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  • 51.
    Fägerstam, Patrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Higher platelet P-selectin in male patients with inflammatory bowel disease compared to healthy males2006Ingår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, nr 8, s. 1270-1272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: To observe if the total amount of platelet P-selectin (tP-selectin) in patients with inflammatory bowel disease (IBD) was related to disease entity or activity, 5-aminosalicylic acid (5-ASA) medication or gender. Methods: tP-selectin was measured by immunoassay in seventeen IBD patients and twelve healthy controls. Results: Compared to controls, there was no difference of tP-selectin in patients related to disease entity or activity and 5-ASA medication. When the groups were split according to gender the male patient group showed higher levels of tP-selectin compared to male controls (153 ng/mL vs 94 ng/mL, P<0.05). Conclusion: Increased tP-selectin levels may alter the inflammatory response and susceptibility to thromboembolic disease. As previously shown with soluble P-selectin, tP-selectin shows gender dependent differences important to consider in future studies. © 2006 The WJG Press. All rights reserved.

  • 52.
    Fägerstam, Patrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Östberg, Anna Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Eriksson, Andreas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Fransson, Sven Göran
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Ex vivo and in vitro effects of iodinated contrast agents on platelet adhesion and platelet P-selectin2007Ingår i: Svensk och nordisk Röntgenvecka,2007, 2007Konferensbidrag (Övrigt vetenskapligt)
  • 53.
    Geng, Lijung
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Persson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Nilsson, SFE
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Angiotensin converting enzyme (ACE) activity in porcine ocular tissue: Effects of diet and ACE inhibitors.2003Ingår i: Journal of Ocular Pharmacology and Therapeutics, ISSN 1080-7683, E-ISSN 1557-7732, Vol. 19, s. 589-598Artikel i tidskrift (Refereegranskat)
  • 54.
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Platelets: intracellular signalling and cellular interaction1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Activation of platelets is essential to prevent excessive blood loss at the site of vascular injury. These highly reactive cell fragments are also involved in several pathological conditions, in particular arterial thrombosis, which, in the coronary vessels, can lead to reduced blood flow, vessel occlusion and myocardial infarction.

    The present research was focused on the anti-platelet properties, mechanisms of actions, and interactions of GEA 3175 and adenosine. The former a novel nitric oxidecontaining and cyclic GMP-elevating compound, the latter a cyclic AMP-elevating · purine nucleoside. Separately, the two substances significantly reduced the cytosolic , Ca2+ responses, but only marginally suppressed subsequent functional responses in thrombin-stimulated human platelets. However, coadministration of the compounds synergistically inhibited platelet aggregation and abolished dense granule secretion 1 and exposure of P-selectin, and also markedly reduced binding of fibrinogen to the i surface of platelets. The results imply that the stronger inhibition of platelet functions was due to potent blocking of the initial Ca2+ transient and abrogation of mechanisms involved in the influx of extracellular Ca2+. Together, the findings clearly manifest the importance of an interaction between different inhibitory intracellular pathways in order to completely suppress the activity of tbrombin activated platelets.

    Cell- and drug-comparative studies revealed that GEA 3175 provoked aremarkable long-acting inhibition of contractile responses and a concomitant i sustained increase in cyclic GMP levels in airway smooth muscle tissue. The mechanisms of relaxation involved iberiotoxin-sensitive K + channels and okadaic ' acid-sensitive phosphatases. Separately, GEA 3175 and adenosine markedly inhibited the respiratory burst in chemoattractant-activated neutrophil granulocytes. Opposite to the situation in platelets, the two compounds did not interact synergistically and coadministration had only a negligible effect on cytosolic Ca2+ signals in neutrophils. These data clearly demonstrate cell type-specific responses to cyclic GMP- and cyclic AMP-elevating agents.

    This thesis also delineates the regulatory effects of platelets on neutrophil cellular and intracellular responses. Simple mixture of suspensions of human platelets and neutrophils caused prominent changes in the neutrophil in regard to cytoskeletal arrangement, cytosolic Ca2+ responsiveness, and capacity to generate reactive oxygen species. Platelet-derived factor(s) induced a marked suppression of the respiratory burst in activated neutrophils, an effect attributed to peripheral accumulation of ! filamentous actin and enhanced release of endogenous adenosine from the neutrophil. The chemotactic-peptide-induced rise in cytosolic Ca2+ in neutrophils was dramatically amplified in the presence of platelets, and ATP released from the platelets may play a role in this priming phenomenon, However, additional experiments showed that the amplified Ca2+ response was virtually independent of the state of activation of the platelet, required extracellular Ca2+ ions, and was completely insensitive to the NO-donor GEA 3175. Further analysis strongly indicated that platelets affected the cyclic AMP-sensitive phase of the Ca2+ response in neutrophils. In conclusion, multiple mediators and mechanisms participate in the platelet-mediated modulation of neutrophil responses, and greater understanding of the complex mechanisms and consequences of the interactions between these blood cells may provide useful information for the design of pharmacological tools and methods to control the inflammatory reaction.

  • 55.
    Grenegård, Magnus
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The novel nitric oxide-donor GEA 3175 and adenosine inhibit intracellular responses in thrombin-activated platelets1997Ingår i: FEBS special meeting: Cell Signalling Mechanisms, From Membrane to Nucleus,1997, 1997Konferensbidrag (Övrigt vetenskapligt)
  • 56. Guo, X-H
    et al.
    Huang, Q-B
    Chen, B
    Wang, S
    Qiang, L
    Zhu, Y
    Hou, F-F
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Zhao, M
    Advanced glycation end products induce actin rearrangement and subsequent hyperpermeability of endothelial cells2006Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 114, nr 12, s. 874-883Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to determine the effects of advanced glycation end products (AGEs) on endothelial cytoskeleton morphology and permeability, and to detect the underlying signaling mechanisms involved in these responses. Cultured endothelial cells (ECs) were exposed to AGE-modified human serum albumin (AGE-HSA), and EC cytoskeletal changes were evaluated by observing fluorescence of F-actin following ligation with labeled antibodies. Endothelial permeability was detected by measuring the flux of TRITC-albumin across the EC monolayers. To explore the signaling pathways behind AGE-induced EC alteration, ECs were treated with either soluble anti-AGE receptor (RAGE) IgG, or the MAPK inhibitors PD98059 and SB203580 before AGE-HSA administration. To further elucidate possible involvement of the ERK and p38 pathways in AGE-induced EC changes, adenovirus-carried recombinant constitutive dominant-negative forms of upstream ERK and p38 kinases, namely MEK1(A) and MKK6b(A), were pre-infected into ECs 24 h prior to AGE-HSA exposure. AGE-HSA induced actin cytoskeleton rearrangement, as well as EC hyperpermeability, in a dose and time-dependent manner. The effects were attenuated in cells pretreated with anti-RAGE IgG, PD98059 or SB203580, respectively. EC pre-infection with MEK1(A) and MKK6b(A) also alleviated the effect of AGEs. Furthermore, adenovirus-mediated administration of activated forms of either MEK1 or MKK6b alone induced rearrangement of F-actin and hyperpermeability. The results indicate that ERK and p38 MAPK play important roles in the mediation of AGE-induced EC barrier dysfunction associated with morphological changes of the F-actin. Copyright © Apmis 2006.

  • 57.
    Hagert, Britt
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Omvårdnad.
    Wahren, Lis Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Wikblad, K
    Ödkvist, Lars
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Oto-Rhino-Laryngologi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
    Hälsorelaterad livskvalité hos personer opererade för snarkning1999Ingår i: Hälso- och sjukvårdsstämman,1999, Stockholm: Vårdförb. SHSTF , 1999Konferensbidrag (Övrigt vetenskapligt)
  • 58.
    Hagert, Britt
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Omvårdnad.
    Wahren, Lis Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Wikblad, K
    Ödkvist, Lars
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Oto-Rhino-Laryngologi. Östergötlands Läns Landsting, RC - Rekonstruktionscentrum, ÖNH - Öron- Näsa- Halskliniken.
    Patients' and cohabitants' reports on snoring and daytime sleepiness, 1-8 years after surgical treatment of snoring.1999Ingår i: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 61, s. 19-24Artikel i tidskrift (Refereegranskat)
  • 59.
    Hagert, Britt
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Omvårdnad.
    Wikblad, K
    Ödqvist, Lars
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Oto-Rhino-Laryngologi.
    Wahren, Lis Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Side effects after surgical treatment of snoring2000Ingår i: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 62, nr 2, s. 76-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a questionnaire study detailed side effects after snoring surgery were examined in 415 individuals 2-8 years after surgery. Three years later a new questionnaire was answered by those with side effects affecting taste, smell and voice (n = 74). At the first follow-up 255 had side effects of globus, regurgitation, taste, smell and voice. The globus was the most common (40%). In all spheres except the globus, a significant improvement was seen 3 years later. However, pharyngeal dryness and phlegm had a reported frequency of nearly 60%. No significant differences were seen between the uvulopalatopharyngoplasty and laser uvulopalatoplasty methods. Taste disturbances might be due to surgical damage to the nerves or oral dryness. The olfactory impairment present in 7 patients still needs to be explained.

