Cystatin C was internalized in BMMs stimulated by LPS but not in unstimulated BMMs. Osteoclast formation induced by LPS was dependent on TNF-alpha, and the 3 inhibitors abolished LPS-induced TNF superfamily 2 (gene encoding TNF-alpha; Tnfsf2) mRNA expression without affecting Il1b, Il6, or oncostatin M (Osm) expression. Formation of osteoclasts in the skull bones after local LPS stimulation was inhibited by E-64. It is concluded that cysteine proteinase inhibitors effectively inhibit LPS-induced osteoclast formation in vivo and in vitro by inhibition of TNF-alpha expression. The targeting of cysteine proteinases might represent a novel treatment modality for prevention of inflammatory bone loss.

  • 256.
    Stäubert, Claudia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Le Duc, Diana
    Schoeneberg, Torsten
    Examining the Dynamic Evolution of G Protein-Coupled Receptors2014In: G Protein-Coupled Receptor Genetics: Research and Methods in the Post-Genomic Era / [ed] Craig W. Stevens, Humana Press, 2014, p. 23-43Chapter in book (Refereed)
    Abstract [en]

    The valuable source of large-scale genomic information initiated attempts to identify the origin(s) of G protein-coupled receptors (GPCR), count and categorize those genes, and follow their evolutionary history. Being present in fungi, plants, and unicellular eukaryotes, GPCR must have evolved before the plant-fungi-animal split about 1.5 billion years ago. Phylogenetic analyses revealed several kinds of evolutionary patterns that occurred during GPCR evolution including one-to-one orthologous relationships, species-specific gene expansion, and episodic duplication of the entire GPCR repertoire in certain species lineages. These data document the highly dynamic process of birth and death of GPCR genes since hundreds of millions of years. Genetic drift and selective forces have shaped the individual structure of a given receptor gene but also of the species-specific receptor repertoire - a process that is still ongoing. These processes have left footprints in the genomic sequence that can be detected by bioinformatic methods and may help to interpret receptor function in the light of a given species in its environment. Reasonable intraspecies sequence variability in GPCR is either physiologically tolerated or promotes individual phenotypes and adaptation, but also susceptibilities for diseases. Therefore, the impact of GPCR variants in epistatic networks will be an important task of future GPCR research. The chapter summarizes evolutionary processes working on GPCR genes and sheds light on their consequences at the levels of receptor structure and function.

  • 257.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Westermark, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Transthyretin amyloidoses: new strategies for therapeutic intervention2010In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 35, no 4, p. 325-332Article in journal (Refereed)
    Abstract [en]

    Liver transplantation as a treatment for transthyretin amyloidosis (ATTR) was introduced 20 years ago and is currently the only available treatment for the disease. Although the procedure has been proven to halt the progression of the disease for most patients, several unexpected complications have emerged, and it is obvious that for several mutations liver transplantation has no impact on the progression of the disease. Heart complications, especially in elderly patients, have been a cause of concern for many patients, including those with the most widespread neuropathic mutation, transthyretin (TTR)Val30Met. These drawbacks and the risk involved with transplantation, together with the need for life-long immunosuppressive therapy, have demonstrated the need for an effective medical treatment. From the experience with liver transplant patients, it appears that the amyloidogenic properties of wild-type TTR are enhanced once amyloid formation has started, and that elimination of the mutated TTR is not sufficient to prevent further amyloid formation in all cases. The development of animal models for the disease has further increased our understanding of factors involved in amyloid formation, and offers the possibility to test new medical treatment modalities. From our experience with liver transplantation, it appears that treatment directed towards stabilizing the TTR tetramer, eliminating misfolded TTR, decreasing TTR serum concentrations, decreasing toxicity and removing amyloid deposits are the most attractive modalities for treatment. Several studies are currently planned or ongoing to explore these possibilities, and promising results are already being reported.

  • 258.
    Sun, Kun
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bröms, Jeanette
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gurram, Bharat Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 7, p. 4123-4130Article in journal (Refereed)
    Abstract [en]

    The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an alpha-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A(1) activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.

  • 259. Sun, Xian-qiang
    et al.
    Chen, Lei
    Li, Yao-zong
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Li, Wei-hua
    Liu, Gui-xia
    Tu, Yao-quan
    Tang, Yun
    Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors2014In: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 35, no 2, p. 301-310Article in journal (Refereed)
    Abstract [en]

    Aim: To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors. Methods: One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures. Results: Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion: The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.

  • 260.
    Sundström, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vitamin D and multiple sclerosis: timing of sampling, treatment and prevention2013In: Biomarkers in Medicine, ISSN 1752-0363, Vol. 7, no 2, p. 193-195Article in journal (Other academic)
  • 261. Sut, Stefania
    et al.
    Dall'Acqua, Stefano
    Baldan, Valeria
    Ngahang Kamte, Stephane L.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Biapa Nya, Prosper C.
    Vittori, Sauro
    Benelli, Giovanni
    Maggi, Filippo
    Cappellacci, Loredana
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Petrelli, Riccardo
    Identification of tagitinin C from Tithonia diversifolia as antitrypanosomal compound using bioactivity-guided fractionation2018In: Fitoterapia (Milano), ISSN 0367-326X, E-ISSN 1873-6971, Vol. 124, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Tithonia diversifolia (Asteraceae), is used as traditional medicine in tropical countries for the treatment of various diseases, including malaria. Although numerous studies have assessed the antimalarial properties, nothing is known about the effect of T. diversifolia extracts on trypanosomiasis. In this study extracts of T. diversifolia aerial parts were evaluated for their bioactivity against Trypanosoma brucei. The activity was studied against bloodstream forms of T. brucei (TC221), as well as against mammalian cells (BALB/3T3 mouse fibroblasts), as a counter-screen for toxicity. Both methanolic and aqueous extracts showed significant effects with IC50 values of 1.1 and 2.2 mu g/mL against T. brucei (TC221) and 5.2 and 3.7 mu g/mL against BALB/3T3 cells, respectively. A bioassay-guided fractionation on the methanolic extract yielded in identification of active fractions (F8 and F9) with IC50 values of 0.41 and 0.43 mu g/mL, respectively, against T. brucei (TC221) and 1.4 and 1.5 mu g/mL, respectively, against BALB/3T3 cells,. The phytochemical composition of the extracts and the purified fractions were investigated using HPLC-ESI-MS/MS and 1D and 2D NMR spectra showing the presence of sesquiterpene lactones that in turn were subjected to the isolation procedure. Tagitinin A and C were rather active but the latter presented a very strong inhibition on T. brucei (TC221) with an IC50 value of 0.0042 mu g/mL. This activity was 4.5 times better than that of the reference drug suramin. The results of this study shed light on the antitrypanosomal effects of T. diversifolia extracts and highlighted tagitinin C as one of the possible responsible for this effect. Further structure activity relationships studies on tagitinins are needed to consider this sesquiterpenes as lead compounds for the development of new antitrypanosomal drugs.

