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  • 301. Andersen, Thomas L.
    et al.
    Friis, Stig D.
    Audrain, Helene
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Skrydstrup, Troels
    Efficient C-11-Carbonylation of Isolated Aryl Palladium Complexes for PET: Application to Challenging Radiopharmaceutical Synthesis2015Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 4, s. 1548-1555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with (CO)-C-11 to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first C-11-carbonyl labeling of an approved PET tracer, [C-11]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [C-11]olaparib and [C-11]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other C-11-labeling strategies.

  • 302.
    Andersson, Anita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Analytical and pharmacokinetic aspects of the antineoplastic drug cisplatin and its monohydrated complex 1995Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 303.
    Andersson, Ann-Catrin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Studies on Human Endogenous Retroviruses (HERVs) with Special Focus on ERV32002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity.

    Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome.

    ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.

    Delarbeten
    1. Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
    Öppna denna publikation i ny flik eller fönster >>Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
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    1996 (Engelska)Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 106, nr 1, s. 125-128Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. Long terminal repeat-envelope (env) gene spliced mRNAs of 9 and 3.5 kb are widely expressed in human tissues and cells, but gag-pol mRNAs have not been found. Furthermore, the env gp70 gene contains an open reading frame throughout its length. The highest expression of ERV3 mRNA detected so far is in placenta and the lowest in choriocarcinoma cell lines. We have previously shown that the human monoblastic cell line U-937 and some normal and neoplastic tissues also express high levels of ERV3 env message by Northern blot analysis; however, this method does not distinguish between mRNA expression in different cell types in tissues. In this report, we have studied the ERV3 mRNA expression in specific cell types of human skin by in situ hybridization. We found high levels expression of ERV3 env mRNA in human sebaceous glands in normal skin and dermoid cysts of the ovary. In all glands, the expression is maximal in the periphery of the lobule and ceases towards the center in the region of characteristic holocrine secretion. Since it is known that the regulation of sebaceous glands is primarily via steroid hormones, particularly androgens, it is possible that expression of ERV3 is hormone dependent.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89897 (URN)10.1111/1523-1747.ep12329612 (DOI)8592062 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
    Öppna denna publikation i ny flik eller fönster >>Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
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    1996 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 67, nr 3, s. 451-456Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. LTR-env-gene-spliced mRNA of 9 and 3.5 Kb is widely expressed in human tissues and cells, but gag-pol mRNA has not been found. Further, the env gp70 gene contains an open reading frame throughout its length and its expression has recently been detected as a full-length protein. The highest expression of ERV3 detected so far is in placenta and the lowest in cytotrophoblasts and choriocarcinoma cell lines. In this report we have studied ERV3 mRNA and protein expression in the human monoblastic cell line U-937 during differentiation into monocytes/macrophages. Differentiation of U-937 cells was induced by 1,25a-dihydroxyvitamin D3 (vitD3), retinoic acid (RA), gamma interferon (IFN-gamma) and phorbol-myristate-acetate (PMA-TPA). The expression of ERV3 env mRNA was found to be differentiation-associated, with high expression detected in the late stages of monocytic development. Using TPA, the expression of ERV3 env was detected as 9- and 3.5-kb transcripts by Northern blotting, as mRNA by in situ hybridization and as a cytoplasmic 65-kDa protein by immunofluorescence and Western blots. Low levels of basal expression were found, with up-regulation of both message and protein at 24 to 48 hr after addition of TPA. Induction with vitD3, IFN-gamma and RA produced higher levels of mRNA at earlier time points. It is concluded that the U-937 cell line represents an excellent model system for further studies to study the relationship between ERV3 expression and cellular differentiation.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89898 (URN)10.1002/(SICI)1097-0215(19960729)67:3<451::AID-IJC23>3.0.CO;2-9 (DOI)8707424 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
    Öppna denna publikation i ny flik eller fönster >>Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
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    2002 (Engelska)Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 297, nr 2, s. 220-225Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89899 (URN)10.1006/viro.2002.1428 (DOI)12083821 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
    Öppna denna publikation i ny flik eller fönster >>ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-89900 (URN)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    5. ERV3 in relation to cell differentiation in normal and neoplastic monocytes
    Öppna denna publikation i ny flik eller fönster >>ERV3 in relation to cell differentiation in normal and neoplastic monocytes
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    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-89901 (URN)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 304.
    Andersson, Annika K.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of Inducible Nitric Oxide Synthase and Melatonin in Regulation of β-cell Sensitivity to Cytokines2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The mechanisms of β-cell destruction leading to type 1 diabetes are complex and not yet fully understood, but infiltration of the islets of Langerhans by autoreactive immune cells is believed to be important. Activated macrophages and T-cells may then secrete cytokines and free radicals, which could selectively damage the β-cells. Among the cytokines, IL-1β, IFN-γ and TNF-α can induce expression of inducible nitric synthase (iNOS) and cyclooxygenase-2. Subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) formation may impair islet function.

    In the present study, the ability of melatonin (an antioxidative and immunoregulatory hormone) to protect against β-cell damage induced by streptozotocin (STZ; a diabetogenic and free radical generating substance) or IL-1β exposure was examined. In vitro, melatonin counteracted STZ- but not IL-1β-induced islet suppression, indicating that the protective effect of melatonin is related to interference with free radical generation and DNA damage, rather than NO synthesis. In vivo, non-immune mediated diabetes induced by a single dose of STZ was prevented by melatonin.

    Furthermore, the effects of proinflammatory cytokines were examined in islets obtained from mice with a targeted deletion of the iNOS gene (iNOS -/- mice) and wild-type controls. The in vitro data obtained show that exposure to IL-1β or (IL-1β + IFN-γ) induce disturbances in the insulin secretory pathway, which were independent of NO or PGE2 production and cell death. Initially after addition, in particular IL-1β seems to be stimulatory for the insulin secretory machinery of iNOS –/- islets, whereas IL-1β acts inhibitory after a prolonged period. Separate experiments suggest that the stimulatory effect of IL-1β involves an increased gene expression of phospholipase D1a/b. In addition, the formation of new insulin molecules appears to be affected, since IL-1β and (IL-1β + IFN-γ) suppressed mRNA expression of both insulin convertase enzymes and insulin itself.