  • 60.
    Handley, Dean A.
    et al.
    Sepracor Inc, Marlborough, MA, USA.
    Senanayake, Chris H
    Sepracor Inc, Marlborough, MA, USA.
    Dutczak, William
    Sepracor Inc, Marlborough, MA, USA.
    Benovic, Jeffrey L
    Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
    Walle, Thomas
    Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA.
    Penn, Raymond B.
    Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA.
    Wilkinson, H. Scott
    Sepracor Inc, Marlborough, MA, USA.
    Tanoury, Gerald J.
    Sepracor Inc, Marlborough, MA, USA.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Fredrik
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Morley, John
    Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy, Guys, King's and St Thomas' School of Medicine, Denmark Hill, London, UK.
    Biological actions of formoterol isomers2002Ingår i: Pulmonary Pharmacology & Therapeutics, ISSN 1094-5539, E-ISSN 1522-9629, Vol. 15, nr 2, s. 135-145Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.

  • 61.
    Hurtig, Ingrid
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Raak, Ragnhild
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Aspegren-Kendall, Sally
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Rehabiliteringsmedicin. Linköpings universitet, Hälsouniversitetet.
    Gerdle, Björn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Rehabiliteringsmedicin. Linköpings universitet, Hälsouniversitetet.
    Wahren, Lis Karin
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups2001Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 17, nr 4, s. 316-322Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To determine perception and pain thresholds in patients with fibromyalgia syndrome and in healthy controls, and to investigate whether patients with fibromyalgia syndrome can be grouped with respect to thermal hyperalgesia and whether these subgroups differ from healthy controls and in clinical appearance. Design: The authors conducted a quasi-experimental clinical study. Subjects: Twenty-nine women patients with fibromyalgia syndrome and 21 healthy pain-free age-matched women participated in the study. Methods: Quantitative sensory testing using a Thermotest instrument was performed on the dorsum of the left hand. Sleep and pain intensity were rated using visual analog scales. Results: Cold and heat pain but not perception thresholds differed significantly between patients with fibromyalgia syndrome and healthy subjects. Based on thermal pain thresholds, two subgroups could be identified in fibromyalgia syndrome using cluster analysis. Conclusion: Patients with fibromyalgia syndrome were subgrouped by quantitative sensory testing (i.e., thermal pain thresholds). Subgroups show clinical differences in pain intensities, number of tender points, and sleep quality. Cold pain threshold was especially linked to these clinical aspects.

  • 62. Hutcheson, I-R
    et al.
    Grifith, T-M
    Pitman, M R
    Towart, R
    Gregersen, M R
    Refsum, H
    Karlsson, J
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Iodinated radiographic contrast media inhibit shear stress- and agonist-evoked release of No by the endothelium.1999Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 128, s. 451-457Artikel i tidskrift (Refereegranskat)
  • 63.
    Jacobsson, Leif
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Yuan, Xi Ming
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Ziedén, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Internmedicin.
    Olsson, Anders G
    IMV Faculty ofHealth Sciences, Linköping.
    Effects of α-tocopherol and astaxanthin on LDL oxidation and atherosclerosis in WHHL rabbits2004Ingår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 173, nr 2, s. 231-237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to evaluate the influence of α-tocopherol and astaxanthin on low-density lipoprotein (LDL) oxidation lag time and atherosclerotic lesion formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one, 3-month-old WHHL rabbits were divided into three experimental groups. One group (n=10) was fed standard rabbit feed alone and served as a control, a second group (n=11) was supplied with the same feed containing 500mg α-tocopherol/kg and a third group (n=10) was given a feed containing 100mg astaxanthin/kg. Plasma lipids, lipoproteins and LDL oxidation lag time were followed for 24 weeks. At the end of the treatment period, the animals were killed and the thoracic aorta was used for evaluation of the degree of atherosclerosis. Colour photographs of the intimal surface of the vessel were taken for determination of the atherosclerotic area. Cross-sections of the thoracic aorta were used for histological examination and for determination of intimal thickening. Specimens of the vessel were used for determination of the tissue cholesterol content. Plasma cholesterol remained at a high level during the time of the experiment and there were no differences between the experimental groups. After 24 weeks, the LDL oxidation lag time was 53.7±1.7min, 109±4min (P<0.001) and 56.4±3.4min (P=0.47) in the control, α-tocopherol and astaxanthin groups, respectively. In the thoracic aorta, the atherosclerotic area was 80.7±5.1%, 67.1±6.7% (P=0.13) and 75.2±5.7% (P=0.49) in the control, α-tocopherol and astaxanthin groups, respectively. The intimal thickening was 45.6±3.2%, 44.0±4.1% (P=0.89) and 40.0±4.5% (P=0.33) in the control, α-tocopherol and astaxanthin groups, respectively. Finally, the cholesterol content was 107±9μmol/g, 95.7±11. 5μmol/g (P=0.31) and 101±5μmol/g (P=0.33) in the control, α-tocopherol and astaxanthin groups, respectively. It can be concluded that α-tocopherol but not astaxanthin prolonged the LDL oxidation lag time. The two antioxidative substances did not prevent atherogenesis in WHHL rabbits in this setting.

  • 64. Jacobsson-Strier, M
    et al.
    Jacobsson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Plasma lipids and atherosclerosis in Watanabe heritable hyperlipidemic rabbits and fat-fed mini-pigs of the Göttingen strain2000Ingår i: Proceedings of the International XII ICLAS and VII FELASA Joint Meeting,1999, London: Laboratory Animals Ltd , 2000, s. 95-Konferensbidrag (Refereegranskat)
  • 65.
    Johansson, Fredrik
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bronchial hyperresponsiveness of ß-adrenoceptor agonists and antagonists in guinea pig airways2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Asthma is one of the most common diseases in the industrialised countries. The underlying mechanisms are complex and still not fully understood although inflammation of the airways plays an important role. There are to day several types of drugs used in the treatment of asthma such as anti-inflammatory drugs, specific antagonists for inflammatory mediators and bronchodilators. Beta-agonists are the main choice for relaxing airway constriction, however unwanted effects of beta-agonists on patients with asthma has been reported. The betaantagonists that are used for treatment of hypertension and various other conditions also is shown to be deleterious in asthmatics. In the present study we have used guinea pig airways to examine the proposed deleterious effects of beta-agonists and antagonists. We have shown that the (S)-enantiomeric forms of salbutamol and formoterol are able to potentiate cholinergic stimuli and we have shown that the potentiation was indomethacin sensitive in airway preparations of sensitised guinea pigs. We also showed and confirmed that the (R)-enantiomeric forms of salbutamol and formoterol were more potent in relaxing airway smooth muscle contracted with different stimuli compared to the (S)-enantiomers. The betaantagonists propranolol and pindolol were shown to be able to contract tracheal preparations if they had been pre-treated with a beta-agonist and the contraction was not simply a blockade of the beta-adrenoceptor induced relaxation. Propranolol contraction was stereo-selective and (S)-propranolol was more effective in inducing contraction than (R)-propranolol. Moreover, atenolol a betacselective antagonist induced significantly smaller contractions compared to general beta-antagonists. This indicates that the beta2-adrenocepor probably is involved in the beta-antagonist induced contraction. The cyclooxygenase inhibitor indomethacin, the 5-lipoxygenase inhibitor MK886 and a thromboxane A2 antagonist as well as capsaicin reduced the beta-antagonist induced contraction. This indicates that several arachidonic acid products as well as neuropeptides may be involved in the beta-antagonistinduced contraction.

    The worsening of asthma by beta-antagonists is well known and the risks associated with beta-agonists are discussed, but the mechanisms behind these effects need further clarification. In this thesis some of the possible mechanism have been discussed, further studies are needed in order to get more safe and effective asthma treatment regime.

    Delarbeten
    1. Effects of albuterol enantiomers on in vitro bronchial reactivity
    Öppna denna publikation i ny flik eller fönster >>Effects of albuterol enantiomers on in vitro bronchial reactivity
    1996 (Engelska)Ingår i: Clinical reviews in allergy and immunology, ISSN 1080-0549, E-ISSN 1559-0267, Vol. 14, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    No abstract available

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84602 (URN)10.1007/BF02772203 (DOI)
    Tillgänglig från: 2012-10-15 Skapad: 2012-10-15 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Biological actions of formoterol isomers
    Öppna denna publikation i ny flik eller fönster >>Biological actions of formoterol isomers
    Visa övriga...
    2002 (Engelska)Ingår i: Pulmonary Pharmacology & Therapeutics, ISSN 1094-5539, E-ISSN 1522-9629, Vol. 15, nr 2, s. 135-145Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.