  • 262. Svensberg, Karin
    et al.
    Björnsdottir, Ingunn
    Wallman, Andy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Kälvemark Sporrong, Sofia
    Nordic Pharmacy Schools' Experience in Communication Skills Training2017In: American Journal of Pharmaceutical Education, ISSN 0002-9459, E-ISSN 1553-6467, Vol. 81, no 9, article id 6005Article in journal (Refereed)
    Abstract [en]

    Objective. To assess communication skills training at Nordic pharmacy schools and explore ways for improvement. Methods. E-mail questionnaires were developed and distributed with the aim to explore current practice and course leaders' opinions regarding teaching of patient communication skills at all the 11 master level Nordic (Denmark, Finland, Iceland, Norway and Sweden) pharmacy schools. The questionnaires contained both closed-and open-ended questions. Results. There was a variation of patient communication skills training among schools. In general, communication skills training was included in one to five courses (mode 1); varied in quantity (6-92 hours); had low use of experiential training methods; and had challenges regarding assessments and acquiring sufficient resources. However, some schools had more focus on such training. Conclusion. The results show room for improvement in patient communication skills training in most Nordic pharmacy schools and give insights into how to enhance communication skill building in pharmacy curricula. Suggestions for improving the training include: early training start, evidence-based frameworks, experiential training, and scaffolding.

  • 263. Svensberg, Karin
    et al.
    Kälvemark Sporrong, Sofia
    Lupattelli, Angela
    Olsson, Erika
    Wallman, Andy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Björnsdottir, Ingunn
    Nordic Pharmacy Students' Opinions of their Patient Communication Skills Training2018In: American Journal of Pharmaceutical Education, ISSN 0002-9459, E-ISSN 1553-6467, Vol. 82, no 2, p. 152-165, article id 6208Article in journal (Refereed)
    Abstract [en]

    Objective. To describe Nordic pharmacy students' opinions of their patient communication skills training (PCST), and the association between course leaders' reports of PCST qualities and students' perceptions of their training. Secondary objective was to determine what factors influence these associations. Methods. A cross-sectional questionnaire-based study was performed. The various curricula were categorized into three types (basic, intermediate and innovative training) and students were divided into three groups according to the type of training they had received. Multivariable logistic regression models were fitted with different opinions as outcomes and three types of training as exposure, using generalized estimation equations. Results. There were 370 students who responded (response rate: 77%). Students within the innovative group were significantly more likely to agree that they had received sufficient training, and to agree with the assertion that the pharmacy school had contributed to their level of skills compared to students in the basic group. Conclusion. There appears to be an association between larger and varied programs of training in patient communication skills and positive attitudes toward this training on the part of the students, with students reporting that they received sufficient training, which likely enhanced their skills.

  • 264.
    Sönnerstam, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Sjölander, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gustafsson, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Clinically relevant drug-drug interactions among elderly people with dementia2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1351-1360Article in journal (Refereed)
    Abstract [en]

    Purpose: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia.

    Methods: People 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley's classification system.

    Results: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n=35) were most frequently observed. Omeprazol-citalopram (n=25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI.

    Conclusion: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed.

  • 265.
    Sönnerstam, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Sjölander, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gustafsson, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Letter to the Editor: Clinically relevant drug-drug interactions among elderly people with dementia2019In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 75, no 9, p. 1321-1322Article in journal (Refereed)
  • 266. Tan, Edwin C. K.
    et al.
    Johnell, Kristina
    Bell, J. Simon
    Garcia-Ptacek, Sara
    Fastbom, Johan
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Eriksdotter, Maria
    Does use of acetylcholinesterase inhibitors prevent or delay the prescribing of psychotropic medications in people with dementia?: Analyses of the Swedish dementia registry (SveDem)2019In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, p. 424-425Article in journal (Other academic)
  • 267. Taylor, David M.
    et al.
    Werneke, Ursula
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Ethnopharmacology2018In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 72, p. S30-S32Article in journal (Refereed)
    Abstract [en]

    Background: Ethnopharmacology relates to the study of substances used medicinally by different ethnic or cultural groups or handling of, drugs-based ethnicity or pharmacogenetics.

    Aims: To review the key aspects of ethnopharmacology.

    Method: This lecture gives an overview of the relationship between geography, culture, pharmacogenomics and prescribing.

    Results: Although the majority of antipsychotics, antidepressants and mood-stabilisers are widely and cheaply available in generic forms, prescription rates can vary. Clozapine is one such example with prescribing-rates ranging from less than 10 patients per 100,000 people to nearly 180 patients/100,000 people. Pharmacogenetic studies of antipsychotics and antidepressants concern gene polymorphisms that may affect both, pharmacodynamic or pharmacokinetic properties. Considerable genetic and ethnic variability has been seen for the P450 microsomal enzymes CYP 2D6 and 1A2.

    Conclusions: With accelerated global mobility and increased understanding of medicinal substances at molecular level, understanding of ethnopharmacology will become increasingly important in routine clinical practice.

  • 268.
    Thors, L
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Burston, J J
    Alter, B J
    McKinney, M K
    Cravatt, B F
    Ross, R A
    Pertwee, R G
    Gereau, R W
    Wiley, J L
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase.2010In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 160, no 3, p. 549-560Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide (AEA), are effective in a number of animal models of pain. Here, we investigated a series of isoflavones with respect to their abilities to inhibit FAAH. EXPERIMENTAL APPROACH: In vitro assays of FAAH activity and affinity for CB receptors were used to characterize key compounds. In vivo assays used were biochemical responses to formalin in anaesthetized mice and the 'tetrad' test for central CB receptor activation. KEY RESULTS: Of the compounds tested, biochanin A was adjudged to be the most promising. Biochanin A inhibited the hydrolysis of 0.5 microM AEA by mouse, rat and human FAAH with IC(50) values of 1.8, 1.4 and 2.4 microM respectively. The compound did not interact to any major extent with CB(1) or CB(2) receptors, nor with FAAH-2. In anaesthetized mice, URB597 (30 microg i.pl.) and biochanin A (100 microg i.pl.) both inhibited the spinal phosphorylation of extracellular signal-regulated kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB(1) receptor antagonist/inverse agonist AM251 (30 microg i.pl.). Biochanin A (15 mg.kg(-1) i.v.) did not increase brain AEA concentrations, but produced a modest potentiation of the effects of 10 mg.kg(-1) i.v. AEA in the tetrad test. CONCLUSIONS AND IMPLICATIONS: It is concluded that biochanin A, in addition to its other biochemical properties, inhibits FAAH both in vitro and peripherally in vivo.