    Delarbeten
    1. Melatonin protects against streptozotocin, but not Interleukin-1β-induced damage of rodent pancreatic β-cells
    Öppna denna publikation i ny flik eller fönster >>Melatonin protects against streptozotocin, but not Interleukin-1β-induced damage of rodent pancreatic β-cells
    2001 Ingår i: J. Pineal Res., ISSN 0742-3098, Vol. 30, nr 3, s. 157-165Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90711 (URN)
    Tillgänglig från: 2003-09-03 Skapad: 2003-09-03Bibliografiskt granskad
    2. Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
    Öppna denna publikation i ny flik eller fönster >>Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
    2001 Ingår i: Biochem. Biophys. Res. Commun., ISSN 0006-291, Vol. 281, nr 2, s. 396-403Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90712 (URN)
    Tillgänglig från: 2003-09-03 Skapad: 2003-09-03Bibliografiskt granskad
    3. Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthase
    Öppna denna publikation i ny flik eller fönster >>Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthase
    (Engelska)Manuskript (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-90713 (URN)
    Tillgänglig från: 2003-09-03 Skapad: 2003-09-03 Senast uppdaterad: 2018-01-13
    4. Role of phospholipase D, insulin and proinsulin convertase gene expression in altered insulin secretion from β-cells deficient in inducible nitric oxide synthase following IL-1β and IFN-γ exposure
    Öppna denna publikation i ny flik eller fönster >>Role of phospholipase D, insulin and proinsulin convertase gene expression in altered insulin secretion from β-cells deficient in inducible nitric oxide synthase following IL-1β and IFN-γ exposure
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-90714 (URN)
    Tillgänglig från: 2003-09-03 Skapad: 2003-09-03 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 305.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Thorvaldson, Lina
    Carlsson, Carina
    Sandler, Stellan
    Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthaseManuskript (Övrigt vetenskapligt)
  • 306.
    Andersson, Annsofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmaceutical knowledge retrieval through reasoning of ChEMBL RDF2011Självständigt arbete på avancerad nivå (masterexamen), 30 poäng / 45 hpStudentuppsats (Examensarbete)
  • 307.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20072008Samlingsverk (redaktörskap) (Övrig (populärvetenskap, debatt, mm))
    Ladda ner fulltext (pdf)
    fulltext
  • 308.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20082009Samlingsverk (redaktörskap) (Övrig (populärvetenskap, debatt, mm))
    Ladda ner fulltext (pdf)
    fulltext
  • 309. Andersson, Cecilia
    et al.
    Henriksson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Magnusson, Karl-Eric
    Nilsson, Mats
    Mirazimi, Ali
    In situ rolling circle amplification detection of Crimean Congo hemorrhagic fever virus (CCHFV) complementary and viral RNA2012Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 426, nr 2, s. 87-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Crimean Congo hemorrhagic fever virus (CCHFV) is a human pathogen that causes a severe disease with high fatality rate for which there is currently no specific treatment. Knowledge regarding its replication cycle is also highly limited. In this study we developed an in situ technique for studying the different stages during the replication of CCHFV. By integrating reverse transcription, padlock probes, and rolling circle amplification, we were able to detect and differentiate between viral RNA (vRNA) and complementary RNA (cRNA) molecules, and to detect viral protein within the same cell. These data demonstrate that CCHFV nucleocapsid protein (NP) is detectable already at 6 hours post infection in vRNA- and cRNA-positive cells. Confocal microscopy showed that cRNA is enriched and co-localized to a large extent with NP in the perinuclear area, while vRNA has a more random distribution in the cytoplasm with only some co-localize with NP. However, vRNA and cRNA did not appear to co-localize directly. 

  • 310. Andersson, Cecilia
    et al.
    Henriksson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Mirazimi, Ali
    Different localization of CCHFV vRNA compared cRNA during infection as determined by in situ padlock probe detectionManuskript (preprint) (Övrigt vetenskapligt)
  • 311.
    Andersson, Charlotte
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Towards Pharmacological Treatment of Cystic Fibrosis2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    S-nitrosogluthatione is an endogenous substance, present at decreased levels in the lungs of CF patients and was recently found to induce mature CFTR in airway epithelial CF cell lines. We show that S-nitrosoglutathione in physiological concentrations increases the presence of ΔF508 CFTR in the cell membrane and induces cAMP dependent chloride transport in cystic fibrosis airway epithelial cells. The properties of S-nitrosoglutathione include other potential benefits for the CF patient and make this agent an interesting candidate for pharmacological treatment of CF that needs to be further evaluated.

    Genistein was found to increase the chloride efflux in both normal and ΔF508 cells without stimulation of cAMP elevating agents and without prior treatment with phenylbutyrate. Genistein, in concentrations close to those that can be detected in plasma after a high soy diet, could induce chloride efflux in cells with the ΔF508 CFTR mutation and its possible use in the treatment of CF should therefore be further investigated.

    Studies on nasal epithelial cells from CF patients showed cAMP dependent chloride efflux in some of the patients with severe genotypes. This may complicate in vitro evaluation of clinical treatment of these patients. The presence of cAMP dependent chloride transport did not necessarily lead to a milder phenotype. Other factors than CFTR may influence the clinical development of the disease.

    Cystic fibrosis (CF) is the most common monogenetic disease among Caucasians. A defective cAMP regulated chloride channel (cystic fibrosis transmembrane conductance regulator, CFTR) in epithelial cells leads to viscous mucus, bacterial infections, inflammation and tissue damage in the lungs that cause death in 95% of the cystic fibrosis patients. There is no cure for the disease although existing treatment has dramatically prolonged the life expectancy. The aim of this thesis was to study pharmacological agents for their ability to restore the cellular deficiency in CF airway epithelial cells. X-ray microanalysis, MQAE fluorescence and immunocytochemistry were used to evaluate the effects.

    Delarbeten
    1. Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX
    Öppna denna publikation i ny flik eller fönster >>Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX
    2000 Ingår i: Eur Respir J., Vol. 15, nr 5, s. 937-41Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89966 (URN)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11Bibliografiskt granskad
    2. Activation of CFTR by genistein in human airway epithelial cell lines
    Öppna denna publikation i ny flik eller fönster >>Activation of CFTR by genistein in human airway epithelial cell lines
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-89967 (URN)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    3. S-Nitrosoglutathione induces functional ?F508-CFTR in airway epithelial cells
    Öppna denna publikation i ny flik eller fönster >>S-Nitrosoglutathione induces functional ?F508-CFTR in airway epithelial cells
    2002 Ingår i: Biochem Biophys Res Commun., Vol. 297, s. 552-557Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89968 (URN)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11Bibliografiskt granskad
    4. Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence
    Öppna denna publikation i ny flik eller fönster >>Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence
    2002 (Engelska)Ingår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 59, nr 6, s. 531-355Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The importance of chloride channels for the cell is demonstrated by a number of serious human diseases that are due to mutations in chloride channels. The most well-known of these diseases is cystic fibrosis. Investigations into the mechanisms of the disease and possible treatments require the study of chloride fluxes at the level of individual cells. The present study compares two methods for studies of chloride transport: X-ray microanalysis and MQAE fluorescence with image analysis. As an experimental system, the cAMP-activated chloride channel in cultured respiratory epithelial cells was chosen. Both methods showed that stimulation with the cAMP-elevating agents forskolin and IBMX decreased the chloride content of the cells by about 20-27%. Inducing a driving force for chloride by replacing extracellular chloride by nitrate resulted in a chloride efflux that was significantly increased in the presence of forskolin and IBMX. This study shows that X-ray microanalysis and MQAE fluorescence are adequate and comparable methods for measuring cAMP-dependent chloride transport in individual cells.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89969 (URN)10.1002/jemt.10234 (DOI)12467030 (PubMedID)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis
    Öppna denna publikation i ny flik eller fönster >>Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis
    2001 Ingår i: J Microsc., Vol. 203, nr 3, s. 277-84Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89970 (URN)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11Bibliografiskt granskad
    6. CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes
    Öppna denna publikation i ny flik eller fönster >>CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes
    2002 Ingår i: Clin Sci., Vol. 103, s. 417-424Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89971 (URN)
    Tillgänglig från: 2002-10-11 Skapad: 2002-10-11Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 312.
    Andersson, D. I., Björkman, J. and Hughes, D.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Fitness and virulence of antibiotic resistant bacteria.2001Ingår i: Antibiotic Development and Resistance., s. 155-162Artikel, recension (Övrigt vetenskapligt)
  • 313.
    Andersson, Dan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Björkman, Johanna
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Antibiotikaresistens: är den reversibel?1998Ingår i: Smittskydd: Smittskyddsinstitutets tidskrift, ISSN 1401-0690, Vol. 4, nr 1, s. 3-5Artikel, recension (Övrigt vetenskapligt)
  • 314.
    Andersson, Dan I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Improving predictions of the risk of resistance development against new and old antibiotics2015Ingår i: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 21, nr 10, s. 894-898Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The methods used today by academic researchers and the pharmaceutical industry to assess the risk of emergence of resistance, for example during development of new antibiotics or when assessing an old antibiotic, are sub-optimal. Even though easy to perform, the presently used serial passage procedures, minimal prevention concentration measurements and determination of mutation rates in vitro are generally providing inadequate knowledge for risk assessment and making decisions to continue/discontinue drug development. These methods need to be complemented and replaced with more relevant methods such as determination of whether resistance genes already pre-exist in various metagenomes, and the likelihood that these genes can transfer into the relevant pathogens and be stably maintained. Furthermore, to determine the risk of emergence of mutationally conferred resistance the fitness effect of the resistance mechanism is key, as this parameter will determine the ability of the resistant mutants to be maintained and enriched in the host after they have emerged. This information combined with knowledge of bacterial population sizes and growth and killing dynamics at relevant infection sites should allow for better forecasting of the risk of resistance emerging in clinical settings.

