uu.seUppsala University Publications
Change search
Refine search result
123 1 - 50 of 102
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Abramsson, Alexandra
    et al.
    Kurup, Sindhulakshmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yamada, Shuhei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblom, Per
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bondjers, Göran
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerhardt, Holger
    Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 3, p. 316-331Article in journal (Refereed)
    Abstract [en]

    During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

  • 2.
    Aldi, S.
    et al.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Eriksson, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Kronqvist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Lengquist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Folkersen, L.
    Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark..
    Perisic, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Grinnemo, K. H.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedin, U.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Osterholm, C.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Dual roles of heparanase in vascular calcification associated with human carotid atherosclerosis2017In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 98, no 3, p. A5-A5Article in journal (Other academic)
  • 3.
    Aldi, Silvia
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Eriksson, Linnea
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Kronqvist, Malin
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Lengquist, Mariette
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Folkersen, Lasse
    Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark.
    Matic, Ljubica P.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden;Tech Univ Munich, Dept Vasc Surg, D-80333 Munich, Germany.
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Österholm, C.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Dual roles of heparanase in human carotid plaque calcification2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 283, p. 127-136Article in journal (Refereed)
    Abstract [en]

    Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.

    Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.

    Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.

    Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.

  • 4. Axelman, Elena
    et al.
    Henig, Israel
    Crispel, Yonatan
    Attias, Judith
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brenner, Benjamin
    Vlodavsky, Israel
    Nadir, Yona
    Novel peptides that inhibit heparanase activation of the coagulation system2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 466-477Article in journal (Refereed)
    Abstract [en]

    Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator tissue factor (IF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11-14 amino acids, inhibited heparanase procoagulant activity but did not affect IF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.

  • 5.
    Barash, Uri
    et al.
    Technion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel.
    Lapidot, Moshe
    Rambam Hlth Care Campus, Dept Gen Thorac Surg, Haifa, Israel.
    Zohar, Yaniv
    Rambam Hlth Care Campus, Dept Pathol, Haifa, Israel.
    Loomis, Cynthia
    NYU, Sch Med, Dept Cardiothorac Surg, Langone Med Ctr, New York, NY USA.
    Moreira, Andre
    NYU, Sch Med, Dept Cardiothorac Surg, Langone Med Ctr, New York, NY USA.
    Feld, Sari
    Technion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel.
    Goparaju, Chandra
    NYU, Sch Med, Dept Cardiothorac Surg, Langone Med Ctr, New York, NY USA.
    Yang, Haining
    Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA.
    Hammond, Edward
    Zucero Therapeut, Darra, Qld, Australia.
    Zhang, Ganlin
    Beijing Hosp Tradit Chinese Med, Beijing, Peoples R China.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ilan, Neta
    Technion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel.
    Nagler, Arnon
    Chaim Sheba Med Ctr, Dept Hematol & Bone Marrow Transplantat, Tel Hashomer, Israel.
    Pass, Harvey I.
    NYU, Sch Med, Dept Cardiothorac Surg, Langone Med Ctr, New York, NY USA.
    Vlodavsky, Israel
    Technion, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel.
    Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications2018In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 10, p. 1102-1114Article in journal (Refereed)
    Abstract [en]

    Background: Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy.

    Methods: The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided.

    Results: Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03).

    Conclusions: Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.

  • 6.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Barash, Uri
    Rappaport Technion, Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodavsky, Israel
    Rappaport Technion, Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells2017In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 98, no 3, p. A10-A11Article in journal (Other academic)
  • 7.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. GlycoNovo Technol Co Ltd, Shanghai, Peoples R China..
    Barash, Uri
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells2017In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) mediates the activity of various growth factors including TGF-beta. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-beta 1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-beta 1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-beta 1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-beta 1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-beta 1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-beta 1 function in tumorigenesis.

  • 8.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Glyconovo Technologies Co., Ltd., TianXiong Road, Shanghai International Medical Zone (SIMZ), Pudong New Area, Shanghai 201318, China.
    Jansson, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhao, Hongxing
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gallant, Caroline J.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed)
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

  • 9. Bode, Lars
    et al.
    Salvestrini, Camilla
    Park, Pyong Woo
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Esko, Jeffrey D
    Yamaguchi, Yu
    Murch, Simon
    Freeze, Hudson H
    Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function2008In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 118, no 1, p. 229-238Article in journal (Refereed)
    Abstract [en]

    Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

  • 10. Boyango, Ilanit
    et al.
    Barash, Uri
    Naroditsky, Inna
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammond, Edward
    Ilan, Neta
    Vlodavsky, Israel
    Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 16, p. 4504-4514Article in journal (Refereed)
    Abstract [en]

    Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.