  • 269. Thors, L.
    et al.
    Koch, B.
    Koch, M.
    Hägglund, L.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden b Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University.
    In vitro human skin penetration model for organophosphorus compounds with different physicochemical properties2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 32, p. 198-204Article in journal (Refereed)
    Abstract [en]

    A flow-through diffusion cell was validated for in vitro human epidermal penetration studies of organophosphorus compounds (OPCs) applied by infinite dosing. By testing OPCs with similar molecular weight but different physicochemical properties, it was shown that hydrophilic and lipophilic properties are major determinants for the penetration rate. Lipophilic OPCs displayed maximum cumulative penetration in the 20-75% agent concentration range whereas the hydrophilic OPCs displayed maximum cumulative penetration at 10 or 20% agent concentration. Low penetration was observed for all agents at 1% agent concentration or when applied as neat agents. The impact of the receptor solution composition was evaluated by comparing the penetration using receptor solutions of different ratios of ethanol and water. For diluted OPCs, a high concentration of ethanol in the receptor solution significantly increased the penetration compared to lower concentrations. When OPCs were applied as neat agents, the composition of the receptor solution only affected the penetration for one of four tested compounds. In conclusion, the flow-through diffusion cell was useful for examining the penetration of OPCs through the epidermal membrane. It was also demonstrated that the penetration rates of OPCs are strongly influenced by dilution in water and the receptor fluid composition.

  • 270. Thors, L.
    et al.
    Lindberg, S.
    Johansson, S.
    Koch, B.
    Koch, M.
    Hagglund, L.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    RSDL decontamination of human skin contaminated with the nerve agent VX2017In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 269, p. 47-54Article in journal (Refereed)
    Abstract [en]

    Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5,10, 30, 60 or 120 min post exposure. Early decontamination of VXwith RSDL, initiated 5-10 min after skin exposure, was very effective. Delayed decontamination initiated 30-60 min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120 min resulted in very low efficacy. Comparing.RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by P-31 NMR spectroscopy of the OPCs following reactions with RSDL and its three nucleophile components. The degradation rate was clearly associated with the high pH of the specific solution investigated; i.e. increased pH resulted in a more rapid degradation. In addition, the solubility of the OPC in RSDL also influenced the degradation rate since the degradation of VX was significantly faster when the NMR analysis was performed in the organic solvent acetonitrile compared to water. In conclusion, we have applied the in vitro flow-through diffusion cell for evaluation of skin decontamination procedures of human epidermis exposed to OPCs. It was demonstrated that early decontamination is crucial for efficient mitigation of epidermal penetration of VX and that almost complete removal of the nerve agent from the skin surface is possible. Our data also indicate that the pH of RSDL together with the solubility of OPC in RSDL are of primary importance for the decontamination efficacy.

  • 271.
    Thors, Lina
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    The cellular processing of the endocannabinoid anandamide and its pharmacological manipulation2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) exert most of their actions by binding to cannabinoid receptors. The effects of the endocannabinoids are short-lived due to rapid cellular accumulation and metabolism, for AEA, primarily by the enzymes fatty acid amide hydrolase (FAAH). This has led to the hypothesis that by inhibition of the cellular processing of AEA, beneficial effects in conditions such as pain and inflammation can be enhanced. The overall aim of the present thesis has been to examine the mechanisms involved in the cellular processing of AEA and how they can be influenced pharmacologically by both synthetic natural compounds.

    Liposomes, artificial membranes, were used in paper I to study the membrane retention of AEA. The AEA retention mimicked the early properties of AEA accumulation, such as temperature-dependency and saturability.

    In paper II, FAAH was blocked by a selective inhibitor, URB597, and reduced the accumulation of AEA into RBL2H3 basophilic leukaemia cells by approximately half. Treating intact cells with the tyrosine kinase inhibitor genistein, an isoflavone found in soy plants and known to disrupt caveolae-related endocytosis, reduced the AEA accumulation by half, but in combination with URB597 no further decrease was seen. Further on, the effects of genistein upon uptake were secondary to inhibition of FAAH. The ability to inhibit the accumulation and metabolism of AEA was shared by several flavonoids (shown in paper III). In paper IV, the isoflavone biochanin A and URB597 had effects in vivo, in a model of persistent pain, effects decreased by the cannabinoid receptor 1 antagonist AM251.

    In paper VI, the cellular processing of the endocannabinoid metabolites following degradation was examined, a mechanism poorly understood. It was found that nitric oxide (NO) donors significantly increased the retention of tritium in cell membranes following incubation with either tritiated AEA or 2-AG. Further experiments revealed that the effect of NO donors mainly involves the arachidonate part of the molecules. Inhibition of FAAH completely reduced the effect of NO donors in cells with a large FAAH component, indicating that the effects were downstream of the enzyme.

    These results suggest that the cellular processing of endocannabinoids can be affected in a manner of different ways by pharmacological manipulation in vitro and that naturally occurring flavonoid compounds can interact with the endocannabinoid system.

  • 272.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Burston, James J
    Department of Pharmacology and Toxicology, Virginia Commenwealth University, Richmond, Virginia.
    Alter, Benedict J
    Department of Anesthesiology, Washington University, School of Medicine, St. Louis, Missouri.
    McKinney, Michele K
    Department of Chemistry and Skaggs Institute for Chemical Biology, La Jolla, California.
    Cravatt, Benjamin F
    Department of Chemistry and Skaggs Institute for Chemical Biology, La Jolla, California.
    Ross, Ruth A
    School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland.
    Pertwee, Roger W
    School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland.
    Gereau 4th, Robert W
    Department of Anesthesiology, Washington University, School of Medicine, St. Louis, Missouri.
    Wiley, Jenny L
    Department of Pharmacology and Toxicology, Virginia Commenwealth University, Richmond, Virginia.
    Fowler , Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Biochanin A acts as a peripheral inhibitor of fatty acid amide hydrolaseManuscript (Other academic)
    Abstract [en]

