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- Berg, Cecilia, 1976-, et al.
(författare)
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Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase
- 2006
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 96:5, s. 652-659
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Tidskriftsartikel (refereegranskat)abstract
- Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A2 inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1-2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis. © 2006 Schattauer GmbH, Stuttgart.
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| 2. |
- Gunnarsson, Svante, 1959-, et al.
(författare)
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Using Course and Program Matrices as Components in a Quality Assurance System
- 2019
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Ingår i: The 15th International CDIO Conference: Proceedings – Full Papers. - Aarhus : Aarhus University. - 9788775074594 ; , s. 110-119
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Konferensbidrag (refereegranskat)abstract
- The CDIO framework is an integrated and important part of the new quality assurance system within the Faculty of Science and Engineering at Linköping University. Both the CDIO Syllabus and the CDIO Standards are used extensively in the system. First, the paper presents the development and use of the second generation of course matrices (previously denoted ITU-matrices) and program matrices, which build upon an adapted and extended version of the CDIO Syllabus. The extension is made to also include bachelor’s and master’s program in subjects outside the engineering field. Second, the paper presents how the CDIO Standards are used in the quality reports, which are vital parts of the quality assurance systems. As a result, the CDIO framework is used for the design, management, and quality assurance of all education programs ( approximately 60 programs) within the Faculty of Science and Engineering at Linköping University.
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| 4. |
- Herbertsson, Helena, 1967-
(författare)
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Studies on a novel cytosolic/nuclear binding protein for the eicosanoid 12(S)-hydroxyeicosatetraenoic acid
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hydroxyeicosatetraenoic acids (HETEs) are lipoxygenase metabolites of arachidonic acid. HETEs were long considered to have few or no important biological function - a view that proved to be incorrect. These compounds have now been identified in many different types of cells, and they have been attributed several important actions, the molecular mechanisms of which are largely unclear. This thesis describes the discovery of a putative receptor for 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE).Specific high-affinity binding sites for 12(S)-HETE were detected in the cytosol (52%) and the nuclei (18%) of cells of the Lewis lung carcinoma (LLC) line. Similar l2(S)-HETE binding sites were detected in the cytosol of several other kinds of cells and in human platelets. Gel permeation chromatography and density gradient centrifugation indicated an apparent molecular weight of about 650 kDa and a sedimentation coefficient of20.5 S for the binding sites in the cytosol ofLLC cells. Treatment with ATP caused the 650 kDa component to dissociate into subunits. The actuall2(S)-HETE binding subunit was subsequently shown to have a molecular weight of about 50 kDa.The subcellular distribution of l2(S)-HETE binding sites in LLC cells was found to resemble the distribution of some nuclear receptors of the steroid hormone receptor superfamily. The untransformed glucocorticoid receptor has been reported to be located in cytosol in association with heat shock proteins 70 and 90, and Western blot analyses and immunoprecipitation revealed the same two proteins in the cytosolic 650 kDa l2(S)-HETE binding complex.A possible relationship to the steroid hormone receptor superfamily was also suggested by the observation that the 50 kDa l2(S)-HETE binding protein interacted with steroid receptor coactivator-l (SRC-l), which is known to be recruited to the site of transcriptional activity by several nuclear receptors. The interaction with SRC-1 occurred only when l2(S)-HETE was bound to its 50 kDa binding protein.In summary, the research presented in this thesis led to the discovery of a novel type of eicosanoid receptor. This binding site resembles the nuclear receptors for steroids and related compounds by virtue of its subcellular distribution, the inclusion of heat shock proteins in its binding complex, and its strictly ligand-dependent interaction with SRC-l.
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| 7. |
- Kurahashi, Yuko, et al.
(författare)
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A 12(S)-hydroxyeicosatetraenoic acid receptor interacts with steroid receptor coactivator-1
- 2000
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 97:11, s. 5779-5783
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Tidskriftsartikel (refereegranskat)abstract
- Lewis lung carcinoma cells contain specific high-affinity binding sites for the eicosanoid 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(S)-HETE]. These binding sites have a cytosolic/nuclear localization and contain the heat shock proteins hsp70 and hsp90 as components of a high molecular weight cytosolic binding complex. The ligand binding subunit of this complex is a protein with an apparent molecular mass of ÿ50 kDa as judged by gel permeation chromatography. In this report, we present data showing that the 50-kDa 12(S)-HETE binding protein interacts as a homodimer with steroid receptor coactivator-1 (SRC-1) in the presence of 12(S)-HETE. Two putative interaction domains were mapped. One of these (amino acids 701-781) was within the nuclear receptor interaction domain in SRC-1 required for binding of various steroid and thyroid hormone receptors. It contains the most C-terminal of the three copies of LXXLL motif present in the nuclear receptor interaction domain. The second interaction domain was present in the N-terminal part of SRC-1 (amino acids 1-221). This region has two LXXLL motifs, one does not bind and the other binds only weakly to steroid and thyroid hormone receptors. Glutathione S-transferase (GST) pulldown experiments and far Western analyses demonstrated that the N-terminal region of SRC-1 (amino acids 1-212) alone does not bind the 50-kDa 12(S)-HETE binding protein, whereas GST/?SRC-11-1138 ligand-dependently pulled down a protein of ÿ50 kDa in size. Our results suggest that the 50-kDa 12(S)-HETE binding protein is a receptor that may signal through interaction with a nuclear receptor coactivator protein.
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