  • 11. Christianson, Helena C.
    et al.
    Svensson, Katrin J.
    van Kuppevelt, Toin H.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Belting, Mattias
    Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 43, p. 17380-17385Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo.

  • 12.
    Cui, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tan, Ying-xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Beijing Inst Transfus Med, Dept Tissue Engn, Beijing, Peoples R China..
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Nova SE Univ, Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Zhang, Xiao-Qun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Vlodavsky, Israel
    Technion Israel Inst Technol, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase expression upregulates platelet adhesion activity and thrombogenicity2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 26, p. 39486-39496Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normal tissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.

  • 13.
    Dierker, Tabea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
    Bachvarova, Velina
    Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
    Krause, Yvonne
    Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kjellen, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Seidler, Daniela G.
    Univ Munster, Inst Physiol Chem & Pathobiochem, D-48149 Munster, Germany..
    Vortkamp, Andrea
    Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
    Altered heparan sulfate structure in Glce(-/-) mice leads to increased Hedgehog signaling in endochondral bones2016In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 49, p. 82-92Article in journal (Refereed)
    Abstract [en]

    One of the key regulators of endochondral ossification is Indian hedgehog (Ihh), which acts as a long-range morphogen in the developing skeletal elements. Previous studies have shown that the distribution and signaling activity of Ihh is regulated by the concentration of the extracellular glycosaminoglycan heparan sulfate (HS). An essential step during biosynthesis of HS is the epimerization of D-glucuronic to L-iduronic acid by the enzyme glucuronyl C5-epimerase (Hsepi or Glce). Here we have investigated chondrocyte differentiation in Glce deficient mice and found increased regions of proliferating chondrocytes accompanied by a delayed onset of hypertrophic differentiation. In addition, we observed increased expression levels of the Ihh target genes Patched1 (Ptch1) and Parathyroid hormone related peptide (Pthrp; Parathyroid hormone like hormone (Pthlh)) indicating elevated Ihh signaling. We further show that Ihh binds with reduced affinity to HS isolated from Glce(-/-) mice. Together our results strongly indicate that not only the level, but also the structure of HS is critical in regulating the distribution and signaling activity of Ihh in chondrocytes.

  • 14.
    Digre, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nan, Jie
    Lund Univ, MAX IV Lab, POB 118, SE-22100 Lund, Sweden..
    Frank, Martin
    Biognos AB, Box 8963, Gothenburg, Sweden..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heparin interactions with apoA1 and SAA in inflammation-associated HDL2016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 474, no 2, p. 309-314Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein A1 (apoA1) is the main protein component responsible for transportation of cholesterol on high-density lipoprotein (HDL). Serum amyloid A (SAA) is an acute phase protein associated with HDL. Apart from their physiological functions, both apoA1 and SAA have been identified as 'amyloidogenic peptides'. We report herein that the polysaccharide heparin interacts with both apoA1 and SAA in HDL isolated from plasma of inflamed mice. The reaction is rapid, forming complex aggregates composed of heparin, apoA1 and SAA as revealed by gel electrophoresis. This interaction is dependent on the size and concentration of added heparin. Mass spectrometry analysis of peptides derived from chemically crosslinked HDL-SAA particles detected multiple crosslinks between apoA1 and SAA, indicating close proximity (within 25 angstrom) of these two proteins on the HDL surface, providing a molecular and structural mechanism for the simultaneous binding of heparin to apoA1 and SAA.

  • 15.
    Digre, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Singh, Kailash
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Åbrink, Magnus
    Swedish Univ Agr Sci, Immunol Sect, Dept Biomed Sci & Vet Publ Hlth, VHC, Box 7028, Uppsala, Sweden.
    Reijmers, Rogier M.
    Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46229Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50 % of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+ and CD8+ T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.

  • 16.
    Ek, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zetterqvist, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Pettersson, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gong, Feng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification and characterization of a mammalian 14-kDa phosphohistidine phosphatase2002In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, p. 5016-5023Article in journal (Refereed)
    Abstract [en]

    Protein histidine phosphorylation in eukaryotes has beensparsely studied compared to protein serine/threonine andtyrosine phosphorylation. In an attempt to rectify this byprobing porcine liver cytosol with the phosphohistidinecontainingpeptide succinyl-Ala-His(P)-Pro-Phe-p-nitroanilide(phosphopeptide I), we observed a phosphataseactivity that was insensitive towards okadaic acid andEDTA. This suggested the existence of a phosphohistidinephosphatase different from protein phosphatase 1, 2Aand 2C. A 1000-fold purification to apparent homogeneitygave a 14-kDa phosphatase with a specific activity of 3lmolÆmin)1Æmg)1 at pH 7.5 with 7 lM phosphopeptide Ias substrate. Partial amino-acid sequence determination ofthe purified porcine enzyme by MS revealed similaritywith a human sequence representing a human chromosome9 gene of hitherto unknown function. Molecularcloning from a human embryonic kidney cell cDNAlibraryfollowed by expression and purification, yielded aprotein with a molecular mass of 13 700 Da, and anEDTA-insensitive phosphohistidine phosphatase activityof 9 lmolÆmin)1Æmg)1 towards phosphopeptide I. Nodetectable activity was obtained towards a set of phosphoserine-,phosphothreonine-, and phosphotyrosine peptides.Northern blot analysis indicated that the humanphosphohistidine phosphatase mRNA was present preferentiallyin heart and skeletal muscle. These resultsprovide a new tool for studying eukaryotic histidinephosphorylation/dephosphorylation.