    Inhibitors of fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for the metabolism of the endogenous cannabinoid (CB) receptor ligand anandamide, are effective in animal models of inflammatory, cancer, visceral and neuropathic pain. No peripherallyrestricted FAAH inhibitors have yet been reported. The isoflavones are a class of naturallyoccurring compounds that show little brain penetration, and two of these, genistein and daidzein, inhibit FAAH at low micromolar concentrations. Here, we report that the related isoflavone biochanin A inhibits the hydrolysis of 0.5 μM anandamide by mouse, rat and human FAAH with IC50 values of 1.8, 1.4, and 2.4 μM, respectively. The inhibition of rat FAAH by biochanin A was mixed type in nature, with Ki slope and Ki intercept values of 1.1 and 8.2 μM, respectively. Anandamide hydrolysis was also inhibited in intact basophilic leukaemia cells at sub- to low- micromolar concentrations. The compound did not interact to any major extent with CB1 or CB2 receptors. In vivo, biochanin A (10 mg/kg i.v.) did not increase brain anandamide concentrations, but produced a modest potentiation of the effects of 10 mg/kg i.v. anandamide in the tetrad test. In anaesthetized mice, URB597 (30 μg/paw) and biochanin A (100 μg/paw) both inhibited the spinal phosphorylation of extracellular receptor kinase produced by the intraplantar injection of formalin. The effects of both compounds were significantly reduced by the CB1 receptor antagonist/inverse agonist AM251 (30 μg/paw). It is concluded that biochanin A may be useful as a template for the design of novel, peripherally-acting FAAH inhibitors.

  • 273.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Effect of nitric oxide donors on membrane tritium accumulation of endocannabinoids and related endogenous lipidsManuscript (Other academic)
    Abstract [en]

    Endocannabinoids refers to a group of lipids with the ability of binding the two known cannabinoid receptors and synthesized by hydrolysis of lipid precursors. But still is the processing of the endocannabinoid metabolites following degradation poorly understood. Using tritium labelled anandamide (AEA) we discovered that nitric oxide (NO) donors significantly increased the amount of tritium accumulated in the cell membranes of RBL2H3 rat basophilic cells, 3T3-L1 mouse fibroblast cells and b.End5 mouse brain endothelioma cells following incubation. In addition, utilizing AEA labelled in either the arachidonate or ethanolamine part of the molecule revealed that the effect of NO donors mainly involved the arachidonate part of the molecule. In enzyme studies, pretreatment of intact cells with NO donors did not increase the activity of the enzyme mainly responsible for metabolism of AEA, fatty acid amide hydrolase (FAAH). Furthermore, inhibition of FAAH completely diminished the effect produced by NO donors in cells with a large FAAH component, indicating that the effects were downstream of the enzyme. Similar results of the NO donors were also obtained when radiolabelled 2-arachidonoylglycerol (2-AG) was used. These data showed that the processing of endocannabinoid metabolites can be regulated by NO donors and may therefore be of importance in recycling lipid compounds to elevate the tissue levels.

  • 274.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Tavelin, Staffan
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Characterization of anandamide retention in synthetic liposomesManuscript (Other academic)
    Abstract [en]

    Anandamide (AEA) is an endogenous ligand for cannabinoid receptors. Prior to termination of signalling activity AEA has to move across the plasma membrane to the reach its intracellular hydrolytic enzyme. The mechanism underlying this transport is under considerable debate. In the present study, we have examined the properties of AEA retention using synthetic large unilamellar liposomes (LUVs). Retention of AEA in LUVs was saturable, time- and temperature-dependent. Preincubation of LUVs with inhibitors of AEA uptake and metabolism did not decrease the tritium retention. These results mimic the “initial” cellular uptake of AEA and indeed argue against the need of a specific membrane transporter protein.

  • 275.
    Tiger, Gunnar
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Signal transduction in the brain: modulation of receptor-mediated inositol phospholipid breakdown by potassium and fluoride ions1990Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neurotransmitter receptor types mediating the generation of intracellular signals are of two types; ligand-gated ion channels and G protein coupled receptors. The effector enzyme phosphoinositide-specific phospholipase C (PLC) is modulated by stimulation of G protein coupled receptors, leading to an increased breakdown of inositol phospholipids ("Ptdlns breakdown").In recent years, the receptors in the brain coupled to PLC and modulation of such receptor-mediated Ptdlns breakdown have been characterised. One such modulation is the "potassium effect", whereby an increase in the assay [K+] from 6 to 18 mM potentiates the Ptdlns breakdown response to the muscarinic agonist carbachol in the rat brain. It has been speculated that this effect is one way of enhancing the signal :noise ratio of muscarinic neurotransmission. The mechanisms responsible for the potassium effect have been studied in this thesis.Initial methodological studies indicated that the temperature of the Krebs buffer used after tissue dissection was an important factor regulating the Ptdlns response to receptor stimulation. Expressing the Ptdlns breakdown response as a fraction of the total labelled phosphoinositides was more useful than other ways of expressing the data. Acid extraction of the Lipid fraction was also superior to neutral extraction.Miniprismspreparedfrompig striatum and hippocampus showed qualitative (but not quantitative) similarities with the rat with respect to stimulation by carbachol, noradrenaline and the potassium effect. Dopamine also stimulated Ptdlns breakdown, though probably via a noradrenergic mechanism.The enhancing actions of potassium appeared to be selective for muscarinic Ml-type receptors. Thus glutamate, quisqualate and NaF-stimulated Ptdlns breakdown are not affected by raised [K+].The potassium effect is brought about by two mechanisms. In calcium-free Krebs buffer, the effect could be mimicked by the calcium channel agonist BAY K-8644 and partially antagonised by verapamil. At an assay [Ca2*] of 2.52 mM, however, modulation of calcium uptake had little effect on carbachol-stimulated Ptdlns breakdown at either normal or raised [K+]. The synergy between potassium and carbachol at252 mM Ca?+ is not dependent upon tissue depolarisation perse, since other ways of depolarising the tissue did not enhance the response to carbachol. It is suggested that potassium might have a direct effect on the muscarinic Ml-type receptor - G protein - PLC complex.In order to investigate this possibility, the effect of fluoride ions (which activate G proteins via formation of AlF4) on basal and carbachol-stimulated Ptdlns breakdown was investigated. Fluoride ions inhibited the enhanced breakdown response to carbachol found at raised [K+]. However, this effect is secondary to effects of fluoride on PLC substrate availibility rather than on G protein function.