    Nyckelord
    ß2 adrenoceptor, Asthma, Formoterol, Isomers, Tracheal tissue
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-26775 (URN)10.1006/pupt.2001.0327 (DOI)11379 (Lokalt ID)11379 (Arkivnummer)11379 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways
    Öppna denna publikation i ny flik eller fönster >>An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways
    2004 (Engelska)Ingår i: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 82, nr 6, s. 393-401Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.

    Nyckelord
    beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-23707 (URN)10.1139/y04-039 (DOI)3208 (Lokalt ID)3208 (Arkivnummer)3208 (OAI)
    Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitro
    Öppna denna publikation i ny flik eller fönster >>Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitro
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    In the present study we establish that the ß-AA antagonist propranolol can, besides its ß-AR blocking effect, either amplify or direct induce a contraction in guinea pig airway preparations, in vitro.

    Propranolol significantly enhanced the contractile response to ovalbumin (OA). The enhancement was reduced by capsaicin but insensitive to indomethacin pretreatment. These results suggest that propranolol produce airway hyperreactivity to OA by activating a pathway involving tachykinins and that COX-products are of minor significance.

    We also confirm that propranolol can induce a tracheal smooth muscle contraction directly, although pre-treatment with carbachol/formoterol is a prerequisite. Direct contractile responses were completely diminished by indomethacin and reduced by capsaicin and L-659,877 (a NK2-receptor antagonist) pre-treatment. The present study shows that propranolol also enhances NANC (excitatory non-adrenergic noncholinergic) contractions but this enhancement requires pre-treatment with a 13-agonist. When the pre-treatment was excluded propranolol failed to exert either a direct or an amplifying effect on EFS (electrical field stimulation). These results contrast to the recorded enhancement of the OA-induced response, which did not request any pre-treatment.

    In addition, propranolol induced an elevation of [Ca2+], in ASMC (airway smooth muscle cells), this effect was not dependent on any pre-treatment and inhibited by indomethacin treatment.

    The mechanism behind these adverse effects of propranolol is not known, but our results demonstrate that contractile mediators do not originate from the airway epithelium. Since, epithelium removal did not reduce the contractile response. Furthermore, pertussis toxin (PTX) treatment did not effect the propranolol-induced contraction, indicating that a PTX sensitive G-protein coupling pathway not is involved.

    In conclusion our results show that both indomethacin and capsaicin sensitive pathways are involved in the contractile response to propranolol. The relative significance of these systems differs; the direct contractile effect is strongly dependent on an indomethacin sensitive pathway, while the amplifying effect is sensitive to capsaicin and insensitive to indomethacin pre-treatment.

    Further studies are required to elucidate the clinical relevance of these results.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84603 (URN)
    Tillgänglig från: 2012-10-15 Skapad: 2012-10-15 Senast uppdaterad: 2012-10-15Bibliografiskt granskad
  • 66.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Albinsson, Sebastian
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindström, Eva
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitroManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    In the present study we establish that the ß-AA antagonist propranolol can, besides its ß-AR blocking effect, either amplify or direct induce a contraction in guinea pig airway preparations, in vitro.

    Propranolol significantly enhanced the contractile response to ovalbumin (OA). The enhancement was reduced by capsaicin but insensitive to indomethacin pretreatment. These results suggest that propranolol produce airway hyperreactivity to OA by activating a pathway involving tachykinins and that COX-products are of minor significance.

    We also confirm that propranolol can induce a tracheal smooth muscle contraction directly, although pre-treatment with carbachol/formoterol is a prerequisite. Direct contractile responses were completely diminished by indomethacin and reduced by capsaicin and L-659,877 (a NK2-receptor antagonist) pre-treatment. The present study shows that propranolol also enhances NANC (excitatory non-adrenergic noncholinergic) contractions but this enhancement requires pre-treatment with a 13-agonist. When the pre-treatment was excluded propranolol failed to exert either a direct or an amplifying effect on EFS (electrical field stimulation). These results contrast to the recorded enhancement of the OA-induced response, which did not request any pre-treatment.

    In addition, propranolol induced an elevation of [Ca2+], in ASMC (airway smooth muscle cells), this effect was not dependent on any pre-treatment and inhibited by indomethacin treatment.

    The mechanism behind these adverse effects of propranolol is not known, but our results demonstrate that contractile mediators do not originate from the airway epithelium. Since, epithelium removal did not reduce the contractile response. Furthermore, pertussis toxin (PTX) treatment did not effect the propranolol-induced contraction, indicating that a PTX sensitive G-protein coupling pathway not is involved.

    In conclusion our results show that both indomethacin and capsaicin sensitive pathways are involved in the contractile response to propranolol. The relative significance of these systems differs; the direct contractile effect is strongly dependent on an indomethacin sensitive pathway, while the amplifying effect is sensitive to capsaicin and insensitive to indomethacin pre-treatment.

    Further studies are required to elucidate the clinical relevance of these results.

  • 67.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindström, Eva
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways2004Ingår i: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 82, nr 6, s. 393-401Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.

  • 68.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Tony P. M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Is effect of (S;S)-formoterol due to contamination of (R;R)-formoterol?Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Formoterol is a long acting selective ß2-adrenoceptor (ß2-AR) agonist of the so-called third generation of ß-adrenoceptor agonists. lt also has an onset action comparable to most short acting ß2-AR agonists. Formoterol has two chiral centres making four enantiomers possible. In this study we have examined (R;R)- and (S;S)-formoterol relaxing effect on guinea pig tracheal ring preparations, affinity to human ß2-AR in transfected COS-7 cells and the ability to influence pigment movement in frog melanophores with stable expression of human ß2AR. We also compared single concentration curves versus cumulative concentration curves on guinea pig tracheal preparations. In all three systems the (R;R)-formoterol is the most potent ß2AR agonist compered to (S;S)-formoterol with eudismic ratios ranging from 11 to 75. We also measure and theoretically calculated the effect of (S;S)-formoterol. VVhen the contamination of (R;R)-formoterol was subtracted the (S;S)-formoterol had effect, although approximately 72 times less then (R;R)-formoterol. We conclude that (R;R)-formoterol is the most potent ß2-AR agonist in three different systems and that (S;S)-formoterol posses an ß2-AR effect. We also show that cumulative concentration curves have higher EC50 values compered to single concentration curves and that this might be a consequence of recaptor desensitisation.

  • 69.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rydberg, Irene
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Aberg, Gunnar
    Sepracor Inc, Pharmaceutical Divisian, Marlborough, MA.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of albuterol enantiomers on in vitro bronchial reactivity1996Ingår i: Clinical reviews in allergy and immunology, ISSN 1080-0549, E-ISSN 1559-0267, Vol. 14, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    No abstract available

  • 70.
    Johansson, Mona
    et al.
    Jönköping.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Weak relationship between ionized and total magnesium in serum of patients requiring magnesium status2007Ingår i: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 115, nr 1, s. 13-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Measurement and monitoring of magnesium (Mg) are important to prevent the development of serious and potentially fatal complications in critically ill patients. Although ion-selective electrodes are available and earlier reports suggest that free ionized magnesium (iMg2+) is the most useful test to estimate Mg status, most clinical laboratories still only measure total Mg. To compare the relationship among iMg2+, total Mg, and albumin in serum, samples were collected from 48 consecutive patients admitted to an intensive care unit or a primary health center. The mean serum level of iMg2+ in 44 patients was 0.53 mmol/L, the total Mg was 0.96 mmol/L, and the albumin was 34.93 g/L. The correlation between iMg2+ and total Mg in serum was r=0.585, the correlation between iMg2+ and albumin in serum was r=378, and the correlation between total Mg and albumin in serum was r=0.340. The mean percent iMg2+ in relation to total Mg in serum was calculated to be 55% in the patient samples. The important level of biologically active iMg2+ was not reflected upon analysis of total Mg in 25% of consecutive patients. This report shows that the correlation of iMg2+ and total Mg is weak, not only in critically ill patients but also in patients in whom Mg status is inquired as a whole.

