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Ny, Tor
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Publications (10 of 152) Show all publications
Glise, L., Larsson, P., Jern, S., Borén, J., Levin, M., Ny, T., . . . Bergh, N. (2019). Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo. Thrombosis and Haemostasis, 119(2), 223-233
Open this publication in new window or tab >>Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo
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2019 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 119, no 2, p. 223-233Article in journal (Refereed) Published
Abstract [en]

Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2019
Keywords
t-PA, artery, fluid shear, fibrinogen/fibrin
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-156885 (URN)10.1055/s-0038-1676638 (DOI)000458811700006 ()30602198 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Wielkoszynski, T., Moghaddam, A., Backman, A., Broden, J., Piotrowski, R., Mond-Paszek, R., . . . Wilczynska, M. (2018). Novel diagnostic ELISA test for discrimination between infections with Yersinia enterocolitica and Yersinia pseudotuberculosis. European Journal of Clinical Microbiology and Infectious Diseases, 37(12), 2301-2306
Open this publication in new window or tab >>Novel diagnostic ELISA test for discrimination between infections with Yersinia enterocolitica and Yersinia pseudotuberculosis
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2018 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 37, no 12, p. 2301-2306Article in journal (Refereed) Published
Abstract [en]

Yersiniosis is a foodborne infection caused by Yersinia enterocolitica or Yersinia pseudotuberculosis. Although yersiniosis is most often self-limiting, some patients develop chronic infections, such as reactive arthritis, glomerulonephritis, or myocarditis, which require an antibiotic treatment. Whereas early infections can be diagnosed by direct detection of bacteria, chronic infections can only be identified by serological tests. At this point, a serological method for differentiation between infections with the two Yersinia species is important since antibiotic susceptibility of these bacteria is different. Traditional immunoassays do not distinguish between infections with Y. enterocolitica and Y. pseudotuberculosis. The only test that allows for this differentiation is Mikrogen's strip test where discrimination between the two types of infection is based on two recombinant bacterial proteins, MyfA and PsaA (specific for Y. enterocolitica and Y. pseudotuberculosis, respectively). Here, we show that Y. enterocolitica and Y. pseudotuberculosis, cultured under the conditions that mimic the natural rout of infection, express surface antigens different from MyfA and PsaA that can also be used in a discrimination test. Further, we describe a new ELISA that is based on the whole bacteria and recombinant MyfA and PsaA as antigens, and that allows the differentiation between infections with Y. enterocolitica and Y. pseudotuberculosis and simultaneous detection of yersiniosis.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Yersinia enterocolitica, Yersinia pseudotuberculosis, Diagnostics, Novel ELISA test, Discrimination between Yersinia species
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-154938 (URN)10.1007/s10096-018-3373-9 (DOI)000449921100010 ()30238343 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Fallah, M., Shen, Y., Brodén, J., Bäckman, A., Lundskog, B., Johansson, M., . . . Ny, T. (2018). Plasminogen activation is required for the development of radiation-induced dermatitis. Cell Death and Disease, 9(11), Article ID 1051.
Open this publication in new window or tab >>Plasminogen activation is required for the development of radiation-induced dermatitis
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2018 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 9, no 11, article id 1051Article in journal (Refereed) Published
Abstract [en]

Skin damage caused by radiation therapy (radiodermatitis) is a severe side effect of radiotherapy in cancer patients, and there is currently a lack of effective strategies to prevent or treat such skin damage. In this work, we show with several lines of evidence that plasminogen, a pro-inflammatory factor, is key for the development of radiodermatitis. After skin irradiation in wild type (plg+/+) mice, the plasminogen level increased in the radiated area, leading to severe skin damage such as ulcer formation. However, plasminogen-deficient (plg−/−) mice and mice lacking plasminogen activators were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreased radiodermatitis in plg+/+ mice and prevented radiodermatitis in plg+/ mice. Together with studies at the molecular level, we report that plasmin is required for the induction of inflammation after irradiation that leads to radiodermatitis, and we propose that inhibition of plasminogen activation can be a novel treatment strategy to reduce and prevent the occurrence of radiodermatitis in patients.

 

 

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Inflammation, plasminogen, radiation-induced dermatitis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-152950 (URN)10.1038/s41419-018-1106-8 (DOI)000447324600005 ()30323258 (PubMedID)
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-11-01Bibliographically approved
Sulniute, R., Shen, Y., Guo, Y.-Z., Fallah, M., Ahlskog, N., Ny, L., . . . Ny, T. (2016). Plasminogen is a critical regulator of cutaneous wound healing. Thrombosis and Haemostasis, 115(5), 1001-1009
Open this publication in new window or tab >>Plasminogen is a critical regulator of cutaneous wound healing
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2016 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 5, p. 1001-1009Article in journal (Refereed) Published
Abstract [en]

Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogen deficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.