  • 276.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Andréen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance to allopregnanolone with focus on the GABA-A receptor2011In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 2, p. 311-327Article in journal (Refereed)
    Abstract [en]

    Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial (VPM) nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.

  • 277.
    Tysklind, Mats
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Patrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Haglund, Peter
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van Bavel, B
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rappe, Christoffer
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Selection of polychlorinated biphenyls for use in quantitative structure-activity modelling1995In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 4, no 1, p. 11-19Article in journal (Refereed)
    Abstract [en]

    By characterizing the 154 tetra- through heptachlorinated biphenyl (PCB) congeners with a multitude of physico-chemical descriptors, a model representing chemical similarities and differences is achieved. The multivariate characterization of the PCBs was based on 47 physico-chemical descriptor variables, which were summarised by using principal component analysis (PCA). By applying statistical design to the orthogonal scores from the PCA, a 24-factorial design was used to select a set of 16 congeners. In addition, four congeners were added to provide information about the interior region of the chemical domain of PCBs. This set of 20 structurally different congeners is suggested to be used in future quantitative structure-activity relationships (QSARs) for screening of the toxicological and biochemical effects of the PCBs.

  • 278.
    Türkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance development to Morris water maze test impairments induced by acute allopregnanolone2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 139, no 2, p. 651-659Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

  • 279.
    Ulfberg, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Mitchell, Ulrike H.
    Efficacy of Sildenafil in a Patient With Restless Legs Syndrome/Willis-Ekbom Disease2015In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 38, no 2, p. 67-68Article in journal (Refereed)
  • 280.
    Ur-Rehman, Tofeeq
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Slepenkin, Anatoly
    Chu, Hencelyn
    Blomgren, Anders
    Dahlgren, Markus K
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zetterström, Caroline E
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Peterson, Ellena M
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion2012In: The Journal of antibiotics, ISSN 0021-8820, Vol. 65, p. 397-404Article in journal (Refereed)
    Abstract [en]

    Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.Journal of Antibiotics advance online publication, 6 June 2012; doi:10.1038/ja.2012.43.

  • 281.
    Uusitalo, Pia
    et al.
    Creative Antibiotics AB, Umeå, Sweden.
    Hägglund, Ulrik
    Rhöös, Elin
    Norberg, Henrik Scherman
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundin, Charlotta
    Creative Antibiotics AB, Umeå, Sweden.
    The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo2017In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 70, no 9, p. 937-943Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa is an opportunistic pathogen that can be very hard to treat because of high resistance to different antibiotics and alternative treatment regimens are greatly needed. An alternative or a complement to traditional antibiotic is to inhibit virulence of the bacteria. The salicylidene acylhydrazide, INP0341, belongs to a class of compounds that has previously been shown to inhibit virulence in a number of Gram-negative bacteria. In this study, the virulence blocking effect of INP0341 on P. aeruginosa was studied in vitro and in vivo. Two important and closely related virulence system were examined, the type III secretion system (T3SS) that translocates virulence effectors into the cytosol of the host cell to evade immune defense and facilitate colonization and the flagella system, needed for motility and biofilm formation. INP0341 was shown to inhibit expression and secretion of the T3SS toxin exoenzyme S (ExoS) and to prevent bacterial motility on agar plates and biofilm formation. In addition, INP0341 showed an increased survival of P. aeruginosa-infected mice. In conclusion, INP0341 attenuates P. aeruginosa virulence.

  • 282. Vaittinen, Olavi
    et al.
    Schmidt, Florian M.
    Metsälä, Markus
    Halonen, Lauri
    Exhaled breath biomonitoring using laser spectroscopy2013In: Current Analytical Chemistry, ISSN 1573-4110, E-ISSN 1875-6727, Vol. 9, no 3, p. 463-475Article in journal (Refereed)
    Abstract [en]

    Biological monitoring usually relies on the collection of blood and urine samples. Although being non-invasive and providing an inextinguishable sampling pool, the analysis of exhaled breath is not well established. A gas phase measurement is, however, inherently simpler than the analysis of complex biological fluids, and modern methods have identified hundreds of volatile compounds in the breath of persons exposed to normal environmental concentrations. The most commonly deployed analytical techniques in breath analysis are gas chromatography combined with mass spectrometry (GC/MS) and other MS-based methods. Lately, also laser-based optical methods, such as cavity ring-down spectroscopy (CRDS), have emerged in the field. With such instruments, it is possible to accurately quantify the concentrations of volatiles in exhaled breath down to below part-per-billion (ppb) levels with sub-second time resolution. Laser spectroscopy thereby enables real-time investigations during and after exposure to exogenous chemicals. In general, depending on the sampling approach used, the measured levels of the breath compounds may vary significantly. It is therefore of importance to systematically study and account for the phenomena affecting the recorded concentrations, and subsequently select an appropriate sampling and measurement strategy. In Helsinki, we have used CRDS to study the background levels of hydrogen cyanide (HCN), ammonia (NH3) and acetylene (C2H2) in the exhaled breath of healthy volunteers. Different sampling techniques have been employed in an effort to standardize the breath sampling event. The realtime elimination kinetics of breath C2H2 after smoking has also been studied.

  • 283.
    van Ede, Karin I.
    et al.
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.
    Andersson, Patrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gaisch, Konrad P. J.
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.
    van den Berg, Martin
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.
    van Duursen, Majorie B. M.
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.
    Comparison of intake and systemic relative effect potencies of dioxin-like compounds in female rats after a single oral dose2014In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 88, no 3, p. 637-646Article in journal (Refereed)
    Abstract [en]

    Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable.

  • 284.
    van Ede, Karin I.
    et al.
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gaisch, Konrad P. J.
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
    van den Berg, Martin
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
    van Duursen, Majorie B. M.
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
    Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 7, p. 847-853Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in "intake" TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e. g., blood and tissues). OBJECTIVE: We compared intake and systemic REPs of 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3', 4,4', 5-pentachlorobiphenyl (PCB-126), 2,3', 4,4', 5-pentachlorobiphenyl (PCB-118), and 2,3,3', 4,4', 5-hexachlorobiphenyl (PCB-156) in female C57BL/6 mice 3 days after a single oral dose. METHODS: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1Al-associated ethoxyresorufin-O-deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points. RESULTS: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4-PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156. CONCLUSIONS: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues.