  • 17.
    Escobar Galvis, Martha L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jia, Juan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Jastrebova, Nadja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gottfridsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van Kuppevelt, Toin H.
    Zcharia, Eyal
    Vlodavsky, Israel
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate2007In: Nature Chemical Biology, ISSN 1552-4450, Vol. 3, no 12, p. 773-778Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis. Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves β-glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism. Metabolic labeling confirmed extensive fragmentation of HS in vivo. In the current study we found that in liver showing excessive heparanase overexpression, HSPG turnover is accelerated along with upregulation of HS N- and O-sulfation, thus yielding heparin-like chains without the domain structure typical of HS. Heparanase overexpression in other mouse organs and in human tumors correlated with increased 6-O-sulfation of HS, whereas the domain structure was conserved. The heavily sulfated HS fragments strongly promoted formation of ternary complexes with fibroblast growth factor 1 (FGF1) or FGF2 and FGF receptor 1. Heparanase thus contributes to regulation of HS biosynthesis in a way that may promote growth factor action in tumor angiogenesis and metastasis.

  • 18. Feyerabend, Thorsten B
    et al.
    Li, Jin-Ping
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rodewald, Hans-Reimer
    Heparan sulfate C5-epimerase is essential for heparin biosynthesis in mast cells.2006In: Nat Chem Biol, ISSN 1552-4450, Vol. 2, no 4, p. 195-6Article in journal (Other scientific)
  • 19.
    Feyzi, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salmivirta, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lidholt, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate - an information package?1997In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 14, no Suppl., p. 14-Article, book review (Other academic)
  • 20.
    Garsen, Marjolein
    et al.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, NL-6525 GA Nijmegen, Netherlands..
    Benner, Marilen
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, NL-6525 GA Nijmegen, Netherlands..
    Dijkman, Henry B.
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 GA Nijmegen, Netherlands..
    van Kuppevelt, Toin H.
    Radboud Univ Nijmegen, Med Ctr, Dept Biochem, NL-6525 GA Nijmegen, Netherlands..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    RabeLink, Ton J.
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands..
    Vlodavsky, Israel
    Technion Israel Inst Technol, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, POB 9649, IL-31096 Haifa, Israel..
    Berden, Jo H. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, NL-6525 GA Nijmegen, Netherlands..
    Rops, Angeligue L. W. M. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, NL-6525 GA Nijmegen, Netherlands..
    Elkin, Michael
    Hadassah Hebrew Univ, Med Ctr, Sharett Inst, Jerusalem, Israel..
    van der Vlag, Johan
    Radboud Univ Nijmegen, Med Ctr, Dept Nephrol, NL-6525 GA Nijmegen, Netherlands..
    Heparanase Is Essential for the Development of Acute Experimental Glomerulonephritis2016In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 186, no 4, p. 805-815Article in journal (Refereed)
    Abstract [en]

    Heparanase, a heparan sulfate (HS)-specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis Led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro, tumor necrosis factor-alpha and Lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the Local cytokine milieu.

  • 21. Gil, Natali
    et al.
    Goldberg, Rachel
    Neuman, Tzahi
    Garsen, Marjolein
    Zcharia, Eyal
    Rubinstein, Ariel M.
    van Kuppevelt, Toin
    Meirovitz, Amichay
    Pisano, Claudio
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van der Vlag, Johan
    Vlodavsky, Israel
    Elkin, Michael
    Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice2012In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 1, p. 208-216Article in journal (Refereed)
    Abstract [en]

    Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for interventions in patients with DN.

  • 22. Goldberg, Rachel
    et al.
    Rubinstein, Ariel M.
    Gil, Natali
    Hermano, Esther
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van der Vlag, Johan
    Atzmon, Ruth
    Meirovitz, Amichay
    Elkin, Michael
    Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4302-4313Article in journal (Refereed)
    Abstract [en]

    Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.