  • 315.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Antibiotic resistance and its cost: is it possible to reverse resistance?2010Ingår i: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 8, nr 4, s. 260-271Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

  • 316.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Gene amplification and adaptive evolution in bacteria2009Ingår i: Annual Review of Genetics, ISSN 0066-4197, E-ISSN 1545-2948, Vol. 43, s. 167-195Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Gene duplication-amplification (GDA) processes are highly relevant biologically because they generate extensive and reversible genetic variation on which adaptive evolution can act. Whenever cellular growth is restricted, escape from these growth restrictions often occurs by GDA events that resolve the selective problem. In addition, GDA may facilitate subsequent genetic change by allowing a population to grow and increase in number, thereby increasing the probability for subsequent adaptive mutations to occur in the amplified genes or in unrelated genes. Mathematical modeling of the effect of GDA on the rate of adaptive evolution shows that GDA will facilitate adaptation, especially when the supply of mutations in the population is rate-limiting. GDA can form via several mechanisms, both RecA-dependent and RecA-independent, including rolling-circle amplification and nonequal crossing over between sister chromatids. Due to the high intrinsic instability and fitness costs associated with GDAs, they are generally transient in nature, and consequently their evolutionary and medical importance is often underestimated.

  • 317.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Microbiological effects of sublethal levels of antibiotics2014Ingår i: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 12, nr 7, s. 465-478Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

  • 318.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Persistence of antibiotic resistance in bacterial populations2011Ingår i: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 35, nr 5, s. 901-911Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Unfortunately for mankind, it is very likely that the antibiotic resistance problem we have generated during the last 60 years due to the extensive use and misuse of antibiotics is here to stay for the foreseeable future. This view is based on theoretical arguments, mathematical modeling, experiments and clinical interventions, suggesting that even if we could reduce antibiotic use, resistant clones would remain persistent and only slowly (if at all) be outcompeted by their susceptible relatives. In this review, we discuss the multitude of mechanisms and processes that are involved in causing the persistence of chromosomal and plasmid-borne resistance determinants and how we might use them to our advantage to increase the likelihood of reversing the problem. Of particular interest is the recent demonstration that a very low antibiotic concentration can be enriching for resistant bacteria and the implication that antibiotic release into the environment could contribute to the selection for resistance.

  • 319.
    Andersson, Dan I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Kubicek-Sutherland, Jessica Z.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mechanisms and consequences of bacterial resistance to antimicrobial peptides2016Ingår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 26, s. 43-57Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.

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  • 320.
    Andersson, D.I
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Björkman, Johanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för molekylärbiologi.
    Antibiotikaresistens här för att stanna?1998Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 95, nr 37, s. 3940-3944Artikel, forskningsöversikt (Övrigt vetenskapligt)
  • 321.
    Andersson Dunstan, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Isolation and structure elucidation of pharmacologically active compounds from Alphitonia zizyphoides (Spreng.) A. Gray, with emphasis on inflammation 1995Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 322.
    Andersson Dunstan, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Liu, Boling
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Welch, Christopher J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Alphitol, a phenolic substance from Alphitonia zizyphoides which inhibits prostaglandin biosynthesis in vitro1998Ingår i: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 48, nr 3, s. 495-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The new phenolic compound, 3,5-dihydroxy-4-methoxy phenethyl alcohol, named alphitol, and betulinic acid were isolated from the bark of Alphitonia zizyphoides. The chemical structure of alphitol was determined by mass spectrometry in combination with one and two dimensional NMR, including HMBC. Both compounds inhibited prostaglandin biosynthesis in vitro, alphitol with an IC50 value of 0.66 mM, which is of the same magnitude as acetyl salicylic acid.

  • 323.
    Andersson Dunstan, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Noreen, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Serrano, Gudelia
    Cox, Paul A
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Evaluation of some Samoan and Peruvian medicinal plants by prostaglandin biosynthesis and rat ear oedema assays1997Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 57, nr 1, s. 35-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In our ongoing program to find new anti-inflammatory compounds, 58 extracts from 46 different medicinal plant species, used in treatment of inflammatory disorders - 38 plants from the traditional medicine of Western Samoa and eight originating from the indigenous medicine of the Shipibo-Conibo tribe of Peruvian Amazonia - were evaluated. The ability of all extracts to inhibit cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro was examined. Of the plant species tested 14 showed moderate to strong inhibition; including 11 Samoan and three Peruvian species. Further, 12 Samoan and all eight Peruvian species were investigated on their inhibitory activity of ethyl phenylpropiolate induced rat ear oedema in vivo Significant activity was shown by 10 of the Samoan and by all eight Peruvian species. An additional evaluation of the most active species was provided through a compilation of existing literature documenting traditional medicinal uses, pharmacological activity and chemical constituents. Several known cyclooxygenase-l inhibitors were reported to which the observed pharmacological activity can be attributed at least partly. The combination of chemical and pharmacological literature data and our experimental data may help to explain the anti-inflammatory use of these species in indigenous medicine.

  • 324.
    Andersson, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Leaching of Pharmaceuticals in Soil Columns amended with Sludge2015Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Occurrence of pharmaceutical residues in surface and ground waters, used as a source for drinking water supply has been studied over the years. Wastewater treatment plants are generally not efficient enough to remove pharmaceuticals from wastewater and sewage sludge. As a result, they are released into the environment mainly via effluent discharges to surface water bodies, the reuse of biosolids in agriculture as soil amendment, and the disposal of biosolids to landfill areas.

    The aim of this study was to investigate the leaching behavior of pharmaceuticals from several therapeutic groups (i.e. atorvastatin, bicalutamide, carbamazepine, furosemide, hydrochlorothiazide, losartan, oxazepam, valsartan, and venlafaxine) using undisturbed soil columns (loamy sand, loam, and clay) and disturbed soil columns (till mixed with peat) amended with sewage sludge at laboratory-scale. The experiment was performed under controlled conditions to gain a better understanding of the leaching behavior of pharmaceuticals in the natural environment. Another objective was to single out the pharmaceuticals with the highest leaching potential (i.e. carbamazepine, hydrochlorothiazide, oxazepam, and valsartan) in order to analyze their effects on the environment based on earlier studies on the subject. Oxazepam, for example, has shown to have effects on fish such as increased feeding rate and activity.

    Leachate analysis show that, in general, pharmaceuticals leach slower in loamy sand compared to loam and clay which might be due to macro pores and funnel flow in the loamy and clayish soil which enhance the leaching rate. The accumulated mass (µg) in the leachate from clay (13) were also higher than in loam (5.7), loamy sand (2.6), and the till and peat (0) soil.  This indicates that the slow leaching of pharmaceuticals in loamy sand, and till and peat might enhance the sorption or degradation of pharmaceuticals compared to clay and loam.