  • 71.
    Karlsson, J
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Brurok, K
    Trondheim.
    Eriksen, M
    Oslo.
    Towart, R
    USA.
    Toft, K
    Oslo.
    Moen, O
    Oslo.
    Engebretsen, B
    Oslo.
    Jynge, P
    Trondheim.
    Refsum, H
    Oslo.
    Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium2001Ingår i: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 42, nr 6, s. 540-547Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury. Material and Methods: Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three ╡mol/kg MnDPDP, 1 ╡mol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 ╡mol/kg/h MnDPDP, 1 ╡mol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed. Results: Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39▒6 and 16▒5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10▒4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites. Conclusion: MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.

  • 72.
    Karlsson, Jan-Olof G
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Brurok, H
    Norwegian University of Science and Technology.
    Towart, R
    Norwegian University of Science and Technology.
    Jynge, Per
    Norwegian University of Science and Technology.
    Letter: The magnetic resonance imaging contrast agent mangafodipir exerts antitumor activity via a previously described superoxide dismutase mimetic activity2006Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, nr 1, s. 598-598Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 73.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Holmgren, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Druid, Henrik
    Stockholm.
    Codeine and morphine blood concentrations increase during blood loss2003Ingår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 48, nr 3, s. 664-667Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During extensive blood loss, a plasma volume refill will take place by transfer of extravascular fluid into the circulation. Drugs present in this fluid may follow and cause a rise or a drop in blood drug concentration, depending on their levels and accessibility in the restoration fluid. This study explored the possible changes of codeine, and its metabolite morphine, in whole blood during a standardized exsanguination in the rat. Three doses containing 5 mg codeine were given orally. In eight rats, blood loss was accomplished by slowly withdrawing 0.8 mL blood at 10 min intervals during 70 min. In control rats, blood was withdrawn only at 0 and 70 min. At 70 min, the final/initial codeine and morphine concentration ratios were 0.70 +/- 0.38 and 0.88 +/- 0.47, respectively, in controls, but increased to 1.28 +/- 0.44 (p=0.014) and 1.41 +/- 0.34 (p=0.021), respectively, in exsanguinated rats. It is concluded that blood loss can affect blood drug concentrations.

  • 74.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Intralysosomal iron chelation protects against oxidative stress-induced cellular damage2006Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, nr 13, s. 3106-3117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxidant-induced cell damage may be initiated by peroxidative injury to lysosomal membranes, catalyzed by intralysosomal low mass iron that appears to comprise a major part of cellular redox-active iron. Resulting relocation of lytic enzymes and low mass iron would result in secondary harm to various cellular constituents. In an effort to further clarify this still controversial issue, we tested the protective effects of two potent iron chelators - the hydrophilic desferrioxamine (dfo) and the lipophilic salicylaldehyde isonicotinoyl hydrazone (sih), using cultured lysosome-rich macrophage-like J774 cells as targets. dfo slowly enters cells via endocytosis, while the lipophilic sih rapidly distributes throughout the cell. Following dfo treatment, long-term survival of cells cannot be investigated because dfo by itself, by remaining inside the lysosomal compartment, induces apoptosis that probably is due to iron starvation, while sih has no lasting toxic effects if the exposure time is limited. Following preincubation with 1 mm dfo for 3 h or 10 μm sih for a few minutes, both agents provided strong protection against an ensuing ∼LD50 oxidant challenge by preventing lysosomal rupture, ensuing loss of mitochondrial membrane potential, and apoptotic/necrotic cell death. It appears that once significant lysosomal rupture has occurred, the cell is irreversibly committed to death. The results lend strength to the concept that lysosomal membranes, normally exposed to redox-active iron in high concentrations, are initial targets of oxidant damage and support the idea that chelators selectively targeted to the lysosomal compartment may have therapeutic utility in diminishing oxidant-mediated cell injury. © 2006 The Authors.

  • 75.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Leake, Alan
    von Zglinicki, Thomas
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Lysosomal redox-active iron is important for oxidative stress-induced DNA damage2004Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, s. 285-288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Data show that specifically chelating lysosomal redox-active iron can prevent most H2O2-induced DNA damage. Lysosomes seem to contain the major pool of redox-active labile iron within the cell. Under oxidative stress conditions, this iron may then relocate to the nucleus and play an important role for DNA damage by taking part in Fenton reactions.

  • 76.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Leake, Alan
    von Zglinicki, Thomas
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage2004Ingår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 378, nr 3, s. 1039-1045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxidative damage to nuclear DNA is known to involve site-specific Fenton-type chemistry catalysed by redox-active iron or copper in the immediate vicinity of DNA. However, the presence of transition metals in the nucleus has not been shown convincingly. Recently, it was proposed that a major part of the cellular pool of loose iron is confined within the acidic vacuolar compartment [Yu, Persson, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1243-1252, Persson, Yu, Tirosh, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1295-1305]. Consequently, rupture of secondary lysosomes, as well as subsequent relocation of labile iron to the nucleus, could be an important intermediary step in the generation of oxidative damage to DNA. To test this concept we employed the potent iron chelator DFO (desferrioxamine) conjugated with starch to form an HMM-DFO (high-molecular-mass DFO complex). The HMM-DFO complex will enter cells only via fluid-phase endocytosis and remain within the acidic vacuolar compartment, thereby chelating redox-active iron exclusively inside the endosomal/lysosomal compartment. Both free DFO and HMM-DFO equally protected lysosomal-membrane integrity against H2O 2-induced oxidative disruption. More importantly, both forms of DFO prevented H2O2-induced strand breaks in nuclear DNA, including telomeres. To exclude the possibility that lysosomal hydrolases, rather than iron, caused the observed DNA damage, limited lysosomal rupture was induced using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride, subsequently, hardly any DNA damage was found. These observations suggest that rapid oxidative damage to cellular DNA is minimal in the absence of redox-active iron and that oxidant-mediated DNA damage, observed in normal cells, is mainly derived from intralysosomal iron translocated to the nucleus after lysosomal rupture.

  • 77.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Terman, Alexei
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Autophagy, ageing and apoptosis: The role of oxidative stress and lysosomal iron2007Ingår i: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 462, nr 2, s. 220-230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As an outcome of normal autophagic degradation of ferruginous materials, such as ferritin and mitochondrial metalloproteins, the lysosomal compartment is rich in labile iron and, therefore, sensitive to the mild oxidative stress that cells naturally experience because of their constant production of hydrogen peroxide. Diffusion of hydrogen peroxide into the lysosomes results in Fenton-type reactions with the formation of hydroxyl radicals and ensuing peroxidation of lysosomal contents with formation of lipofuscin that amasses in long-lived postmitotic cells. Lipofuscin is a non-degradable polymeric substance that forms at a rate that is inversely related to the average lifespan across species and is built up of aldehyde-linked protein residues. The normal accumulation of lipofuscin in lysosomes seems to reduce autophagic capacity of senescent postmitotic cells-probably because lipofuscin-loaded lysosomes continue to receive newly formed lysosomal enzymes, which results in lack of such enzymes for autophagy. The result is an insufficient and declining rate of autophagic turnover of worn-out and damaged cellular components that consequently accumulate in a way that upsets normal metabolism. In the event of a more substantial oxidative stress, enhanced formation of hydroxyl radicals within lysosomes jeopardizes the membrane stability of particularly iron-rich lysosomes, specifically of autophagolysosomes that have recently participated in the degradation of iron-rich materials. For some time, the rupture of a limited number of lysosomes has been recognized as an early upstream event in many cases of apoptosis, particularly oxidative stress-induced apoptosis, while necrosis results from a major lysosomal break. Consequently, the regulation of the lysosomal content of redox-active iron seems to be essential for the survival of cells both in the short- and the long-term. © 2007 Elsevier Inc. All rights reserved.

  • 78.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Terman, Alexei
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Lysosomes and oxidative stress in aging and apoptosis2008Ingår i: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1780, nr 11, s. 1291-1303Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lysosomal compartment consists of numerous acidic vesicles (pH ~ 4-5) that constantly fuse and divide. It receives a large number of hydrolases from the trans-Golgi network, while their substrates arrive from both the cell's outside (heterophagy) and inside (autophagy). Many macromolecules under degradation inside lysosomes contain iron that, when released in labile form, makes lysosomes sensitive to oxidative stress. The magnitude of generated lysosomal destabilization determines if reparative autophagy, apoptosis, or necrosis will follow. Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from autophagosomes, resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders. © 2008 Elsevier B.V. All rights reserved.

  • 79.
    Larsson, Jenny
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Sonesson, Linus
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundqvist-Gustafsson, Helen
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Platelet-mediated inhibition of polymorphonuclear neutrophil apoptosis principally involves membranes structures: role of sialyl-Lewisχ epitopes and CD18Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective and design: To clarify the long-time effects of platelets on polymorphonuclear neutrophils (PMNs) apoptosis, with particular emphasis on the involvement of cell adhesion molecules (CAMs).