  • 23.
    Gong, Feng
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Escobar Galvis, Martha L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodavsky, Israel
    Horner, Aalan
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Processing of macromolecular heparin by heparanase2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 37, p. 35152-35158Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-glucuronidase expressed in a variety of tissues and cells that selectively cleaves extracellular and cell-surface heparan sulfate. Here we propose that this enzyme is involved also in the processing of serglycin heparin proteoglycan in mouse mast cells. In this process, newly synthesized heparin chains (60-100 kDa) are degraded to fragments (10-20 kDa) similar in size to commercially available heparin (Jacobsson, K. G., and Lindahl, U. (1987) Biochem. J. 246, 409-415). A fraction of these fragments contains the specific pentasaccharide sequence required for high affinity binding to antithrombin implicated with anticoagulant activity. Rat skin heparin, which escapes processing in vivo, was used as a substrate in reaction with recombinant human heparanase. An incubation product of commercial heparin size retained the specific pentasaccharide sequence, although oligosaccharides (3-4 kDa) containing this sequence could be degraded by the same enzyme. Commercial heparin was found to be a powerful inhibitor (I50 approximately 20 nM expressed as disaccharide unit, approximately 0.7 nM polysaccharide) of heparanase action toward antithrombin-binding oligosaccharides. Cells derived from a serglycin-processing mouse mastocytoma expressed a protein highly similar to other mammalian heparanases. These findings strongly suggest that the intracellular processing of the heparin proteoglycan polysaccharide chains is catalyzed by heparanase, which primarily cleaves target structures distinct from the antithrombin-binding sequence.

  • 24. Gui, Chuan-Zhi
    et al.
    Ran, Long-Yan
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Guan, Zhi-Zhong
    Changes of learning and memory ability and brain nicotinic receptors of rat offspring with coal burning fluorosis2010In: Neurotoxicology and Teratology, ISSN 0892-0362, E-ISSN 1872-9738, ISSN 20381606, Vol. 32, no 5, p. 536-541Article in journal (Refereed)
    Abstract [en]

    The purpose of the investigation is to reveal the mechanism of the decreased ability of learning and memory induced by coal burning fluorosis. Ten offspring SD rats aged 30 days, who were born from the mothers with chronic coal burning fluorosis, and ten offspring with same age from the normal mothers as controls were selected. Spatial learning and memory of the rats were evaluated by Morris Water Maze test. Cholinesterase activity was detected by photometric method. The expressions of nicotinic acetylcholine receptors (nAChRs) at protein and mRNA levels were detected by Western blotting and Real-time PCR, respectively. The results showed that in the rat offspring exposed to higher fluoride as compared to controls, the learning and memory ability declined; the cholinesterase activities in the brains were inhibited; the protein levels of alpha 3, alpha 4 and alpha 7 nAChR subunits were decreased which showed certain significant correlations with the declined learning and memory ability: and the mRNA levels of alpha 3 and alpha 4 nAChRs were decreased, whereas the alpha 7 mRNA increased. The data indicated that coal burning fluorosis can induce the decreased ability of learning and memory of rat offspring, in which the mechanism might be connected to the changed nAChRs and cholinesterase.

  • 25.
    Gustafsen, Camilla
    et al.
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Olsen, Ditte
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Vilstrup, Joachim
    Aarhus Univ, Dept Mol Biol & Genet, Gustav Wieds Vej 10, DK-8000 Aarhus, Denmark..
    Lund, Signe
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Reinhardt, Anika
    Scienion AG, Volmerstr 7b, D-12489 Berlin, Germany..
    Wellner, Niels
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Larsen, Torben
    Aarhus Univ, Dept Anim Sci, Blichers Alle 20, DK-8830 Tjele, Denmark..
    Andersen, Christian B. F.
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Weyer, Kathrin
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Seeberger, Peter H.
    Max Planck Inst Colloids & Interfaces, Dept Biomol Syst, Muhlenberg 1 OT Golm, D-14476 Potsdam, Germany..
    Thirup, Soren
    Aarhus Univ, Dept Mol Biol & Genet, Gustav Wieds Vej 10, DK-8000 Aarhus, Denmark..
    Madsen, Peder
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Glerup, Simon
    Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
    Heparan sulfate proteoglycans present PCSK9 to the LDL receptor2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 503Article in journal (Refereed)
    Abstract [en]

    Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9: LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.