  • 325.
    Andersson, H. S.
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, Norra Vagen 49, S-39234 Kalmar, Sweden..
    Jacobsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Eriksson, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Hedstrom, M.
    Lund Univ, Dept Biotechnol, Box 118, S-22100 Lund, Sweden..
    Seth, H.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Sundberg, P.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Rosengren, K. J.
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Strand, M.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden.;Swedish Univ Agr Sci, Swedish Species Informat Ctr, Backlosavagen 10, S-75651 Uppsala, Sweden..
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    The toxicity of ribbon worms: Alpha-nemertides or tetrodotoxin, or both?2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 326.
    Andersson, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Peptidomimetics derived from the bioactive hexapeptide angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) have been designed and synthesized. These peptidomimetics are aimed at inhibiting the insulin-regulated amino peptidase (IRAP), also known as the AT4 receptor. This membrane-bound zinc-metallopeptidase is currently under investigation regarding its potential as a target for cognitive enhancers. The work presented herein was based on stepwise replacement of the amino acid residues in Ang IV by natural and unnatural amino acids, non-peptidic building blocks, and also on the introduction of conformational constraints. Initially, we focused on the introduction of secondary structure mimetics and backbone mimetics. The C-terminal tripeptide His-Pro-Phe was successfully replaced by a γ-turn mimetic scaffold, 2-(aminomethyl)phenylacetic acid (AMPA), which was coupled via an amide bond to the carboxyl terminus of Val-Tyr-Ile. Substitution of Val-Tyr-Ile, Val-Tyr, Tyr-Ile and Tyr, respectively, by 4-hydroxydiphenylmethane scaffolds comprising a 1,3,5-substituted benzene ring as a central moiety unfortunately rendered peptidomimetics that were less potent than Ang IV. The subsequent approach involved the introduction of conformational constraints into Val-Tyr-Ile-AMPA by replacing Val and Ile by amino acid residues appropriate for disulfide cyclization or ring-closing metathesis. Chemically diverse structures encompassing an N-terminal 13- or 14-membered macrocyclic tripeptide and a C-terminal non-peptidic moiety were developed. Tyr2 and AMPA were modified to acquire further knowledge about the structure-activity relationships and, in addition, to improve the metabolic stability and reduce the polarity. Several of the compounds displayed a high capacity to inhibit IRAP and exhibited Ki values in the low nanomolar range. Hence, the new compounds were more than ten times more potent than the parent peptide Ang IV. Enhanced selectivity over the closely related aminopeptidase N (AP-N) was achieved, as well as improved stability against proteolysis by metallopeptidases present in the assays. However, additional investigations are required to elucidate the bioactive conformation(s) of the relatively flexible N-terminal macrocycles. The compounds presented in this thesis have provided important information on structure-activity relationships regarding the interaction of Ang IV-related pseudopeptides and peptidomimetics with IRAP. The best compounds in the series constitute important starting points for further discovery of Ang IV peptidomimetics suitable as tools in the investigation of IRAP and other potential targets for Ang IV. The literature presents strong support for the hypothesis that drug-like IRAP inhibitors would serve as a new type of future cognitive enhancers with potential use in the treatment of cognitive disorders, e.g. Alzheimer’s disease.

    Delarbeten
    1. Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
    Öppna denna publikation i ny flik eller fönster >>Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
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    2007 (Engelska)Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, nr 7, s. 434-444Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

    Nyckelord
    Adult neural stem cells, Angiotensin IV, Bioactive conformation, Insulin-regulated aminopeptidase, IRAP, Peptide synthesis, Peptidemimetic, Structure-activity relationship, Turn mimetic
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-16622 (URN)10.1002/psc.859 (DOI)000248164400002 ()17559064 (PubMedID)
    Tillgänglig från: 2008-05-29 Skapad: 2008-05-29 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    2. Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
    Öppna denna publikation i ny flik eller fönster >>Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
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    2008 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 14, s. 6924-6935Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

    Nyckelord
    Angiotensin IV, Insulin-regulated aminopeptidase (IRAP), Cystinyl aminopeptidase (CAP), Aminopeptidase N (AP-N), Structure–activity relationship, Peptide synthesis, Peptide mimetic, 4-Hydroxydiphenylmethane, Tyrosine mimetic
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-102954 (URN)10.1016/j.bmc.2008.05.046 (DOI)000257829600031 ()18556208 (PubMedID)
    Tillgänglig från: 2009-05-13 Skapad: 2009-05-13 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    3. Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
    Öppna denna publikation i ny flik eller fönster >>Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
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    2010 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 22, s. 8059-8071Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

    Nyckelord
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, disulfide, NAMFIS
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-122213 (URN)10.1021/jm100793t (DOI)000284287200016 ()21047126 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2018-03-20Bibliografiskt granskad
    4. Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
    Öppna denna publikation i ny flik eller fönster >>Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis
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    2011 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 11, s. 3779-3792Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

    Nyckelord
    angiotensin IV, insulin-regulated aminopeptidase, inhibitor, macrocyclic, ring-closing metathesis
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-122208 (URN)10.1021/jm200036n (DOI)000291082500008 ()21476495 (PubMedID)
    Tillgänglig från: 2010-04-07 Skapad: 2010-04-07 Senast uppdaterad: 2018-05-29Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 327.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Johnsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussels.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Erdélyi, Máté
    Department of Chemistry, University of Gothenburg.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Potent Macrocyclic Inhibitors of Insulin-Regulated Aminopeptidase (IRAP) by Olefin Ring-Closing Metathesis2011Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 11, s. 3779-3792Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrocyclic analogues of angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His4-Pro5-Phe6 by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val1 and Ile3 by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon–carbon bridge was assessed. The ring size generally affects the potency more than the carbon–carbon bond characteristics. Replacing Tyr2 by β3hTyr or Phe is accepted, while N-methylation of Tyr2 is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (Ki = 4.1 nM) and 19 (Ki = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.

  • 328.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Vauquelin, Georges
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr22008Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 14, s. 6924-6935Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.

  • 329.
    Andersson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Demaegdt, Heidi
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Vauquelin, Georges
    Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Erdélyi, Máté
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 22, s. 8059-8071Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.

  • 330.
    Andersson, Helen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Garscha, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of PCB126 and 17 beta-oestradiol on endothelium-derived vasoactive factors in human endothelial cells2011Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 285, nr 1-2, s. 46-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epidemiological and experimental studies suggest an association between elevated serum levels of co-planar PCBs and hypertension, and one study indicate that this effect is dependent on the level of oestrogen. This study investigated the effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 17 beta-oestradiol (E-2) on vasoactive factors in human umbilical vein endothelial cells (HUVEC). The results reveal that PCB126 stimulated the vasoconstriction factors COX-2 and PGF(2 alpha), in HUVEC. An up-regulation of COX-2 expression was demonstrated using qRT-PCR, western blot and immunofluorescence and increased production of PGF(2 alpha), was demonstrated using LC/MS2 and enzyme immunoassay. Also. PCB126 slightly increased ROS production and decreased NO production in HUVEC. The addition of E2 enhanced PCB126-induced transcription of CYP1A1, CYP1B1 and COX-2 in HUVEC whereas an increased transcription of eNOS only occurred following combined treatment with E-2 and PCB126. Immunofluorescence demonstrated that HUVEC expressed AHR and ER beta but lacked ER alpha and the involvement of AHR and ER beta on the effects of PCB126 was examined by the addition of AHR and ER antagonists. The binding of PCB126 to AHR was critical for the effects of PCB126 whereas the role of ER beta was equivocal. In conclusion, these studies suggest that PCB126 induced changes in human endothelial cells that are characteristic for endothelial dysfunction in human hypertension and that PCB126-induced transcription of genes important for vascular function in human endothelial cells can be elevated by increased oestrogen levels. These findings may help understanding the mechanism for the association between PCB126 exposure and hypertension reported in human subjects and experimental animals.

  • 331.
    Andersson, Helena
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för systemteknik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Reglerteknik.
    Medvedev, Alexander
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för systemteknik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Reglerteknik.
    Cubo, Rubén
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för systemteknik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Reglerteknik.
    The impact of deep brain stimulation on a simulated neuron: Inhibition, excitation, and partial recovery2018Ingår i: Proc. 16th European Control Conference, IEEE, 2018, s. 2034-2039Konferensbidrag (Refereegranskat)
  • 332.
    Andersson, Helén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Experimental Studies of Endocrine Disrupting Compounds in Vascular Cells and Tissues2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Epidemiological evidence suggest that exposure to endocrine disrupting compounds (EDCs) is a risk factor for diseases that involves the cardiovascular system but we know little about the mechanisms whereby these compounds can cause injury in the vasculature. The aim of this thesis was to characterize the effects and mechanisms of some EDCs in vascular cells and highly vascularized tissues.