  • 285. van Ede, Karin I
    et al.
    Aylward, Lesa L
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van den Berg, Martin
    van Duursen, Majorie BM
    Tissue distribution of dioxin-like compounds: potential impacts on systemic relative potency estimates2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 220, no 3, p. 294-302Article in journal (Refereed)
    Abstract [en]

    Relative effect potencies (REPs) for dioxins and dioxin-like compounds based on tissue concentration or internal dose ((systemic)REPs) can be considered of high relevance for human risk assessment. Within the EU-project SYSTEQ, (systemic)REPs for 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8,-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) were calculated based on a plasma, adipose tissue or liver concentration in Sprague Dawley rats and C57bl/6 mice three days after a single oral dose. Compound-specific distribution as well as differences in accumulation and elimination can influence the tissue concentration and thereby the relative potency estimate of a congener. Here, we show that distribution patterns are generally similar for the tested congeners between the SYSTEQ dataset and other studies using either a single dose or subchronic dosing. Furthermore, the responding concentration for TCDD in single dose studies is comparable to the responding concentrations reported in subchronic studies. In contrast with data for laboratory rodents, available distribution data for humans in the general population display little or no hepatic sequestration. Because hepatic sequestration due to CYP1A2 protein binding may affect the amount of congener that is bioavailable for the AhR to produce hepatic responses, estimates of relative potencies between congeners with differing degrees of hepatic sequestration based on hepatic responses may be misleading for application to human risk assessment. Therefore, extra-hepatic concentration in blood serum/plasma or adipose tissue together with a biological extra-hepatic response might give a more accurate prediction of the relative potency of a congener for human responses under environmental conditions.

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

  • 286. van West, Dirk
    et al.
    Van Den Eede, Filip
    Del-Favero, Jurgen
    Souery, Daniel
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Van Duijn, Cornelia
    Sluijs, Sam
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Mendlewicz, Julien
    Deboutte, Dirk
    Van Broeckhoven, Christine
    Claes, Stephan
    Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression2006In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 31, no 3, p. 620-627Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

  • 287. Varghese, Geena P.
    et al.
    Folkeresen, Lasse
    Elmabsout, Ali A.
    Gabrielsen, Anders
    Jansson, Jan-Håkan
    Fransen, Karin
    Eriksson, Per
    Sirsjo, Allan
    Association of genetic variants in the NLRP3 region with expression of proximal genes and myocardial infarction2012In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 56, no 5-6, p. 377-377Article in journal (Other academic)
  • 288.
    Vicente, André
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Visual Sciences Study Center, Faculty of Medicine, Lisbon University.
    Prud'homme, Sylvie
    Ferreira, Joana
    Abegão Pinto, Luís
    Stalmans, Ingeborg
    Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015)2017In: Ophthalmic Research, ISSN 0030-3747, E-ISSN 1423-0259, Vol. 57, no 4, p. 201-207Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVES: To analyse drug development for open-angle glaucoma during the last 20 years.

    METHODS: Research was performed by referring to clinical trials registered at the International Clinical Trials Registry Platform (ICTRP). A search for the condition "open-angle glaucoma" with the intervention "drug" was performed. We included trials registered from 01/01/1995 to 01/01/2015, only involving studies in phases 1, 2, and 3. Only studies resorting to novel treatment strategies (either novel drugs or yet-untested fixed associations of approved medication) were considered.

    RESULTS: We recorded 158 studies for the condition of open-angle glaucoma with a drug-based intervention; 65 of the studies reported phase 2 trials and 74 reported phase 3 trials. Pharmaceutical companies were the primary sponsors of 95.3% of the trials. Most of the studies (66.5%, n = 105) involved a new drug, and the remainder (33.5%, n = 53) tested fixed drug associations. The bulk of the trials (n = 99, 62.7%) involved the use of prostaglandin analogues, either as a comparator or a study drug. In descending order of frequency, the studies conducted involved Rho-kinase inhibitors (n = 15), carbonic anhydrase inhibitors (n = 14), β-blockers (n = 7), angiostatic steroids (n = 6), α2-adrenergic agonists (n = 4), 5-HT2A receptor agonists (n = 4), and NMDA receptor antagonists (n = 2). A cyclin-dependent kinase inhibitor, an LIM-domain kinase 2 inhibitor, an A1 adenosine receptor agonist, catechin, macrolide, saffron, and seawater were each tested in 1 clinical trial.

    CONCLUSION: Research into the medical treatment of glaucoma indicates the use of prostaglandin analogues. However, there are a significant number of trials testing other drug classes, particularly Rho-kinase inhibitors. This new focus could lead to a potential increase in the number of therapeutical options for the management of glaucoma in the future.

  • 289.
    Vodnala, Munender
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pavlova, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    de Koning, Harry P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Trypanosoma brucei Methylthioadenosine Phosphorylase Protects the Parasite from the Antitrypanosomal Effect of Deoxyadenosine: IMPLICATIONS FOR THE PHARMACOLOGY OF ADENOSINE ANTIMETABOLITES2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 22, p. 11717-11726Article in journal (Refereed)
    Abstract [en]

    Trypanosoma brucei causes African sleeping sickness for which no vaccine exists and available treatments are of limited use due to their high toxicity or lack of efficacy. T. brucei cultivated in the presence of deoxyadenosine accumulates high levels of dATP in an adenosine kinase-dependent process and dies within a few hours. Here we show that T. brucei treated with 1 mM deoxyadenosine accumulates higher dATP levels than mammalian cells but that this effect diminishes quickly as the concentration of the deoxynucleoside decreases. Radioactive tracer studies showed that the parasites are partially protected against lower concentrations of deoxyadenosine by the ability to cleave it and use the adenine for ATP synthesis. T. brucei methylthioadenosine phosphorylase (TbMTAP) was found to be responsible for the cleavage as indicated by the phosphate dependence of deoxyadenosine cleavage in T. brucei cell extracts and increased deoxyadenosine sensitivity in TbMTAP knockdown cells. Recombinant TbMTAP exhibited higher turnover number (k(cat)) and K-m values for deoxyadenosine than for the regular substrate, methylthioadenosine. One of the reaction products, adenine, inhibited the enzyme, which might explain why TbMTAP-mediated protection is less efficient at higher deoxyadenosine concentrations. Consequently, T. brucei grown in the presence of adenine demonstrated increased sensitivity to deoxyadenosine. For deoxyadenosine/adenosine analogues to remain intact and be active against the parasite, they need to either be resistant to TbMTAP-mediated cleavage, which is the case with the three known antitrypanosomal agents adenine arabinoside, tubercidin, and cordycepin, or they need to be combined with TbMTAP inhibitors.