  • 26.
    Gutter-Kapon, Lilach
    et al.
    Technion, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, IL-31096 Haifa, Israel..
    Alishekevitz, Dror
    Technion, Bruce Rappaport Fac Med, Dept Cell Biol & Canc Sci, IL-31096 Haifa, Israel..
    Shaked, Yuval
    Technion, Bruce Rappaport Fac Med, Dept Cell Biol & Canc Sci, IL-31096 Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aronheim, Ami
    Technion, Bruce Rappaport Fac Med, Dept Mol Genet, IL-31096 Haifa, Israel..
    Ilan, Neta
    Technion, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, IL-31096 Haifa, Israel..
    Vlodavsky, Israel
    Technion, Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, IL-31096 Haifa, Israel..
    Heparanase is required for activation and function of macrophages2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 48, p. E7808-E7817Article in journal (Refereed)
    Abstract [en]

    The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized and is encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, very little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here we used a genetic approach and examined the behavior and function of macrophages isolated from wild-type (WT) and heparanase-knockout (Hpa-KO) mice. Hpa-KO macrophages express lower levels of cytokines (e.g., TNF alpha, IL1-beta) and exhibit lower motility and phagocytic capacities. Intriguingly, inoculation of control monocytes togetherwith Lewis lung carcinoma (LLC) cells into Hpa-KO mice resulted in nearly complete inhibition of tumor growth. In striking contrast, inoculating LLC cells together with monocytes isolated from Hpa-KO mice did not affect tumor growth, indicating that heparanase is critically required for activation and function of macrophages. Mechanistically, we describe a linear cascade by which heparanase activates Erk, p38, and JNK signaling in macrophages, leading to increased c-Fos levels and induction of cytokine expression in a manner that apparently does not require heparanase enzymatic activity. These results identify heparanase as a key mediator of macrophage activation and function in tumorigenesis and cross-talk with the tumor microenvironment.

  • 27.
    Hagner-McWhirter, Asa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Oscarson, Stefan
    Lindahl, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Irreversible glucuronyl C5-epimerization in the biosynthesis of heparan sulfate.2004In: J Biol Chem, ISSN 0021-9258, Vol. 279, no 15, p. 14631-8Article in journal (Refereed)
  • 28.
    Heindryckx, Femke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Role of proteoglycans in neuro-inflammation and central nervous system fibrosis2018In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 68–69, p. 589-601Article, review/survey (Refereed)
    Abstract [en]

    Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans.

  • 29. Hunter, K. E.
    et al.
    Palermo, C.
    Kester, J. C.
    Simpson, K.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tang, L. H.
    Klimstra, D. S.
    Vlodavsky, I.
    Joyce, J. A.
    Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors2014In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 14, p. 1799-1808Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.

  • 30. Jendresen, Charlotte B.
    et al.
    Cui, Hao
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vlodavsky, Israel
    Nilsson, Lars N. G.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-beta Precursor Protein Transgenic Mice2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 8, p. 5053-5064Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-beta (A beta) deposits in Alzheimer disease brain and in A beta precursor protein (A beta PP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of A beta pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human A beta PP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect A beta PP processing because the steady-state levels of A beta(1-40), A beta(1-42), and soluble A beta PP beta were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the A beta burden, measured by A beta(x-40) and A beta(x-42) immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the A beta(x-42) burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated A beta(1-42)-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing A beta fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with A beta-HSPG interactions might be a potential strategy for Alzheimer disease treatment.

  • 31.
    Jendresen, Charlotte
    et al.
    Univ Oslo, Dept Pharmacol, Postboks 1057, NO-0316 Oslo, Norway;Oslo Univ Hosp, Postboks 1057, NO-0316 Oslo, Norway.
    Digre, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cui, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. College of Life Science, Jiangxi Normal University, Nanchang, 330022, China.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, POB 9649, IL-31096 Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nilsson, Lars N. G.
    Univ Oslo, Dept Pharmacol, Postboks 1057, NO-0316 Oslo, Norway;Oslo Univ Hosp, Postboks 1057, NO-0316 Oslo, Norway.
    Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4600Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta (A(beta) is the main constituent of amyloid deposits in Alzheimer's disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and A beta deposition in A beta PP-mice and doubletransgenic mice with brain expression of A beta PP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 mu g LPS or vehicle, and were sacrificed 1.5 months thereafter. A beta in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total A beta deposition and increased Tween-soluble A beta. This was associated with a reduced CXCL1, IL-1 beta, TNF-alpha-level and microgliosis, which correlated with amyloid deposition and total A beta. In contrast, LPS did not change A beta accumulation or inflammation marker in the doubletransgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers A beta-clearance in A beta PP-transgenic mouse brain. The effects depend on HS and heparanase.