    Elevated exposure to environmental EDCs is associated with an increased risk for cardiovascular diseases. In vitro studies demonstrated that the environmental EDCs, 1-nitropyrene, PCB126 and bisphenol A, caused distinct changes in primary human endothelial cells. 1‑Nitropyrene induced cell stress and DNA damage, PCB126 caused changes that indicate endothelial dysfunction and vasoconstriction, and BPA induced changes that indicate angiogenesis and vasoconstriction. Further studies demonstrated that long-term exposure of rats to BPA induced changes in rat cardiac tissues in vivo similar to those observed in human endothelial cells in vitro. The type of cellular alterations that were demonstrated is known to play to play a role in cardiovascular disease in humans. These findings suggest that environmental EDCs can cause damage to the human endothelium that may contribute to the development of cardiovascular disease.

    The beneficial effects of the pharmaceutical EDC tamoxifen in breast cancer treatment are compromised by an increased risk for bleedings, hyperplasia, and cancer in the endometrium. Ex vivo studies identified the glandular and surface epithelia as potential target sites for tamoxifen adduct formation and tamoxifen-induced cell stress the human endometrium. No signs of tamoxifen-induced changes were detected in the blood vessels. The results suggest that bioactivation of tamoxifen and subsequent cell injury in endometrial epithelial cells may play a role for tamoxifen’s side effects in the endometrium.

    Taken together, this thesis provide evidence that may help understanding how exposure to EDCs can increase the risk for diseases in that involves the cardiovascular system.

    Delarbeten
    1. Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells
    Öppna denna publikation i ny flik eller fönster >>Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells
    Visa övriga...
    2009 (Engelska)Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 262, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.

    Nyckelord
    1-Nitropyrene, ER stress, DNA damage, HUVEC, Endothelium, Diesel exhaust
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-119883 (URN)10.1016/j.tox.2009.05.008 (DOI)000268383900046 ()19460413 (PubMedID)
    Tillgänglig från: 2010-03-02 Skapad: 2010-03-02 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    3. Proangiogenic Effects of Environmentally Relevant Levels of Bisphenol A in Human Primary Endothelial Cells
    Öppna denna publikation i ny flik eller fönster >>Proangiogenic Effects of Environmentally Relevant Levels of Bisphenol A in Human Primary Endothelial Cells
    2012 (Engelska)Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 86, nr 3, s. 465-474Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Bisphenol A (BPA) is widely used in the manufacturing of consumer products such as plastic food containers and food cans. Experimental studies suggest a relationship between exposure to BPA and changes in metabolic processes and reproductive organs. Also, epidemiological studies report an association between elevated exposure to BPA and cardiovascular disease and diabetes. Although alterations in the vascular endothelium are implicated in pathological conditions associated with BPA, little is known about the effects of BPA in the human endothelium. This study aimed to investigate the effects of 0.1 nM-1 μM of BPA on selected biomarkers of endothelial dysfunction, inflammation, and angiogenesis in human umbilical vein endothelial cells (HUVEC). The mRNA expression of biomarkers was assayed using qRT-PCR, and the production of nitric oxide and reactive oxygen species was measured using the H(2)DCFDA and the DAF-FM assays. The effect of BPA on phosphorylated eNOS was examined using Western blot and immunofluorescence, and the endothelial tube formation assay was used to investigate in vitro angiogenesis. BPA (≤1 μM) increased the mRNA expression of the proangiogenic genes VEGFR-2, VEGF-A, eNOS, and Cx43 and increased the production of nitric oxide in HUVEC. Furthermore, BPA increased the expression of phosphorylated eNOS and endothelial tube formation in HUVEC. These studies demonstrate that environmentally relevant levels of BPA have direct proangiogenic effects on human primary endothelial cells in vitro suggesting that the human endothelium may be an important target for BPA.

    Nyckelord
    Bisphenol A, endothelium, HUVEC, angiogenesis, tube formation, nitric oxide
    Nationell ämneskategori
    Arbetsmedicin och miljömedicin
    Forskningsämne
    Toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-160660 (URN)10.1007/s00204-011-0766-2 (DOI)000300575900012 ()22045264 (PubMedID)
    Projekt
    Helén Andersson
    Tillgänglig från: 2011-10-28 Skapad: 2011-10-28 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. Increased expression of genes encoding proangiogenic and vasoconstriction factors in the cardiac tissues of rats following long‑term exposure to bisphenol A
    Öppna denna publikation i ny flik eller fönster >>Increased expression of genes encoding proangiogenic and vasoconstriction factors in the cardiac tissues of rats following long‑term exposure to bisphenol A
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Arbetsmedicin och miljömedicin
    Identifikatorer
    urn:nbn:se:uu:diva-160661 (URN)
    Tillgänglig från: 2011-10-28 Skapad: 2011-10-28 Senast uppdaterad: 2018-01-12
    5. Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands
    Öppna denna publikation i ny flik eller fönster >>Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands
    Visa övriga...
    2010 (Engelska)Ingår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 38, nr 1, s. 200-207Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.

    Nationell ämneskategori
    Farmakologi och toxikologi
    Forskningsämne
    Toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-119884 (URN)10.1124/dmd.109.029488 (DOI)000272758300023 ()19812351 (PubMedID)
    Forskningsfinansiär
    EU, FP7, Sjunde ramprogrammet
    Tillgänglig från: 2010-03-02 Skapad: 2010-03-02 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    fulltext
  • 333.
    Andersson, Helén
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Helmestam, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Zebrowska, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands2010Ingår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 38, nr 1, s. 200-207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.

  • 334.
    Andersson, Helén
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Piras, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Demma, Jemal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells2009Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 262, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.

  • 335.
    Andersson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. University of Auckland, Faculty of Medical and Health Sciences.
    Identifying and adapting a questionnaire to assess patient satisfaction with long-term conditions services2017Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Aim: In order to deliver high quality pharmacy services, it is essential to evaluate patients’ satisfaction with the services. However, no study has yet assessed patient satisfaction with the Long-Term Conditions (LTC) service in New Zealand. Therefore, the aim of this study is twofold. Firstly, to identify questionnaires that are used to assess patient satisfaction with community pharmacy services. Secondly, to adapt a questionnaire that can be used to measure patient satisfaction with the LTC service in New Zealand.

    Methods: A literature review was conducted to identify questionnaires that had been used to measure patient satisfaction with community pharmacy services. The utilised databases were EMBASE, Medline, International Pharmaceutical Abstracts, and PsychInfo. Retrieved articles were evaluated against pre-determined inclusion and exclusion criteria. Upon completion of the review, a questionnaire was selected and modified before being pilot tested on six LTC patients from a community pharmacy in Auckland, New Zealand.

    Results: The database search yielded 13 articles that were eligible for the final review. In these articles, six different questionnaires for measuring patient satisfaction were identified. The questionnaire that was selected for adaptation had eight items removed, four modified, and 13 added from other sources. The final version consisted of 20 items. Overall, the questionnaire proved to be comprehensible and convenient to use during the piloting phase. However, the patients had a tendency to misunderstand two of the negative statements.

    Conclusions: Selecting and utilising an appropriate tool for measuring patient satisfaction could help to enhance the quality of pharmacy services, leading to improved patient care. This study has identified and adapted a questionnaire for measuring patient satisfaction with the LTC service in New Zealand. Based on the findings of the pilot study, alterations must be made to the questionnaire before it is psychometrically analysed in a larger sample. The final goal is then to apply it in a nation-wide survey in New Zealand.