Keywords
Plasminogen, wound healing, inflammation
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-121571 (URN)10.1160/TH15-08-0653 (DOI)000375372400015 ()
Available from: 2016-06-30 Created: 2016-06-03 Last updated: 2018-10-31Bibliographically approved
Moonens, K., Gideonsson, P., Subedi, S., Bugaytsova, J., Romao, E., Mendez, M., . . . Remaut, H. (2016). Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host and Microbe, 19(1), 55-66
Open this publication in new window or tab >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, no 1, p. 55-66Article in journal (Refereed) Published
Abstract [en]

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)
Available from: 2016-04-04 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
Cheng, F., Shen, Y., Mohanasundaram, P., Lindstrom, M., Ivaska, J., Ny, T. & Eriksson, J. E. (2016). Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling. Proceedings of the National Academy of Sciences of the United States of America, 113(30), E4320-E4327
Open this publication in new window or tab >>Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 30, p. E4320-E4327Article in journal (Refereed) Published
Abstract [en]

Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-beta 1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM-/-) wounds. Correspondingly, VIM-/- wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM-/- wounds. Vimentin reconstitution in VIM-/- fibroblasts restored both their proliferation and TGF-beta 1 production. Similarly, restoring paracrine TGF-beta-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-beta 1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.

Keywords
vimentin intermediate filaments, wound healing, epithelial-mesenchymal transition, fibroblast proliferation, keratinocyte migration
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-124504 (URN)10.1073/pnas.1519197113 (DOI)000380346200011 ()27466403 (PubMedID)
Available from: 2016-08-22 Created: 2016-08-15 Last updated: 2018-06-07Bibliographically approved
Hellström, S., Shen, Y. & Ny, T. (2015). A reply to the commentary on "Animal models of chronic tympanic membrane perforation: in response to plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice" by Wang AY, Shen Y, Wang JT, Eikelboom RH and Dilley RJ; Clin Translat Med, 2014; 3 [Letter to the editor]. Clinical and translational medicine, 4(8)
Open this publication in new window or tab >>A reply to the commentary on "Animal models of chronic tympanic membrane perforation: in response to plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice" by Wang AY, Shen Y, Wang JT, Eikelboom RH and Dilley RJ; Clin Translat Med, 2014; 3
2015 (English)In: Clinical and translational medicine, ISSN 2001-1326, Vol. 4, no 8Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Springer, 2015
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-116889 (URN)10.1186/s40169-014-0044-z (DOI)25852824 (PubMedID)
Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2018-06-07Bibliographically approved
Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., . . . Floto, R. A. (2014). A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus. Science, 346(6209), 641-646
Open this publication in new window or tab >>A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus
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2014 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 346, no 6209, p. 641-646Article in journal (Refereed) Published
Abstract [en]

Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-96463 (URN)10.1126/science.1258705 (DOI)000343799700052 ()25359976 (PubMedID)
Funder
Wellcome trust, 084953Wellcome trust, 089981
Available from: 2014-11-21 Created: 2014-11-21 Last updated: 2018-06-07Bibliographically approved
Shen, Y., Guo, Y., Wilczynska, M., Li, J., Hellström, S. & Ny, T. (2014). Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice. Journal of Translational Medicine, 12, Article ID 5.
Open this publication in new window or tab >>Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice
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2014 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 12, article id 5Article in journal (Refereed) Published
Abstract [en]

Background: Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. We have also shown that the healing of TM perforations is completely arrested in plg-deficient (plg(-/-)) mice and that these mice develop chronic TM perforations. In the present study, we investigated the therapeutic potential of local plg injection in acute and chronic TM perforation mice models. Methods: Plg(-/-) mice and wild-type mice were subjected to standardized TM perforations followed by local injection of plg into the soft tissue surrounding the TM. TM perforations with chronic characteristics were induced by leaving TM perforations in plg(-/-) mice untreated for 9 days before treatment. The healing process was observed through otomicroscope and finally confirmed by immunostaining. The quality of TM healing was evaluated based on the morphology of the TM. Result: Daily local injections of plg into the soft tissue surrounding the TM restored the ability to heal TM perforations in plg(-/-) mice in a dose-dependent manner, and potentiated the healing rate and quality in wild-type mice. A single local injection of plg initiated the healing of the chronic-like TM perforations in these mice, resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. However, three plg injections led to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer. Conclusion: Our data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keywords
Plasminogen, wound healing, tympanic membrane perforations
National Category
Basic Medicine Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-68759 (URN)10.1186/1479-5876-12-5 (DOI)000330279900001 ()24393366 (PubMedID)
Funder
Swedish Research Council, B0322301
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2018-06-08Bibliographically approved
Shen, Y., Guo, Y., Du, C., Wilczynska, M., Hellström, S. & Ny, T. (2012). Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations. PLoS ONE, 7(12), e51303
Open this publication in new window or tab >>Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51303-Article in journal (Refereed) Published
Abstract [en]

Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA(-/-)) or tPA (tPA(-/-)) after TM perforation. Delayed healing of TM perforations was observed in uPA(-/-) mice but not tPA(-/-) mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA(-/-) mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA(-/-) mice are most likely due to the reduced generation of plasmin.

Place, publisher, year, edition, pages
Public library of science, 2012
Keywords
receptor; upa; keratinocytes; system; gene; model
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-64176 (URN)10.1371/journal.pone.0051303 (DOI)000312064100090 ()23236466 (PubMedID)
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2018-06-08Bibliographically approved
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