  • 32.
    Jia, Juan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Maccarana, Marco
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bespalov, Maxim
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lack of L-iduronic acid in heparan sulfate affects interaction with growth factors and cell signaling2009In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 23, p. 15942-15950Article in journal (Refereed)
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of D-glucuronic acid to L-iduronic acid in heparan sulfate (HS) biosynthesis. Disruption of the Hsepi gene in mouse yielded a lethal phenotype with selective organ defects, but had remarkably little effect on other organ systems. We have approached the underlying mechanisms by examining the course and effects of FGF2 signaling in a mouse embryonic fibroblast (MEF) cell line derived from the Hsepi-/- mouse. The HS produced by these cells is devoid of IdoA residues, but shows upregulated N- and 6-O-sulfation compared to wildtype (WT) MEF HS. In medium fortified with 10% FCS the Hsepi-/- MEFs proliferated and migrated similar to WT cells. Under starvation conditions both cell types showed attenuated proliferation and migration, that could be restored by addition of FGF2 to WT cells whereas Hsepi-/- cells were resistant. Moreover, ERK phosphorylation following FGF2 stimulation was delayed in Hsepi-/- compared to WT cells. Assessment of HS-growth factor interaction by nitrocellulose filter trapping revealed strikingly aberrant binding property of FGF2 and glia-derived neurotropic factor (GDNF) to Hsepi-/- but not to WT HS. GDNF has a key role in kidney development, defective in Hsepi-/- mice. By contrast, Hsepi-/- and WT HS interacted similarly and in conventional mode with FGF10. These findings correlate defective function of growth factors with their mode of HS interaction, and may help explain the partly modest organ phenotypes observed after genetic ablation of selected enzymes in HS biosynthesis.

  • 33.
    Jia, Juan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Zcharia, Eyal
    Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Dept. of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase cleavage of heparin modulates protease storage in mast cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Overexpression of heparanase caused extensive degradation of heparan sulfate (HS), and elimination of heparanase resulted in non-degraded HS chains in mice. In this study, we have investigated the impact of heparanase in the processing of heparin and storage of proteases in mast cells. We used fetal skin mast cells (FSMCs) isolated from wild type (WT) embryos and embryos either overexpressing human heparanase (hpa-tg), or lacking heparanase (Hpse-KO). FSMCs from hpa-tg embryos produced substantially shorter heparin chains than did WT counterparts, whereas FSMCs from Hpse-KO embryos expressed longer chains than WT cells. Extensive fragmentation of heparin in hpa-tg FSMC caused losing of proteases in the cells; in contrast, increased storage of proteases was observed in Hpse-KO cells. These results provide the first in vivo evidence demonstrating that heparanase is responsible for processing of mast cell heparin. Control of heparin degradation by heparanase in mast cell may contribute to modulating protease storage in the cells.

  • 34. Karlsson-Lindahl, Linda
    et al.
    Schmidt, Linnea
    Haage, David
    Hansson, Caroline
    Taube, Magdalena
    Egeciouglu, Emil
    Tan, Ying-Xia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Admyre, Therese
    Jansson, John-Olov
    Vlodavsky, Israel
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dickson, Suzanne L.
    Heparanase Affects Food Intake and Regulates Energy Balance in Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34313-Article in journal (Refereed)
    Abstract [en]

    Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.

  • 35.
    Khanna, Mayank
    et al.
    Australian Natl Univ, John Curtin Sch Med Res, ACRF Dept Canc Biol & Therapeut, Canc & Vasc Biol Grp, Canberra, ACT, Australia;Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Mol Mucosal Vaccine Immunol Grp, Canberra, ACT, Australia.
    Ranasinghe, Charani
    Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Mol Mucosal Vaccine Immunol Grp, Canberra, ACT, Australia.
    Browne, Anna M.
    Australian Natl Univ, John Curtin Sch Med Res, ACRF Dept Canc Biol & Therapeut, Canc & Vasc Biol Grp, Canberra, ACT, Australia.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodaysky, Israel
    Technion Israel Inst Technol, Rappaport Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel;Technion Israel Inst Technol, Res Inst, Haifa, Israel.
    Parish, Christopher R.
    Australian Natl Univ, John Curtin Sch Med Res, ACRF Dept Canc Biol & Therapeut, Canc & Vasc Biol Grp, Canberra, ACT, Australia.
    Is host heparanase required for the rapid spread of heparan sulfate binding viruses?2019In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 529, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Vaccinia virus (VACV), like many other viruses, binds to cell surface heparan sulfate (HS) prior to infecting cells. Since HS is ubiquitously expressed extracellularly, it seemed likely that VACV-HS interaction may impede virus spread, with host heparanase, the only known mammalian endoglycosidase that can degrade HS, potentially overcoming this problem. In support of this hypothesis, we found that, compared to wild type, mice deficient in heparanase showed a 1-3 days delay in the spread of VACV to distant organs, such as ovaries, following intranasal inoculation, or to ovaries and spleen following intramuscular inoculation. These delays in spread occurred despite heparanase deficiency having no effect on VACV replication at inoculation sites. Subsequent in vitro studies revealed that heparanase treatment released VACV from HS expressing, but not HS deficient, infected cell monolayers. Collectively these data suggest that VACV relies on host heparanase to degrade HS in order to spread to distant sites.