  • 336.
    Andersson, Jan O
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Bacterial DNA in the human genome2003Ingår i: Encyclopedia of the Human Genome, Nature Publishing Group; London; UK , 2003Kapitel i bok, del av antologi (Refereegranskat)
  • 337.
    Andersson, Jan O
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi. Mikrobiologi.
    Lateral gene transfer in eukaryotes.2005Ingår i: Cell Mol Life Sci, ISSN 1420-682X, Vol. 62, nr 11, s. 1182-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lateral gene transfer -- the transfer of genetic material between species -- has been acknowledged as a major mechanism in prokaryotic genome evolution for some time. Recently accumulating data indicate that the process also occurs in the evolution of eukaryotic genomes. However, there are large rate variations between groups of eukaryotes; animals and fungi seem to be largely unaffected, with a few exceptions, while lateral gene transfer frequently occurs in protists with phagotrophic lifestyles, possibly with rates comparable to prokaryotic organisms. Gene transfers often facilitate the acquisition of functions encoded in prokaryotic genomes by eukaryotic organisms, which may enable them to colonize new environments. Transfers between eukaryotes also occur, mainly into larger phagotrophic eukaryotes that ingest eukaryotic cells, but also between plant lineages. These findings have implications for eukaryotic genomic research in general, and studies of the origin and phylogeny of eukaryotes in particular.

  • 338.
    Andersson, Jan O.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Roger, Andrew J.
    Evolution of glutamate dehydrogenase genes: evidence for lateral gene transfer within and between prokaryotes and eukaryotes2003Ingår i: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 3, s. 14-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Lateral gene transfer can introduce genes with novel functions into genomes or replace genes with functionally similar orthologs or paralogs. Here we present a study of the occurrence of the latter gene replacement phenomenon in the four gene families encoding different classes of glutamate dehydrogenase (GDH), to evaluate and compare the patterns and rates of lateral gene transfer (LGT) in prokaryotes and eukaryotes.

    Results

    We extend the taxon sampling of gdh genes with nine new eukaryotic sequences and examine the phylogenetic distribution pattern of the various GDH classes in combination with maximum likelihood phylogenetic analyses. The distribution pattern analyses indicate that LGT has played a significant role in the evolution of the four gdh gene families. Indeed, a number of gene transfer events are identified by phylogenetic analyses, including numerous prokaryotic intra-domain transfers, some prokaryotic inter-domain transfers and several inter-domain transfers between prokaryotes and microbial eukaryotes (protists).

    Conclusion

    LGT has apparently affected eukaryotes and prokaryotes to a similar extent within the gdh gene families. In the absence of indications that the evolution of the gdh gene families is radically different from other families, these results suggest that gene transfer might be an important evolutionary mechanism in microbial eukaryote genome evolution.

  • 339.
    Andersson, Jonas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Complement Activation Triggered by Biomaterial Surfaces: Mechanisms and Regulation2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Today there are a vast number of medical devices in temporary or permanent contact with human tissues. Blood-biomaterial contact is known to trigger the complement system and results in generation of fluid phase anaphylatoxins C3a and C5a, and surface-bound C3b and iC3b. All these products together are able to attract and activate leukocytes and trigger release of inflammatory mediators leading to a systemic inflammation indirectly causing hemostatic problems and even organ failure. The aim of this study was to identify how complement is triggered on a biomaterial surface and to find ways to regulate this activation.

    The finding that complement activation on biomaterials can be divided into initiation and amplification will facilitate regulation of complement activation biomaterial surfaces. This concept is also compatible with the two techniques to regulate complement activation on a surface.

    Delarbeten
    1. Complement activation on a model biomaterial surface: Binding of C3b via the alternative pathway amplification loop to plasma proteins adsorbed to the surface
    Öppna denna publikation i ny flik eller fönster >>Complement activation on a model biomaterial surface: Binding of C3b via the alternative pathway amplification loop to plasma proteins adsorbed to the surface
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-90375 (URN)
    Tillgänglig från: 2003-04-24 Skapad: 2003-04-24 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    2. C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase
    Öppna denna publikation i ny flik eller fönster >>C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase
    Visa övriga...
    2002 Ingår i: Journal of Immunology, ISSN 0022-1767, Vol. 168, nr 11, s. 5786-5791Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90376 (URN)
    Tillgänglig från: 2003-04-24 Skapad: 2003-04-24Bibliografiskt granskad
    3. Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation
    Öppna denna publikation i ny flik eller fönster >>Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation
    Visa övriga...
    2001 Ingår i: Biomaterials, ISSN 0142-9612, Vol. 22, nr 17, s. 2435-2443Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90377 (URN)
    Tillgänglig från: 2003-04-24 Skapad: 2003-04-24Bibliografiskt granskad
    4. Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro
    Öppna denna publikation i ny flik eller fönster >>Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro
    Visa övriga...
    2003 (Engelska)Ingår i: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67, nr 2, s. 458-466Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Contact between blood and a biomaterial surface takes place in many applications and is known to activate the coagulation and complement systems. Heparin surface coatings have been shown to reduce blood activation upon contact with artificial surfaces. To establish the optimal heparin surface concentration, blood was incubated in a tubing loop model at 37 degrees C. The tubing was coated with different surface concentrations of heparin and rotated at three different velocities. We demonstrate that the blood compatibility of a surface with regard to coagulation, complement, and platelet activation can be improved by increasing the heparin surface concentration in the 6-12 pmol antithrombin/cm2 concentration interval. The binding of factor H is not influenced by the increased heparin surface concentration, suggesting that this factor is not the primary regulator of complement on heparin surfaces. In addition, the heparin coating has no effect on the complement activation that occurs on gas surfaces in extracorporeal circuits.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90378 (URN)10.1002/jbm.a.10104 (DOI)14566786 (PubMedID)
    Tillgänglig från: 2003-04-24 Skapad: 2003-04-24 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
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  • 340. Andersson, Julia
    et al.
    Helenius, Clara
    Effekter av neurokirurgi i vaket tillstånd på postoperativ tal- och språkförmåga2015Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    ABSTRACT

    Gliomas are the most common type of brain tumours and are often diffusely localised in areas that give permanent functional symptoms, so called eloquent areas. These areas partly control speech and language. Low-grade glioma (LGG) is the most suitable type of tumour for awake surgery. By performing surgery while the patient is awake, intra-operative testing of language and speech is possible and a more secure tumour resection can be performed. Patients that are to undergo such surgery execute a pre-operative speech and language testing, done by a speech and language pathologist, which is later used as a reference for the intra- and post-operative assessment. In this study the pre- and post-operative results for 20 patients with gliomas, who underwent awake surgery on 23 occasions at the Akademiska hospital in Uppsala from June 2013 until August 2015 were analysed. The aim of this study was to evaluate how the tumour resection affected speech and language. Furthermore, possible correlations between language deficits and tumour localisation were investigated. The results showed considerable variations in whether the patients improved and/or deteriorated. Overall, more patients deteriorated than improved. More pronounced deficits were shown for naming and verbal fluency pre- and post-operatively. A correlation analysis showed that patients with a tumour located in insula had greater difficulties with naming than patients with other tumour locations. This study provides an evaluation of the language outcomes of patients who underwent awake surgery in Uppsala. Additionally, the study resulted in an overview of the development of speech and language pathologists’ assessments since the start of awake surgery in 2013, and specific recommendations for improvement.