  • 290.
    Wang, Mengying
    et al.
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Xue, Senhai
    Xijing Hospital, Medical University of the Air Force, Xi'an, People's Republic of China.
    Fang, Qian
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Zhang, Meng
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    He, Ying
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Zhang, Ying
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Cao, Junling
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Chen, Jinghong
    School of Public Health, Xi'an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, People's Republic of China.
    Expression and localization of the small proteoglycans decorin and biglycan in articular cartilage of Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency2019In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 36, no 6, p. 451-459Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is an endemic degenerative osteoarthropathy of uncertain etiology. Our study sought to identify a correlation between small proteoglycans decorin and biglycan expression and Kashin-Beck Disease. Immunohistochemistry was used to assess the decorin and biglycan levels in cartilage specimens from both child KBD patients, and rats fed with T-2 toxin under a selenium-deficient condition. Real-time PCR and Western blot were used to assess mRNA and protein levels of decorin and biglycan in rat cartilages, as well as in C28/I2 chondrocytes stimulated by T-2 toxin and selenium in vitro. The result showed that decorin was reduced in all zones of KBD articular cartilage, while the expression of biglycan was prominently increased in KBD cartilage samples. Increased expression of biglycan and reduced expression of decorin were observed at mRNA and protein levels in the cartilage of rats fed with T-2 toxin and selenium- deficiency plus T-2 toxin diet, when compared with the normal diet group. Moreover, In vitro stimulation of C28/I2 cells with T-2 toxin resulted in an upregulation of biglycan and downregulation of decorin, T-2 toxin induction of biglycan and decorin levels were partly rescued by selenium supplement. This study highlights the focal nature of the degenerative changes that occur in KBD cartilage and may suggest that the altered expression pattern of decorin and biglycan have an important role in the onset and pathogenesis of KBD.

  • 291.
    Wang, Ming-De
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Rahman, Mozibur
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Protons inhibit Cl- conductance by direct or allosteric interaction with the GABA-binding site in the rat recombinant alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptor2005In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 528, no 1-3, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Functional roles of external pH on the Cl- conductance were examined on Xenopus oocytes expressing rat recombinant alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors. Acidic pH inhibited GABA-response in a reversible and concentration-dependent manner, significantly increasing the EC50 without appreciably changing the slope or maximal currents induced by GABA in the alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) receptors. In contrast, protonation did not influence the pentobarbital-gated Currents in the alpha(1)beta(2)gamma(2L) receptors, suggesting that protons do not modulate channel activity by directly affecting the channel gating process. Protons competitively inhibited the bicuculline-induced antagonism on GABA in the alpha(1)beta(2)gamma(2L) receptors. The data support the hypothesis that protons inhibit GABA(A) receptor function by direct or allosteric interaction with the GABA-binding site.

  • 292.
    Wang, Xiaoqing
    et al.
    Outpatient Service Office, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
    Jin, Zhankui
    Department of Orthopaedics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
    Chen, Ming
    Department of Orthopaedics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
    Duan, Dapeng
    Department of Orthopaedics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Guo, Xiong
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
    Chang, Yanhai
    Department of Orthopaedics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
    Inhibiting the aberrant activation of Wnt/β-catenin signaling by selenium supplementation ameliorates deoxynivalenol-induced toxicity and catabolism in chondrocytes2019In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is an endemic degenerative osteoarticular disorder associated with physical disability and a heavy economic burden. Contamination by mycotoxin deoxynivalenol (DON) and selenium deficiency have been proposed to be key etiological factors for KBD, and can work together to aggravate the progression of KBD. Nevertheless, the mechanism of DON in KBD remains elusive. In the present study, exposure to DON dose-dependently suppressed cell viability and expression of pro-proliferation marker PCNA in human chondrocytes, whereas it enhanced lactate dehydrogenase release, cell apoptosis, and caspase-3/9 activity. In addition, DON incubation shifted metabolism homeostasis towards catabolism by suppressing the transcription of collagen II and aggrecan, and the production of sulphated glycosaminoglycans and TIMP-1, while increasing matrix metalloproteinase levels (MMP-1 and MMP-13). Mechanistically, DON exposure induced the activation of Wnt/β-catenin signaling. Intriguingly, blocking this pathway reversed the adverse effects of DON on cytotoxic damage and metabolism disruption to catabolism. Notably, supplementation with selenium reduced DON-induced activation of the Wnt/β-catenin pathway. Moreover, selenium addition abrogated cytotoxic injury and excessive pro-catabolic gene expression in chondrocytes upon DON conditions. These findings confirm that DON may facilitate the development of KBD by inducing cell injury, inhibiting matrix synthesis, and increasing cellular catabolism by activating the Wnt/β-catenin signaling, which were partially reversed by selenium supplementation. Thus, the current study may presents a new viewpoint for how selenium supplementation ameliorates the development of KBD by inhibiting DON-induced cytotoxic injury and metabolism imbalance in chondrocytes.

  • 293. Watt, Danielle L
    et al.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Burgers, Peter M
    Kunkel, Thomas A
    Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases2011In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, no 8, p. 897-902Article in journal (Refereed)
    Abstract [en]

    The major replicative DNA polymerases of S. cerevisiae (Pols α, δ, and ɛ) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols α, δ, and ɛ copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols δ and ɛ were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol ɛ, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine.

  • 294.
    Werneke, Ursula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Sciences, Sunderby Research Unit.
    Ott, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Response to "The impact of modern treatment principles may have eliminated lithium-induced renal failure" Aiff et al. 20142014In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 28, no 12, p. 1189-1190Article in journal (Refereed)
  • 295. Westerlund, Jessica
    et al.
    Graff, Pål
    Bryngelsson, Ing-Liss
    Westberg, Håkan
    Eriksson, Kåre
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Löfstedt, Håkan
    Occupational exposure to trichloramine and trihalomethanes in Swedish indoor swimming pools: evaluation of personal and stationary monitoring2015In: Annals of Occupational Hygiene, ISSN 0003-4878, E-ISSN 1475-3162, Vol. 59, no 8, p. 1074-1084Article in journal (Refereed)
    Abstract [en]