    Material: Isolated human platelets and PMNs.

    Treatment: PMNs were treated with antibodies towards adhesion molecules CD18 (2 µg/ml), sialyl-Lewisχ (2 µg/ml) or P-selectin glycoprotein ligand 1 (5 µg/ml) and then incubated in the absence or presence of resting, thrombin-activated or inhibited platelets (PMN:platelet ratio of 1:50), platelet membrane (0.7 mg/ml; equivalent to the 1:50 ratio), or supematant from thrombin-activated platelets.

    Methods: Measurement of DNA fragmentation using flow cytometry, microscopical evaluation of adhesion and cell death. Light transmission analysis for recording platelet aggregation.

    Results: Activated, and to lesser extent, resting platelets prevented spontaneous PMN apoptosis. Comparable effects were detected by using platelet membrane. Platelet-mediated suppression of PMN apoptosis and PMN-platelet adhesion were reversed by pretreatment with antibodies directed towards the adhesive structures sialyl-Lewisχ (p<0.001).

    Conclusions: Our results point to a central role of CAMs in plateletinduced inhibition of PMN apoptosis. Furthermore, the results add new evidences for a close association between the hemostatic and the inflammatory systems.

  • 80.
    Li, Wei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Hellsten, Anna
    Linköpings universitet, Institutionen för biomedicin och kirurgi.
    Jacobsson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Blomqvist, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Internmedicin.
    Olsson, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Internmedicin. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Yuan, Xi Ming
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits2004Ingår i: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 37, nr 5, s. 969-978Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants α-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg α-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and α-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by α-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants. © 2004 Elsevier Ltd. All rights reserved.

  • 81.
    Li, Wei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Hellsten, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Xu, Lihua
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Zhuang, D-M
    Jansson, Katarina
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Yuan, Xi Ming
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Foam cell death induced by 7β-hydroxycholesterol is mediated by labile iron-driven oxidative injury: Mechanisms underlying induction of ferritin in human atheroma2005Ingår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 39, nr 7, s. 864-875Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human atherosclerotic lesions typically contain large amounts of ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between ferritin induction and occurrence of apoptosis in 7β-hydroxycholesterol (7β-OH)-treated monocytic cells and macrophages. We found that 7β-OH enlarges the intracellular labile iron pool, increases formation of reactive oxygen species (ROS), and induces ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since ferritin is a phase II-type protective protein, our findings suggest that ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable iron chelator 10-phenanthroline and the non-membrane-permeable iron chelators apoferritin and desferrioxamine afforded significant protection against the 7β-OH-induced effects. Consequently, endocytosed iron compounds dramatically augmented 7β-OH-induced cytotoxicity. We conclude that oxidized lipid 7β-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular iron. The findings suggest that modulation of iron metabolism in human atheroma may be a potential therapeutic strategy against atherosclerosis. © 2005 Elsevier Inc. All rights reserved.

  • 82.
    Li, Wei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Östblom, Mattias
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik.
    Xu, Lihua
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Hellsten, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi.
    Leanderson, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Yrkes- och miljömedicin. Östergötlands Läns Landsting, Smärt- och yrkesmedicinskt centrum, Yrkes- och miljömedicinskt centrum.
    Liedberg, Bo
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Eaton, John Wallace
    USA .
    Yuan, Xi Ming
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Cytocidal effects of atheromatous plaque components: the death zone revisited.2006Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 20, s. 2281-2290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

       

  • 83.
    Lindström, Eva G.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Regulation of experimentally induced airway obstruction1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Asthma is one of the commonest diseases in industrialized countries. The cause and mechanisms of !he disorder are still not fully unden;tood, al!hough it is known that inflammation in !he airways plays an important role. Inflammatory mediators, e.g. leukotrienes, prostaglandins, histamine and bradykinin, are all possible acton; in !he asthmatic condition. Moreover, disturbance in !he neurogenic system has been discussed: the cholinergic, adrenergic, and nonadrenergic noncholinergic systems may influence the airway tone. Structural changes in !he airways of as!hmatics, e.g. epithelial damage, have also been observed. The consequence of epithelial damage is not fully understood, but it is clear that the epithelial layer can act as a physical and metabolic barrier.

    In the present research, we developed an in vitro model for detenninadon of airway smooth muscle tension and concomitant mediator release in guinea pig airways. This method also allows manipulation of the airway epithelium. We found !he condition of !he airway epithelium to be of great significance for smooth muscle response and mediator release. An intact epithelium acted as a powerful barrier; removal of the epithelium resulted in increased responses to histamine, acetylcholine and potassium ions. An intact epithelial layer was also important for leukotriene and prostaglandin production, whereas in !he absence of epithelium, antigen-induced contractions were almost completely dependent on histamine.

    Sensory nerve activation provoked by electrical field stimulation (EFS), capsaicin (CAP) and antigen-induced mediators was investigated by analyzing !he amount of neurokinin A-like immunoreactivity (NKA-Ll). Multiple agents were shown to regulate this release. EFSinduced outflow of NKA-LI was powerfully decreased by morphine, and !his reduction was not reversed by naloxone. In contrast, the inhibition obtained upon CAP-challenge was reven;ible. These results may imply !hat EFS also activates endugenous inhibitory systems.

    Antigen challenge of epithelial-denuded bronchial tube preparations resulted in contractions and concomitant release of histamine and tachykinins. Exposure to pyrilamine (a histamine H 1 receptor antagonist) and icatibant (a bradykinin B2 receptor antagonist) markedly depressed !he NKA-LI outflow. Furthermore, pyrilamine significantly reduced !he basal outflow of NKA-LI and antigen-induced contractions, while icatibant did not. These results show that, among !he mediators released in response to antigen-challenge, histamine and bradykinin are able to modulate both the outflow of tachykinins and contractile responses.

    The long-acting 132 receptor agonist formoterol was characterized with regard to relaxing properties and effects on tachykinin and histamine release. The RR enantiomer was most potent in relaxing tracheal preparations, followed by racemic and SS-formoterol. Formoterol also reduced the antigen-induced outflow of NKA-LI. RR-formoterol also lowered both CAPand EFS-induced NKA-LI outflow but not histamine release. These results indicate that, in addition to its ability to directly relax smooth muscle, formoterol may decrease the responses of airway tissue to antigen by inhibiting mediator release from sensory neurons, probably through direct interaction with sensory neurones.

    In summary, we have developed a method for determination of epithelial inlluence, mediator release and smooth muscle contraction in guinea pig airways. We have shown that antigen-challenge release inflammatory mediators and activates sensory neurons. Both histamine and bradykinin are involved in the regulation of the tackykinin release. It was also shown that formoterol reduoed NKA-LI outflow.

  • 84. Lundahl, TH
    et al.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Larsson, R
    Lindahl, TL
    Platelet activation before and after hemodialysis measured utilising flow cytometry and aggregometry1997Ingår i: Congress of the international society of thrombosis and haemostasis,1997, 1997Konferensbidrag (Övrigt vetenskapligt)
  • 85. Lundgren, A
    et al.
    Wahren, Lis Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effect of education on evidence-based care and handling of perpheral intravenous lines.1999Ingår i: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 8, s. 577-585Artikel i tidskrift (Refereegranskat)
  • 86.
    Lundström, Ingemar
    et al.
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Natural nanosystems2002Ingår i: Current applied physics, ISSN 1567-1739, E-ISSN 1878-1675, Vol. 2, nr 1, s. 17-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A short review of our work on pigment containing cells as biosensors is given. It is pointed out that they combine several natural nanosystems, namely membrane bound receptors and their biochemical machinery, and the tubulin/actin network inside the cells for transport of submicron-sized pigment particles driven by molecular motors of 10-100 nm size.

  • 87.
    Monstein, H.-J.
    et al.
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Isabelle
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Ellnebo-Svedlund, Katarina
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, S.P.S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs1998Ingår i: Receptors and Channels, ISSN 1060-6823, E-ISSN 1607-856X, Vol. 6, nr 3, s. 165-177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report here the cloning and characterization of a 5'-end alternatively spliced human cholecystokinin-B (CCK-B) receptor mRNA. The 5'-end of this CCK-B receptor transcript (termed CCK-BRtx) consisted of exon Ia, present in the ordinary full-length CCK-B receptor mRNA (CCK-BRwt), and exon Ib, present in a previously described 5'-end alternatively spliced CCK-B receptor mRNA (CCK-BRt). A short open reading frame preceded the AUG translation initiation codon of the CCK-BRtx. Transfection of COS-7 cells with the CCK-BRtx or CCK-BRt cDNAs did not lead to the appearance of peptidergic and non-peptidergic binding sites. Cell free in vitro translation yielded proteins of approximately 44 kDa (CCK-B receptor) and 40 kDa (CCK-BRt receptor) whereas no 40 kDa product was detected from the cloned CCK-BRtx cDNA. Instead, a protein product of approximately 9 kDa was visualized, the size corresponding to the predicted protein encoded by the short open reading frame. The alternatively spliced CCK-B receptor transcripts were concomitantly expressed with the ordinary full-length CCK-B receptor mRNA in the brain, pancreas, and stomach. The possibility that such transcripts are translated in vivo into truncated CCK-B receptors is discussed.