  • 36.
    Kreuger, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Interactions between heparan sulfate and proteins: the concept of specificity2006In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 174, no 3, p. 323-327Article, review/survey (Refereed)
    Abstract [en]

    Proteoglycan (PG) coreceptors carry heparan sulfate (HS) chains that mediate interactions with growth factors, morphogens, and receptors. Thus, PGs modulate fundamental processes such as cell survival, division, adhesion, migration, and differentiation. This review summarizes recent biochemical and genetic information that sheds new light on the nature of HS-protein binding. Unexpectedly, many interactions appear to depend more on the overall organization of HS domains than on their fine structure.

  • 37.
    Kurup, S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Abramsson, A
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Betsholtz, C
    Gerhardt, H
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulphate requirement in platelet-derived growth factor B-mediated pericyte recruitment2006In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 34, no Pt 3, p. 454-455Article in journal (Refereed)
    Abstract [en]

    HS (heparan sulphate) plays a key role in angiogenesis, by interacting with growth factors required in the process. it has been proposed that HS controls the diffusion, and thus the availability, of platelet-derived growth factor B that is needed for pericyte recruitment around newly formed capillaries. The present paper summarizes our studies on the importance of HS structure in this regulatory process.

  • 38.
    Kurup, Sindhulakshmi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wijnhoven, Tessa J M
    Jenniskens, Guido J
    Kimata, Koji
    Habuchi, Hiroko
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van Kuppevelt, Toin H
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of anti-heparan sulfate phage display antibodies AO4B08 and HS4E42007In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 29, p. 21032-21042Article in journal (Refereed)
    Abstract [en]

    Heparan sulfates (HS) are linear carbohydrate chains, covalently attached to proteins, that occur on essentially all cell surfaces and in extracellular matrices. HS chains show extensive structural heterogeneity and are functionally important during embryogenesis and in homeostasis due to their interactions with various proteins. Phage display antibodies have been developed to probe HS structures, assess the availability of protein-binding sites, and monitor structural changes during development and disease. Here we have characterized two such antibodies, AO4B08 and HS4E4, previously noted for partly differential tissue staining. AO4B08 recognized both HS and heparin, and was found to interact with an ubiquitouys, N-, 2-O-, and 6-O-sulfated saccharide motif, including an internal 2-O-sulfate group. HS4E4 turned out to preferentially recognize low-sulfated HS motifs containing iduronic acid, and N-sulfated as well as N-acetylated glucosamine residues. Contrary to AO4B08, HS4E4 did not bind highly O-sulfated structures such as found in heparin.

  • 39.
    Ledin, Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Staatz, William
    Li, Jin-Ping
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Götte, Martin
    Selleck, Scott
    Kjellén, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate structure in mice with genetically modified heparan sulfate production.2004In: J Biol Chem, ISSN 0021-9258, Vol. 279, no 41, p. 42732-41Article in journal (Refereed)
  • 40. Li, Jimei
    et al.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lu, Zhongyang
    Yu, Shan Ping
    Wei, Ling
    Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia2012In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1433, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Heparanase is a heparan sulfate degrading endoglycosidase. Previous work has demonstrated that heparanase plays important roles in various biological processes including angiogenesis, wound healing and metastasis. However, the role of heparanase in the post-ischemic brain is not well defined. Transient focal cerebral ischemia in adult mice was induced by ligations of the right middle cerebral artery (MCA) and both common carotid arteries (CCAs). All mice were subjected to bromodeoxyuridine (BrdU) injection and sacrificed at different time points after stroke for immunohistochemical and Western blot analyses. Heparanase expression increased after ischemia in both cell-specific and time-dependent manners. Three to 7 days after stroke, levels of the 50-kD heparanase, basic fibroblast growth factor (FGF-2), and angiopoietin-2 (Ang-2) increased in the peri-infarct region. At early time points, heparanase expression was largely confined to proliferating vascular endothelial cells. At 14 days after ischemia, this expression had shifted to astrocytes in the same region. These data show that cerebral ischemia markedly increases heparanase levels in endothelial cells and then in astrocytes. The unique features of the heparanase upregulation imply that heparanase may play specific roles in the pathological and regenerative processes during the acute and sub-acute/chronic phases in the post-stroke brain.