    Introduction: Chlorination is a method commonly used to keep indoor swimming pool water free from pathogens. However, chlorination of swimming pools produces several potentially hazardous by-products as the chlorine reacts with nitrogen containing organic matter. Up till now, exposure assessments in indoor swimming pools have relied on stationary measurements at the poolside, used as a proxy for personal exposure. However, measurements at fixed locations are known to differ from personal exposure. Methods: Eight public swimming pool facilities in four Swedish cities were included in this survey. Personal and stationary sampling was performed during day or evening shift. Samplers were placed at different fixed positions around the pool facilities, at similar to 1.5 m above the floor level and 0-1 m from the poolside. In total, 52 personal and 110 stationary samples of trichloramine and 51 personal and 109 stationary samples of trihalomethanes, were collected. Results: The average concentration of trichloramine for personal sampling was 71 µg m-3, ranging from 1 to 240 µg m-3 and for stationary samples 179 µg m-3, ranging from 1 to 640 µg m-3. The air concentrations of chloroform were well below the occupational exposure limit (OEL). For the linear regression analysis and prediction of personal exposure to trichloramine from stationary sampling, only data from personal that spent > 50% of their workday in the pool area were included. The linear regression analysis showed a correlation coefficient (r2) of 0.693 and a significant regression coefficient β of 0.621; (95% CI = 0.329-0.912, P = 0.001). Conclusion: The trichloramine exposure levels determined in this study were well below the recommended air concentration level of 500 µg m-3; a WHO reference value based on stationary sampling. Our regression data suggest a relation between personal exposure and area sampling of 1:2, implying an OEL of 250 µg m-3 based on personal sampling.

  • 296. Wigenstam, Elisabeth
    et al.
    Elfsmark, Linda
    Ågren, Lina
    Akfur, Christine
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Jonasson, Sofia
    Anti-inflammatory and anti-fibrotic treatment in a rodent model of acute lung injury induced by sulfur dioxide2018In: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 56, no 12, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Context: Inhalation of sulfur dioxide (SO2) affects the lungs and exposure to high concentrations can be lethal. The early pulmonary response after inhaled SO2 involves tissue injury, acute neutrophilic lung inflammation and airway hyperresponsiveness (AHR). In rats, long-term pulmonary fibrosis is evident 14 days post-exposure as indicated by analysis of collagen deposition in lung tissue. Early treatment with a single dose of dexamethasone (DEX,10 mg/kg) significantly attenuates the acute inflammatory response in airways. However, this single DEX-treatment is not sufficient for complete protection against SO2-induced injuries.

    Methods: Female Sprague–Dawley rats exposed to SO2 (2200 ppm, nose-only exposure, 10 min) were given treatments (1, 5 and 23 h after SO2-exposure) with the anti-fibrotic and anti-inflammatory substance Pirfenidone (PFD, 200 mg/kg) or DEX (10 mg/kg) to evaluate whether the inflammatory response, AHR and lung fibrosis could be counteracted.

    Results: Both treatment approaches significantly reduced the total leukocyte response in bronchoalveolar lavage fluid and suppressed pulmonary edema. In contrast to DEX-treatment, PFD-treatment reduced the methacholine-induced AHR to almost control levels and partially suppressed the acute mucosal damage whereas multiple DEX-treatment was the only treatment that reduced collagen formation in lung tissue.

    Conclusions: To enable an accurate extrapolation of animal derived data to humans, a detailed understanding of the underlying mechanisms of the injury, and potential treatment options, is needed. The findings of the present study suggest that treatments with the capability to reduce both AHR, the inflammatory response, and fibrosis are needed to achieve a comprehensive mitigation of the acute lung injury caused by SO2.

  • 297.
    Wigenstam, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Jonasson, Sofia
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Koch, Bo
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation2012In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 301, no 1-3, p. 66-71Article in journal (Refereed)
    Abstract [en]

    Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. Methods: C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1,2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Results: Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Conclusion: Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 298. Wilson, Alan A
    et al.
    Hicks, Justin W
    Sadovski, Oleg
    Parkes, Jun
    Tong, Junchao
    Houle, Sylvain
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Vasdev, Neil
    Radiosynthesis and evaluation of [C-11-Carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 1, p. 201-209Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) plays a key role in regulating the tone of the endocannabinoid system. Radiotracers are required to image and quantify FAAH activity in vivo. We have synthesized a series of potent FAAH inhibitors encompassing two classes of N-alkyl-O-arylcarbamates and radiolabeled eight of them with carbon-11. The [C-11-carbonyl]-radiotracers were evaluated in vitro and ex vivo in rats as potential FAAH imaging agents for positron emission tomography (PET). Both sets of [C-11] O-arylcarbamates showed good to excellent brain penetration and an appropriate regional distribution. Pretreatments with a FAAH inhibitor demonstrated that 80-95% of brain uptake of radioactivity constituted binding of the radiotracers to FAAH. Brain extraction measurements showed that binding to FAAH was irreversible and kinetically different for the two classes of carbamates. These promising results are discussed in terms of the requirements of a suitable radiotracer for the in vivo imaging of FAAH using PET.

  • 299. Winham, Stacey
    et al.
    Cuellar-Barboza, Alfredo
    Batzler, Anthony
    Adolfsson, Rolf
    Umeå University.
    Alda, Martin
    Andreassen, Ole
    Di Florio, Arianna
    Forstner, Andreas J.
    Kelsoe, John
    Landen, Mikael
    Vincent, John
    McElroy, Susan
    Frye, Mark
    Biernacka, Joanna
    Genetic variants as modifiers of the association of body mass index with bipolar disorder2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S838-S839Article in journal (Other academic)
  • 300.
    Wu, Xiaofang
    et al.
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    Han, Jing
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    Yi, Jianhua
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    Wang, Zuyong
    Biomat lab, Department of Mechanical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Li, Danyang
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    Yu, Fangfang
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    Guo, Xiong
    College of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, PR China.
    The effects of chondroitin and/or glucosamine on patients with Kashin-Beck disease2016In: Science Insights Medicine, ISSN 2378-8097, Vol. 2016, article id e00019Article, review/survey (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD), an endemic disease, is a special type of osteoarthritis (OA). Nowadays, due to prevention and treatment methods including selenium supplements, changing grains and water source as well as health education, the morbidity of KBD is reduced significantly as compared to that in the 1950s. However, many elderly adult KBD patients are still suffering from the degenerative changes of cartilage, pain, stiffness and deformation of joints, which are quite similar or even more serious than OA. Chondroitin sulfate and glucosamine have been widely used as symptomatic slow-acting drugs for the treatment of OA. Although their therapeutic effects, biochemical data, pharmacokinetics, preclinical studies, safety and economic evaluation have been well investigated in OA, they are not clearly studied in KBD. In this review, we will evaluate the clinical evidence (randomized controlled trials and non-randomized controlled trials), safeties and cost-effectiveness of chondroitin sulfate and glucosamine for the treatment of KBD. Moreover, the therapeutic mechanisms of chondroitin sulfate and glucosamine are also discussed in details.

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