  • 88.
    Mårtensson, Lena G. E.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    New pharmacological aspects of melatonin1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Melatonin is a hormone that takes part in the regulation of biological rhythms. It is produced in the pineal gland and is stimulated by darkness and inhibited by exposure to light. The increased amouot of melatonin during the hours of darkness sends a chronobiological message throughout the body, and translates it into a chemical message that can be read by target cells. This process requires that a receiving protein, a receptor, is present on the cell surface, and that it can recognize melatonin and transfer the signal from outside of the cell to the inside, where it can be transformed into a cellular response. The present investigation was focused on receptor recognition, receptor activation and receptor-mediated signaling.

    The scales of the cuckoo wrasse (Labrus ossifagus L.), a teleost fish, bear melanophores that contain pigment granules that can be transported to the center of the cell (pigment aggregation) or distributed throughout the melanophore (pigment dispersion). Pigment aggregation is governed by sympathetic nerve endings that stimulate an α2-adrenoceptor, and also by circulating hormones, for example melatonin. To answer questions regarding receptor interactions, melatonin was used in the melanophore bioassay.

    The results show that melatonin did not induce pigment aggregation when administrated alone. The hormone did, however, reinforce aggregation induced by noradrenaline, which reveals a melatonin-noradrenaline synergism. Pharmacological studies were performed to elucidate this synergism. Data obtained using α2-adrenoceptor and melatonin receptor ligands, and by investigating intracellular mediators, indicate that, hypothetically, the noradrenaline-melatonin synergism may be due to the existence of an α2-adrenergic receptor with two functional sites: one site for catecholamines, such as noradrenaline, and a second "modulatory" site for melatonin.

    It is known that smooth muscle cells from pregnant human myometrium express adrenoceptors and that labor tends to begin during the dark hours. The effect of melatonin on myometrial contractility was examined in order to investigate if the same synergism appeares in the myometrium as in the melanophores. The contractility of biopsied myometrial samples taken from women undergoing cesarean sections was measured in vitro. The results show that melatonin alone did not increased myometrial contractility, but it did reinforce noradrenaline-induced contraction, i.e. a melatonin-noradrenaline synergism. Consequently, it is possible that the greater production of melatonin at night induces increased myometrial contractility that leads to the beginning of labor.

  • 89.
    Naidu Sjöswärd, Kerstin
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Anestesiologi. Linköpings universitet, Hälsouniversitetet.
    Josefsson, Martin
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Rättsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Rättsmedicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Schmekel, Birgitta
    Linköpings universitet, Institutionen för medicin och vård, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet.
    Metabolism of salbutamol differs between asthmatic patients and healthy volunteers2003Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, nr 1, s. 27-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.

  • 90.
    Nayeri, Fariba
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Holmgren Peterson, Kajsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Perskvist, Nasrin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Forsberg, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    An in vitro model for assessment of the biological activity of hepatocyte growth factor2007Ingår i: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 25, nr 1, s. 33-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocyte growth factor (HGF) is a multifunctional growth factor with potent wound-healing properties that functions in the healing of chronic injuries. However, there may be a loss of HGF activity in certain chronic cases; this might be indicated by the presence of high amounts of HGF in body fluids and by the elevated expression of the HGF receptor in tissue biopsies. In such cases, a reliable means of assessing the activity of endogenous HGF would be valuable in allowing clinicians to decide if treatment with HGF would be useful. In this study, we developed an in vitro wound assay that used a mouse skin epithelial cell line to evaluate the biological activity of HGF. We showed that HGF accelerated the motility of the epithelial cells in a dose-dependent fashion with high sensitivity and specificity. This in vitro assay might be used to determine the activity of both endogenous and recombinant HGF.

  • 91.
    Nayeri, Fariba
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Olsson, Hans
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Hepatocyte growth factor, expression, concentration and biological activity in chronic leg ulcers2005Ingår i: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 37, nr 2, s. 75-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    Hepatocyte growth factor (HGF) is a multifunctional cytokine that is involved in recovery process after organ injuries.

    Objective:

    We studied HGF and the membrane bound receptor, c-met locally in patients who suffered from chronic leg ulcers (≥1 year) caused by venous insufficiency.

    Methods:

    Skin biopsies from the edge of the ulcers were taken from patients (n = 13) and studied by immunohistochemical staining for detection of HGF and c-met. Skin biopsies from healthy volunteers (n = 10) were used as the control material. Ulcer secretion from chronic ulcers (n = 11) was examined for the presence of HGF by ELISA and the concentration of HGF was compared with acute ulcers in healthy controls (n = 10) and in patients operated for a non-invasive breast cancer (n = 12).

    Results:

    We observed that c-met expression in the ulcer area increased significantly in chronic ulcers compared to controls (p = 0.005). Concentration of ulcer-HGF in the patients with chronic ulcer was significantly higher than acute ulcers (p < 0.01). The biological activity of HGF in ulcer secret was assessed in-vitro in transferred, mouse skin epithelial cell monolayer. Enhanced migration and morphologic changes were seen after adding ulcer secret from acute ulcers (>1 ng/mL) that was inhibited by anti-HGF antibodies. No biological activity was observed by adding ulcer secret from chronic ulcers irrespective HGF concentration.

    Conclusion:

    We conclude that in chronic skin ulcers decreased biological activity of endogenous HGF and overexpression of c-met is seen which might explain fibrosis and delayed recovery. Administration of exogenous active HGF might contribute to accelerated healing in these patients.

  • 92.
    Nayeri, Fariba
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Olsson, Hans
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Söderström, Claes
    Department of Infectious Diseases, County Hospital in Kalmar, Sweden.
    Forsberg, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Brudin, Lars
    Department of Clinical Physiology, County Hospital in Kalmar, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Hepatocyte growth factor in chronic leg ulcers – no biological activity – no improvement2005Ingår i: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 39, nr 1, s. 62-64s. 62-64Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    No abstract available.

  • 93.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren Peterson, Kajsa
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    HgCl2-sensitive aquaporins are not involved in melanosome aggregation in Xenopus laevis melanophoresManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Melanophores are cells specialized for transport of pigment-filled organelles called melanosomes. Melanosomes are aggregated in the center of a melanophore or dispersed throughout the cytoplasm by motor proteins moving along the actin and microtubule cytoskeleton. In angelfish (Pterophyllum scalare), aggregation of melanosomes (as compared to dispersion) increases the height of the central part of melanophores by 300%. Our objective was to detennine whether such a height increase also occurs in frog (Xenopus laevis) melanophores. In analogy with theories explaining the leading edge of migrating cells, we investigated the possibility that elevation of the melanophore plasma membrane is due to local swelling caused by influx of water through HgCl2-sensitive aquaporins and subsequent polymerization of actin. Confocal microscopy revealed a 30% increase in height in X. laevis melanophores during melatonin-induced aggregation. This was not due to actin polymerization, because it also occurred when aggregation was induced by the polymerization inhibitor latrunculin B. The nitric oxide (NO) synthase inhibitor L-NAME induced dispersion and lowered the plasma membrane, which suggests that NO is involved in the upward movement. Furthermore, neither dispersion nor aggregation was affected by inhibition of water flux through HgCl2 sensitive aquaporins. Together, these observations imply that melanosomes in X. laevis melanophores are driven upwards during aggregation by a mechanism other than actin polymerization, possibly involving microtubules, intermediate filaments, or a motor protein that may be regulated by NO. Furthermore, influx of water through HgCl2-sensitive aquaporins is probably not necessary for aggregation-induced elevation of the cell membrane, because both aggregation and dispersion can occur in the presence of HgCl2.