     

    Keywords: Low-grade gliomas, awake surgery, pre- and post-operative speech and language testing, speech and language pathology, naming, verbal fluency, insula

    SAMMANFATTNING

    Gliom är den vanligaste typen av hjärntumör och är ofta diffust lokaliserad i områden som ger bestående funktionsnedsättning vid skada, så kallade elokventa områden. Dessa områden kontrollerar bland annat tal och språk. Av dessa är det de lågmaligna/låggradiga gliomen (LGG) som oftast är aktuella för resektion i vaket tillstånd. Genom att utföra operationen när patienten är vaken tillåts intraoperativ testning av tal och språk vilket leder till säkrare resektion. Alla patienter som ska genomgå denna typ av operation utför preoperativ tal- och språkbedömning hos logoped, som senare används som referenspunkt för den intra- och postoperativa bedömningen. I denna studie analyserades pre- och postoperativa resultat för 20 patienter med gliom som opererats vid 23 olika tillfällen på Akademiska sjukhuset i Uppsala sedan verksamheten startade juni 2013. Två frågeställningar skulle besvaras: Hur har tumörresektionen påverkat tal- och språkförmågan hos patienter som genomgått kirurgi i vaket tillstånd? Finns det något samband mellan språkliga symptom och tumörlokalisation? Resultatet visade stora variationer i huruvida patienterna förbättrades och/eller försämrades i sin tal- och språkfunktion efter operation. Generellt noterades dock fler försämringar än förbättringar. Benämning och verbalt ordflöde var de två parametrar där störst svårigheter påvisades både pre- och postoperativt. Korrelationsanalys visade att patienter med tumörer i insula hade större svårigheter med benämning än patienter med övriga tumörlokalisationer. Förutom att beskriva det språkliga utfallet för de patienter som genomgått kirurgi i vaket tillstånd så har denna studie resulterat i en översikt av hur logopedbedömningarna sett ut pre- och postoperativt sedan vakenkirurgin infördes i Uppsala, och även förslag på hur de kan förbättras i framtiden.

     

    Nyckelord: Lågmaligna gliom, vakenkirurgi, pre- och postoperativ tal- och språkbedömning, logopedi, benämning, verbalt ordflöde, insula 

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  • 341.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Bringing time into molecular and cellular biology2013Ingår i: Journal of Analytical Oncology, ISSN 1927-7229, Vol. 2, nr 2, s. 65-68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In conjunction with the defense of a doctoral thesis on the deciphering of complex protein interactions on living cells, six scientists shared their view on time in molecular and cellular biology. This brief review takes the form of a conference report and summarizes the contributions of the speakers and the defense. Opportunities and challenges for time resolved assays in molecular and cellular biology were vividly discussed during two days with a pan-European audience. Awareness of biological timeframes and understanding the temporal aspects were claimed critical for analytical applications in biology.

  • 342.
    Andersson, Ken G.
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR: 2377 affibody molecule labeled with 99mTc using a peptide-based cysteine-containing chelator2016Ingår i: International journal of oncology, ISSN 1791-2423, Vol. 49, nr 6, s. 2285-2293Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide 99mTc should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with 99mTc using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, 99mTc-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that 99mTc-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6±1 and 2.5±0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8±0.4 and 8±3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of 99mTc-labeled ZEGFR:2377 for imaging of EGFR in vivo.

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  • 343.
    Andersson, Ki
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper, Paleontologigruppen.
    Aspects of locomotor evolution in the Carnivora (Mammalia)2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In this thesis, the shape of the distal humerus trochlea is analysed using landmark-based morphometrics and multivariate methods, with the aim of exploring locomotor evolution in carnivorans. Elbow joint morphology is used together with body size and craniodental morphology to characterize past and present carnivorans. Evolutionary implications are studied at the ordinal, familial, and species levels, testing specific hypotheses about scaling, morphological constraints, evolutionary trajectories, and potential for social pack-hunting behaviour. The circumference of the distal humerus trochlea is found to be highly correlated with body mass, and appears to scale similarly throughout the order Carnivora. A general predictive model for carnivoran bodymass is presented (a=0.601; b= 2.552; r2=0.952, SEE=0.136, p<0001, n=92), which removes the need for the investigator to actively choose between the diverging estimates that different predictors and their equations often produce. At the elbow joint, manual manipulation and locomotion appear to be conflicting functions, thus suggesting mutually exclusive lifestyles involving either forelimb grappling or pursuit. At large body sizes, carnivorans are distributed over a strongly dichotomised pattern (grappling or locomotion), a pattern coinciding with the postulated threshold in predator-prey size ratio at 21.5-25 kg. This pattern is compared to that of two carnivoran faunas from the Tertiary. In the Oligocene (33.7-23.8 Myr BP), the overall pattern is remarkably similar to that observed for extant Carnivora. In the Miocene (23.8-11.2 Myr BP) carnivores show a similarly dichotomised pattern as the Oligocene and Recent, although the whole pattern is shifted towards larger body sizes. This difference is suggested to be a reflection of the extraordinary species richness of browsing ungulates in the early Miocene of North America. Such an increase in prey spectrum would create a unique situation, in which large carnivores need not commit to a cursorial habitus in order to fill their nutritional requirements. Finally, the elbow joints and craniodental morphology (14 measurements) of fossil canids were examined with the aim of assessing the potential for pack-hunting in fossil canids. It is clear that small and large members of the Recent Caninae share similar craniodental morphologies. However, this pattern is not present in Borophaginae and Hesperocyoninae. In the latter, large representatives are characterized by being short-faced, with reduced anterior premolars and enlarged posterior premolars, thus approaching a “pantherine-like” craniodental configuration. These traits are interpreted as an adaptation for killing prey with canine bites. It is similarly determined that, unlike recent Caninae, all analyzed species of borophagines and hesperocyonines have retained the ability to supinate their forearms. It is therefore likely that manual manipulation was part of their hunting behaviour, thus removing an essential part of the argument for social pack-hunting in these forms, as the benefits of such a strategy become less obvious.