  • 94.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Annika M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Loitto, Vesa-Matti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Nitric oxide modulates intracellular translocation of pigment organelles in Xenopus laevis melanophores2000Ingår i: Cell Motility and the Cytoskeleton, ISSN 0886-1544, E-ISSN 1097-0169, Vol. 47, nr 3, s. 209-218Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pigment organelles in Xenopus laevis melanophores are used by the animal to change skin color, and they provide a good model for studying intracellular organelle transport. Movement of organelles and vesicles along the cytoskeleton is essential for many processes, such as axonal transport, endocytosis, and intercompartmental trafficking. Nitric oxide (NO) is a signaling molecule that plays a role in, among other things, relaxation of blood vessels, sperm motility, and polymerization of actin. Our study focused on the effect NO exerts on cytoskeleton-mediated transport, which has previously received little attention. We found that an inhibitor of NO synthesis, N-nitro-L-arginine methyl ester (L-NAME), reduced the melatonin-induced aggregation of the pigment organelles, melanosomes. Preaggregated melanosomes dispersed after treatment with L-NAME but not after exposure to the inactive stereoisomer (D-NAME) or the substrate for NO synthesis (L-arginine). Signal transduction by NO can be mediated through the activation of soluble guanylate cyclase (sGC), which leads to increased production of cGMP and activation of cGMP-dependent kinases (PKG). We found that both the sGC inhibitor 1H-(1,2,4) oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) and the cGMP analogue 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP) reduced melanosome aggregation, whereas the PKG inhibitor KT582 did not. Our results demonstrate that melanosome aggregation depends on synthesis of NO, and NO deprivation causes dispersion. It seems, thus, as if NO and cGMP are essential and can regulate melanosome translocation.

  • 95.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    L-NAME-induced dispersion of melanosomes in melanophores activates PKC, MEK and ERK12001Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 14, nr 6, s. 450-455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanosome movement represents a good model of cytoskeleton-mediated transport of organelles in eukaryotic cells. We recently observed that inhibiting nitric oxide synthase (NOS) with Nω-nitro-l-arginine methyl ester (l-NAME) induced dispersion in melanophores pre-aggregated with melatonin. Activation of cyclic adenosine 3′,5′-monophosphate (cAMP)-dependent protein kinase (PKA) or calcium-dependent protein kinase (PKC) is known to cause dispersion. Also, PKC and NO have been shown to regulate the mitogen/extracellular signal-regulated kinase (MEK)-ERK pathway. Accordingly, our objective was to further characterize the signaling pathway of l-NAME-induced dispersion. We found that the dispersion was decreased by staurosporine and PD98059, which respectively inhibit PKC and MEK, but not by the PKA inhibitor H89. Furthermore, Western blotting revealed that ERK1 kinase was phosphorylated in l-NAME-dispersed melanophores. l-NAME also caused dispersion in latrunculin-B-treated cells, suggesting that this effect is not due to inhibition of the melatonin signaling pathway. Summarizing, we observed that PKC and MEK inhibitors decreased the l-NAME-induced dispersion, which caused phosphorylation of ERK1. Our results also suggest that NO is a negative regulator of phosphorylations that leads to organelle transport.

  • 96.
    Nilsson, Isabelle
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    The cholecystokinin receptor family: molecular cloning and pharmacological characterization2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cholecystokinin (CCK) and gastrin are hormones/neurotransmittors of the gastrointestinal tract and central nervous system. The receptors for gastrin and CCK are members of the G protein-coupled receptor family. The aim of this study was to clone and pharmacologically characterize vertebrate and invertebrate CCK receptors and splice variants. Three 5'-end alternatively spliced human CCK2 receptor mRNAs were cloned: the CCK-BRwt mRNA, that encodes the ordinary full-length CCK2 receptor, CCK-BRt mRNA that contains exon 1b and that encodes a N-terminally truncated receptor protein, and CCK-BRtx mRNA that contains exon 1a (also present in CCKBRwt mRNA) and exon 1b. The CCK-BRtx mRNA contains two open reading frames: a short open reading frame that precedes the open reading frame of the N-terminally truncated receptor. In vitro transcription/translation of the mRNAs yielded proteins of 44 kDa (CCK-BRwt), 40 kDa (CCK-BRt), and 9 kDa (CCK-BRtx). The 9 kDa product corresponded to the predicted size of the short open reading frame of CCK-BRtx. No 40 kDa product was produced by the cloned CCK-BRtx. Pharmacological analysis of CCK2 receptor ligands was performed using the cloned human CCK2 receptor (CCKBRwt) transiently expressed in COS-7 and SK-N-MC cells. The binding of YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450 was analyzed by radioligand competition using [3H]L-365,260 as the labeled ligand. The binding data for four ofthe ligands fitted a one-site model (YF476, YM022, L-740,093, and AG041R), while the data for the three others fitted a two-site model (PD134308, PD136450, and JB93182) using COS-7 cell membranes in radioligand binding experiments. The data for YM022 and YF476 fitted a one-site model while the data for JB93182 and PD134308 fitted a two-site model using SK-N-MC cell membranes in the radioligand binding experiments. In the presence of a GTP-analogue, similar results were obtained. The human CCK2 receptor seems to exist in a low and/or high affmity state that does not reflect the degree ofG protein-coupling. A chicken brain CCK receptor, CCK-CHR, was cloned using a polymerase chain reaction (PCR)-based cloning strategy that included an initial PCR with deoxyinosine-containing primers targeting conserved regions in vertebrate CCK receptors, followed by rapid amplification of cDNA ends (RACE) and full-length PCR amplification. The CCK-CHR full-length PCR amplicon contained a short upstream open reading frame (uORF) followed by a long ORF encoding the 436 amino acid long receptor protein. CCK-CHR shared ≈50% amino acid sequence homology with cloned vertebrate receptors. The pharmacological profile of CCK-CHR resembled that of mammalian CCK2 receptors using agonists, but CCK1 receptors using subtype-specific antagonists. A putative cionin receptor (CioR), a new member of the CCK/gastrin receptor family was cloned from the gastrointestinal tract of the urochordate Ciona intestinalis using RACE PCR followed by full-length PCR amplification. The full-length PCR amplicon contained an uORF followed by a long ORF encoding the 526 amino acid long receptor protein. At the amino acid level, CioR shared 35-40% homology with vertebrate CCK receptors.

    Delarbeten
    1. Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs
    Öppna denna publikation i ny flik eller fönster >>Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs
    1998 (Engelska)Ingår i: Receptors and Channels, ISSN 1060-6823, E-ISSN 1607-856X, Vol. 6, nr 3, s. 165-177Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We report here the cloning and characterization of a 5'-end alternatively spliced human cholecystokinin-B (CCK-B) receptor mRNA. The 5'-end of this CCK-B receptor transcript (termed CCK-BRtx) consisted of exon Ia, present in the ordinary full-length CCK-B receptor mRNA (CCK-BRwt), and exon Ib, present in a previously described 5'-end alternatively spliced CCK-B receptor mRNA (CCK-BRt). A short open reading frame preceded the AUG translation initiation codon of the CCK-BRtx. Transfection of COS-7 cells with the CCK-BRtx or CCK-BRt cDNAs did not lead to the appearance of peptidergic and non-peptidergic binding sites. Cell free in vitro translation yielded proteins of approximately 44 kDa (CCK-B receptor) and 40 kDa (CCK-BRt receptor) whereas no 40 kDa product was detected from the cloned CCK-BRtx cDNA. Instead, a protein product of approximately 9 kDa was visualized, the size corresponding to the predicted protein encoded by the short open reading frame. The alternatively spliced CCK-B receptor transcripts were concomitantly expressed with the ordinary full-length CCK-B receptor mRNA in the brain, pancreas, and stomach. The possibility that such transcripts are translated in vivo into truncated CCK-B receptors is discussed.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84493 (URN)10100325 (PubMedID)
    Tillgänglig från: 2012-10-10 Skapad: 2012-10-10 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor
    Öppna denna publikation i ny flik eller fönster >>Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor
    Visa övriga...
    2002 (Engelska)Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 103, nr 1, s. 29-37Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A series of CCK2 receptor ligands were analysed with respect to their interaction with binding sites in the membranes of COS-7 cells and SK-N-MC cells transiently expressing the human CCK2 receptor (short isoform). The ligands were YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450. Their binding was analysed by radioligand competition using [3H]L-365,260 as the labelled ligand. Saturation binding analysis indicated that [3H]L-365,260 interacted with a single class of binding sites. In competition binding experiments using COS-7-cell membranes, all seven ligands were incubated together with 2 nM [3H]L-365,260. The data for four of the compounds fitted a one-site model (pKi values: YM022: 9.2±0.02; YF476: 9.6±0.04; L-740,093: 9.2±0.01; and AG041R: 8.3±0.06), while the data for the three others fitted a two-site model (pKi values: JB93182: 8.8±0.04 and 6.0±0.15; PD134308: 9.0±0.04 and 6.1±0.15; and PD136450: 9.0±0.02 and 5.4±0.41). SK-N-MC cell membranes and 2 nM [3H]L-365,260 were incubated together with YM022, YF476, JB93182, and PD134308. The data for YM022 and YF476 fitted a one-site model (pKi values: YM022: 9.3±0.06; YF476: 9.4±0.02), while the data for JB93182 and PD134308 fitted a two-site model (pKi values: JB93182: 8.7±0.06 and 6.2±0.06; PD134308: 9.1±0.06 and 7.0±0.17). Competition binding experiments in the presence of the GTP-analogue guanylylimidodiphosphate, using either of the two cell types, produced similar binding data for PD134308 and JB93182 as in the absence of GTP-analogue. The human receptor seems to exist in a low and/or high affinity state. The shift from low to high affinity does not seem to reflect the degree of G protein coupling.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-28364 (URN)10.1016/S0167-0115(01)00324-X (DOI)13499 (Lokalt ID)13499 (Arkivnummer)13499 (OAI)
    Tillgänglig från: 2009-10-09 Skapad: 2009-10-09 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study
    Öppna denna publikation i ny flik eller fönster >>Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study
    2003 (Engelska)Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 114, nr 1, s. 37-43Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared ∼50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, l-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27051 (URN)10.1016/S0167-0115(03)00068-5 (DOI)11696 (Lokalt ID)11696 (Arkivnummer)11696 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Molecular cloning of a putative Ciona intestinalis cionin receptor, a new member of the CCK/gastrin receptor family
    Öppna denna publikation i ny flik eller fönster >>Molecular cloning of a putative Ciona intestinalis cionin receptor, a new member of the CCK/gastrin receptor family
    2003 (Engelska)Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 323, nr 1-2, s. 79-88Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cionin, a peptide showing similarities with cholecystokinin and gastrin has been shown to be expressed in the gut and neural ganglion of the protochordate Ciona intestinalis. The present report describes the cloning of a putative cionin receptor (CioR), a new member of the CCK/gastrin family from the gastrointestinal tract of C. intestinalis. mRNA from the stomach of C. intestinalis was isolated using a modified RNA extraction procedure and, subsequently, reverse-transcribed into single-stranded cDNA by means of rapid amplification of 5′- and 3′-cDNA ends (RACE-PCR), followed by full-length PCR amplification. The cloned full-length PCR amplicons contained a short upstream open-reading frame (uORF) coding for a putative 16 amino acid long peptide, followed by a long open reading frame encoding a 526 amino acid putative CioR protein. At the amino acid level, the putative CioR protein shared 35–40% homology with cloned mammalian, chicken, and Xenopus laevis CCK receptors. Phylogenetic analysis revealed that the chicken and X. laevis CCK receptors are orthologues of the mammalian CCK2 receptors whereas CioR protein forms a clade with vertebrate cholecystokinin receptors. Moreover, we found that the CioR cDNA and deduced amino acid sequences were found to correspond to the annotated CCK/gastrin-like receptor gene on Scaffold 117 (C. intestinalis draft genome project, Joint Genome Institute database; http://www.jgi.doe.gov).

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27050 (URN)10.1016/j.gene.2003.09.002 (DOI)11695 (Lokalt ID)11695 (Arkivnummer)11695 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
  • 97.
    Nilsson, Isabelle
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jurg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland.
    Lindström, Erik
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Håkanson, Rolf
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor2002Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 103, nr 1, s. 29-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of CCK2 receptor ligands were analysed with respect to their interaction with binding sites in the membranes of COS-7 cells and SK-N-MC cells transiently expressing the human CCK2 receptor (short isoform). The ligands were YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450. Their binding was analysed by radioligand competition using [3H]L-365,260 as the labelled ligand. Saturation binding analysis indicated that [3H]L-365,260 interacted with a single class of binding sites. In competition binding experiments using COS-7-cell membranes, all seven ligands were incubated together with 2 nM [3H]L-365,260. The data for four of the compounds fitted a one-site model (pKi values: YM022: 9.2±0.02; YF476: 9.6±0.04; L-740,093: 9.2±0.01; and AG041R: 8.3±0.06), while the data for the three others fitted a two-site model (pKi values: JB93182: 8.8±0.04 and 6.0±0.15; PD134308: 9.0±0.04 and 6.1±0.15; and PD136450: 9.0±0.02 and 5.4±0.41). SK-N-MC cell membranes and 2 nM [3H]L-365,260 were incubated together with YM022, YF476, JB93182, and PD134308. The data for YM022 and YF476 fitted a one-site model (pKi values: YM022: 9.3±0.06; YF476: 9.4±0.02), while the data for JB93182 and PD134308 fitted a two-site model (pKi values: JB93182: 8.7±0.06 and 6.2±0.06; PD134308: 9.1±0.06 and 7.0±0.17). Competition binding experiments in the presence of the GTP-analogue guanylylimidodiphosphate, using either of the two cell types, produced similar binding data for PD134308 and JB93182 as in the absence of GTP-analogue. The human receptor seems to exist in a low and/or high affinity state. The shift from low to high affinity does not seem to reflect the degree of G protein coupling.

  • 98.
    Nilsson, Isabelle
    et al.
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jurg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Molecular cloning of a putative Ciona intestinalis cionin receptor, a new member of the CCK/gastrin receptor family2003Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 323, nr 1-2, s. 79-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cionin, a peptide showing similarities with cholecystokinin and gastrin has been shown to be expressed in the gut and neural ganglion of the protochordate Ciona intestinalis. The present report describes the cloning of a putative cionin receptor (CioR), a new member of the CCK/gastrin family from the gastrointestinal tract of C. intestinalis. mRNA from the stomach of C. intestinalis was isolated using a modified RNA extraction procedure and, subsequently, reverse-transcribed into single-stranded cDNA by means of rapid amplification of 5′- and 3′-cDNA ends (RACE-PCR), followed by full-length PCR amplification. The cloned full-length PCR amplicons contained a short upstream open-reading frame (uORF) coding for a putative 16 amino acid long peptide, followed by a long open reading frame encoding a 526 amino acid putative CioR protein. At the amino acid level, the putative CioR protein shared 35–40% homology with cloned mammalian, chicken, and Xenopus laevis CCK receptors. Phylogenetic analysis revealed that the chicken and X. laevis CCK receptors are orthologues of the mammalian CCK2 receptors whereas CioR protein forms a clade with vertebrate cholecystokinin receptors. Moreover, we found that the CioR cDNA and deduced amino acid sequences were found to correspond to the annotated CCK/gastrin-like receptor gene on Scaffold 117 (C. intestinalis draft genome project, Joint Genome Institute database; http://www.jgi.doe.gov).

  • 99.
    Nilsson, Isabelle
    et al.
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jürg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study2003Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 114, nr 1, s. 37-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared ∼50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, l-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

  • 100.
    Nilsson, S F E
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Mäepea, O
    Alm, A
    Narfström, K
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Internmedicin.
    Ocular blood flow and retinal metabolism in abyssinian cats with hereditary retinal degeneration2001Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 42, nr 5, s. 1038-1044Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose. To investigate if retinal blood flow decreases with progression of the disease in Abyssinian cats with progressive retinal atrophy (PRA), to examine if the choroidal blood flow was affected by the disease, and to determine the uptake of glucose and formation of lactate in the outer retina. Methods. Local blood flow in different parts of the eye was determined with radioactive microspheres, in 9 normal cats and in 10 cats at different stages of PRA. Three blood flow determinations were made in each animal, during control conditions, after IV administration of indomethacin and after subsequent administration of Nw-nitro-L-arginine (L-NA). Blood samples from a choroidal vein and a femoral artery were collected to determine the retinal formation of lactate and uptake of glucose. Results. In Abyssinian cats with PRA (n = 10), the retinal blood flow was significantly (P = 0.01) lower than in normal cats (n = 9) during control conditions, 6.4 ▒ 1.7 compared with 14.1 ▒ 1.9 g min-1 (100 g)-1. The vascular resistance in the iris and ciliary body was significantly higher in the cats at a late stage of PRA, both compared with normal cats and to cats at an early stage of the disease, whereas the choroidal vascular resistance was not significantly affected. Indomethacin had no effect on ocular blood flows in normal cats, but in cats with PRA, iridal blood flow was more than doubled after indomethacin. The retinal formation of lactate was significantly (P = 0.001) lower in cats with PRA than in normal cats, 0.111 ▒ 0.035 (n = 8) compared with 0.318 ▒ 0.024 (n = 8) ╡mol rain-1. The uptake of glucose was not significantly different in cats with PRA. Conclusions. Retinal blood flow is severely decreased in Abyssinian cats at a late stage of retinal degeneration, whereas the choroidal microcirculation is not significantly affected by the disease. At a late stage of retinal degeneration, vascular resistance in the iris is significantly increased, which at least in part could be caused by cyxlooxygenase products.

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