    Delarbeten
    1. Predicting carnivoran body mass from a weight bearing joint
    Öppna denna publikation i ny flik eller fönster >>Predicting carnivoran body mass from a weight bearing joint
    2004 (Engelska)Ingår i: Journal of Zoology, ISSN 0952-8369, E-ISSN 1469-7998, Vol. 262, nr 2, s. 161-172Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Predictors used to calculate the body mass of extinct carnivorans often scale differently between different taxa, thus yielding body mass estimates that diverge considerably depending on which predictive equation is used. This requires the investigator to choose the ones most suitable, a procedure that is best avoided if possible. The carnivoran elbow joint is here explored with the aim of producing a single general body mass predictor that can be used over a broad range of terrestrial and arboreal carnivorans. The circumference of the distal humerus trochlea is found to be highly correlated with body mass, and trochlea circumference seems to scale similarly throughout the order Carnivora. This scaling is not as theoretically predicted by elastic similarity and is slightly higher than that predicted by geometric similarity, indicating a slight positive allometry for the latter. Some degree of differential scaling between carnivoran families and between animals of large and small size cannot be ruled out, but this result is inconclusive. A predictive model that allows mass estimations for a broad range of carnivorans is presented (a=0.601; b=2.552; r2=0.952, SEE=0.136, P<0001, n=92). Body mass for eight extinct carnivoran species are calculated and these generally conform to earlier mass predictions.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90745 (URN)10.1017/S0952836903004564 (DOI)
    Tillgänglig från: 2003-09-01 Skapad: 2003-09-01 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Elbow-joint morphology as a guide to forearm function and foraging behaviour in mammalian carnivores
    Öppna denna publikation i ny flik eller fönster >>Elbow-joint morphology as a guide to forearm function and foraging behaviour in mammalian carnivores
    2004 (Engelska)Ingår i: Zoological Journal of the Linnean Society, ISSN 0024-4082, E-ISSN 1096-3642, Vol. 142, nr 1, s. 91-104Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Among the hunting strategies employed by members of the order Carnivora (Mammalia), two, stalk and ambush and sustained pursuit, are particularly prevalent among larger species of the order. It has been difficult to identify morphological traits that support this distinction and ecological observations have shown that most carnivorans adopt a continuum of strategies, depending on available habitat and prey. In this paper, the shape of the distal humerus articulation is analysed, with the aim of exploring the use of the forelimb in prey procurement, and as a guide to such behaviour among fossil carnivorans. The results suggest that manual manipulation and locomotion are conflicting functions. Elbow-joint morphology supports a division between grapplers (i.e. ambushers) and nongrapplers (i.e. pursuers). Joints of the former are characterized by being relatively wide and the latter, by being relatively narrow and box-like with pronounced stabilizing features. At intermediate and large body sizes, carnivorans show a pattern suggesting mutually exclusive feeding strategies that involve either grappling with prey or sustained pursuit. The former allows for large body sizes, such as pantherine felids and ursids; the latter includes species of only moderate size, such as hyenids and canids. Elbow-joint morphology is closely linked to phylogeny, but the morphology of the cheetah converges with that of nongrapplers, showing that strong selective forces may override the phylogenetic component. Two taxa of giant mustelids from the Miocene were analysed to test whether this sort of analysis is applicable to carnivorans of the past. The African Late Miocene species Ekorus ekakeran has a joint morphology comparable to that of modern-day nongrapplers. Two joint morphologies were found in the North American Late Oligocene-Early Miocene Megalictis ferox. The first morphology is comparable to that of modern pantherine cats and the second forms  an  intermediate  between  grapplers  and  nongrapplers  that  is  not  present  in  the  modern  carnivoran  fauna.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90746 (URN)10.1111/j.1096-3642.2004.00129.x (DOI)
    Tillgänglig från: 2003-09-01 Skapad: 2003-09-01 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. The evolution of cursorial carnivores in the Tertiary: implications of elbow-joint morphology
    Öppna denna publikation i ny flik eller fönster >>The evolution of cursorial carnivores in the Tertiary: implications of elbow-joint morphology
    2003 Ingår i: Biology letters, Vol. Published online 6 AugustArtikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90747 (URN)
    Tillgänglig från: 2003-09-01 Skapad: 2003-09-01Bibliografiskt granskad
    4. Potential for pack-hunting in Tertiary canids (Canidae, Carnivora)
    Öppna denna publikation i ny flik eller fönster >>Potential for pack-hunting in Tertiary canids (Canidae, Carnivora)
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-90748 (URN)
    Tillgänglig från: 2003-09-01 Skapad: 2003-09-01 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
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    FULLTEXT01
  • 344.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Biological screening of and chemical studies on some Swedish marine organisms 1987Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 345.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Domestic animals as models for biomedical research2016Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, nr 1, s. 1-11Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene.

  • 346.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Uppsala, Sweden;Texas A&M Univ, College Stn, TX 77843 USA.
    Fisher's quantitative genetic model and the molecular genetics of multifactorial traits2018Ingår i: Journal of Animal Breeding and Genetics, ISSN 0931-2668, E-ISSN 1439-0388, Vol. 135, nr 6, s. 391-392Artikel i tidskrift (Övrigt vetenskapligt)
  • 347.
    Andersson, Leif
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Swedish University of Agricultural Sciences.
    Archibald, Alan L.
    Bottema, Cynthia D.
    Brauning, Rudiger
    Burgess, Shane C.
    Burt, Dave W.
    Casas, Eduardo
    Cheng, Hans H.
    Clarke, Laura
    Couldrey, Christine
    Dalrymple, Brian P.
    Elsik, Christine G.
    Foissac, Sylvain
    Giuffra, Elisabetta
    Groenen, Martien A.
    Hayes, Ben J.
    Huang, LuSheng S.
    Khatib, Hassan
    Kijas, James W.
    Kim, Heebal
    Lunney, Joan K.
    McCarthy, Fiona M.
    McEwan, John C.
    Moore, Stephen
    Nanduri, Bindu
    Notredame, Cedric
    Palti, Yniv
    Plastow, Graham S.
    Reecy, James M.
    Rohrer, Gary A.
    Sarropoulou, Elena
    Schmidt, Carl J.
    Silverstein, Jeffrey
    Tellam, Ross L.
    Tixier-Boichard, Michele
    Tosser-Klopp, Gwenola
    Tuggle, Christopher K.
    Vilkki, Johanna
    White, Stephen N.
    Zhao, Shuhong
    Zhou, Huaijun
    Coordinated international action to accelerate genome-to-phenome with FAANG, the Functional Annotation of Animal Genomes project2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the genomes of domesticated animal species.

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  • 348.
    Andersson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. UCL School of Pharmacy.
    Delivery of patient adherence support: The role of pharmacists and doctors.2013Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction:  Patient non-adherence is a well-known issue that causes problems on many levels, and many interventions regarding improving adherence have been evaluated. Pharmacists and doctors are in good positions to influence and support patient adherence, which makes them suitable intervention targets. However, to date, no one has specifically reviewed interventions with a defined role of pharmacists and/or doctors. Aim:  To evaluate the role of pharmacists and doctors in the delivery of patient adherence support.  Materials and Methods:  A systematic review was carried out. An electronic search was performed in MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsycINFO and CINAHL for papers including randomised controlled trials of interventions to improve adherence, where pharmacists and/or doctors had a defined role in terms of delivery. The retrieved papers were screened to decide whether to include or exclude. The results of the included papers were then summarized, discussed and evaluated in line with the objectives. Results:  A total of 103 papers met the inclusion criteria and was included in the review. Only 14 of the interventions (14%) were delivered by doctors, and the rest by different kinds of pharmacists. The overall effectiveness was very good in most studies. Sixty-eight of the 103 papers resulted in enhanced medication adherence. However, 35 interventions failed to show improvement in adherence. Conclusions:  This review shows that pharmacists and doctors have a good potential to influence patients’ adherence. However, it also shows that more research is needed to get control over this growing global issue.  

  • 349.
    Andersson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Diskrepanser i läkemedelslistor efter införandet av ett strukturerat arbetsflöde: En analys vid inläggning på sjukhus2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 350.
    Andersson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Läkemedelspotentialen hos Melanotan II och andra melanokortinreceptoragonister2013Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Melancortin II, eller Melanotan II, är en melanokortinreceptoragonist som säljs på internet mot impotens, för att gå ned i vikt och för att inducera solbränna. Melanotan II är inte ett godkänt läkemedel men flera kliniska studier har undersökt dess effekt samt effekten hos andra melanokortinreceptoragonister, främst Melanotan I och bremelanotid. Syftet var att utröna huruvida melanokortinreceptoragonister har potential som läkemedel. Metoden var främst sökningar på databasen PubMed.  Rapporten visar att både Melanotan I och II ger ökad pigmentering. Melanotan I verkar även minska UV-inducerade DNA-skador. Subkutana implantat med Melanotan I har också visats ge effekt hos patienter med erytropoetisk protofyri, acne vulgaris, urtikaria utlöst av solljus och vitiligo.

    Melanotan II och bremelanotid ger båda erektil effekt hos studiedeltagare. En effekt av bremelanotid på kvinnlig sexuell dysfunktion har också setts. Bremelanotid har gett förhöjt systoliskt blodtryck som biverkan och denna biverkan verkar inte kunna elimineras genom receptorselektivitet. Ett ställningstagande kring huruvida biverkan är rimlig i behandlingen av kvinnlig sexuell dysfunktion, där andra behandlingsalternativ inte finns, behövs.

    Melanotan II har hos råttor minskat födointag, reducerat kroppsvikten, ökat energiåtgången, påverkat fettmetabolismen och insulinkänsligheten. MC4R verkar ha den viktigaste funktionen. Problem finns dock med desensitisering och en selektiv MC4R-agonist gav inte en permanent, långsiktig reducering av kroppsvikt hos människa. På grund av det förefaller melanokortinreceptoragonister inte ha en potential i läkemedelsbehandlingen av fetma.

    Sammanfattningsvis tyder rapporten på en potential hos melanokortinreceptoragonister i behandlingen av kvinnlig sexuell dysfunktion och ett flertal hudsjukdomar.

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