  • 41.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Glucuronyl C5-epimerase: an enzyme converting glucuronic acid to iduronic acid in heparan sulfate/heparin biosynthesis2010In: Progress in molecular biology and translational science, ISSN 1877-1173, Vol. 93, p. 59-78Article, review/survey (Refereed)
    Abstract [en]

    The glucuronyl C5 epimerase (HSepi) is one of the modification enzymes involved in biosynthesis of heparan sulfate (HS) and heparin, catalyzing the epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) at polymer level. IdoA is critical for HS and heparin to interact with protein ligands, because of its flexible conformation. Although the enzyme recognizes both GlcA and IdoA as substrates catalyzing a reversible reaction of the hexuronic acids in vitro, the reaction appears irreversible in vivo. Targeted interruption of the gene, Glce, in mice resulted in neonatal lethality accompanied with kidney agenesis, premature lung, and skeletal malformations, demonstrating that the single gene coded enzyme is essential for animal development. Elimination of the enzyme resulted in abnormal HS and heparin structure that completely lacks IdoA residues. Loss of 2-O-sulfation due to lacking IdoA in HS chains appears compensated by increased N- and O-sulfation of the glucosamine residues. Recombinant HSepi is used to generate HS/heparin related compounds having potential to be used for therapeutic purposes.

  • 42.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparin, heparan sulfate and heparanase in cancer: remedy for metastasis?2008In: Anti-Cancer Agents in Medicinal Chemistry, ISSN 1871-5206, Vol. 8, no 1, p. 64-76Article, review/survey (Refereed)
    Abstract [en]

    Malignant tumor cells invade normal tissues in the vicinity of cancer through devastating the extracelluar matrix and blood vessel wall of the tissues. An important step in this process is degradation of heparan sulfate proteoglycan, a carbohydrate-protein complex. Heparan sulfate proteoglycan is a major component of the extracellular matrix, and is essential for the self-assembly, insolubility and barrier properties of basement membranes. Heparanase is an endoglucuronidase that cleaves heparan sulfate and expression level of this enzyme correlates with metastatic potential of tumor cells. Treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin, a widely used anticoagulant, is structurally related to heparan sulfate and a natural substrate of heparanase. Long-term treatment of cancer patients having venous thromboembolism with low molecular weight heparin showed improved survival rate. Understanding the functional roles and the corresponding molecular mechanisms of heparin, heparan sulfate and heparanase in cancer development may pave the way for exploring remedies against tumor metastasis.

  • 43.
    Li, Jin-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Galvis, Martha L. Escobar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gong, Feng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zcharia, Eyal
    Metzger, Shula
    Vlodavsky, Israel
    Kisilevsky, Robert
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 18, p. 6473-7Article in journal (Refereed)
    Abstract [en]

    Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.

  • 44.
    Li, Jin-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hagner-McWhirther, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kjellén, Lena
    Palgi, Jaan
    Jalkanen, Markku
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Biosynthesis of heparin / heparan sulfate: cDNA cloning and expression of D-glucuronyl C5-epimerase from bovine lung1997In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 272, no 44, p. 28158-28163Article in journal (Refereed)
    Abstract [en]

    Glucuronyl C5-epimerases catalyze the conversion of D-glucuronic acid (GlcUA) to L-iduronic acid (IdceA) units during the biosynthesis of glycosaminoglycans. An epimerase implicated in the generation of heparin/heparan sulfate was previously purified to homogeneity from bovine liver (Campbell, P., Hannesson, H. H., Sandbäck, D., Rodén, L., Lindahl, U., and Li, J.-p. (1994) J. Biol. Chem. 269, 26953-26958). The present report describes the molecular cloning and functional expression of the lung enzyme. The cloned enzyme contains 444 amino acid residues and has a molecular mass of 49,905 Da. N-terminal sequence analysis of the isolated liver enzyme showed this species to be a truncated form lacking a 73-residue N-terminal domain of the deduced amino acid sequence. The coding cDNA insert was cloned into a baculovirus expression vector and expressed in Sf9 insect cells. Cells infected with recombinant epimerase showed a 20-30-fold increase in enzyme activity, measured as release of 3H2O from a polysaccharide substrate containing C5-3H-labeled hexuronic acid units. Furthermore, incubation of the expressed protein with the appropriate (GlcUA-GlcNSO3)n substrate resulted in conversion of approximately 20% of the GlcUA units into IdceA residues. Northern analysis implicated two epimerase transcripts in both bovine lung and liver tissues, a dominant approximately 9-kilobase (kb) mRNA and a minor approximately 5-kb species. Mouse mastocytoma cells showed only the approximately 5-kb transcript. A comparison of the cloned epimerase with the enzymes catalyzing an analogous reaction in alginate biosynthesis revealed no apparent amino acid sequence similarity.

  • 45.
    Li, Jin-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    D-glucuronyl C5-epimerase in heparin/heparan sulfate biosynthesis2002In: Handbook of glycosyltransferases and related genes / [ed] N. Taniguchi, K. Honke, M. Fukuda, Tokyo: Springer , 2002, p. 403-409Chapter in book (Other academic)
  • 46.
    Li, Jin-ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate proteoglycans as multifunctional cell regulators: cell surface receptors2012In: Proteoglycans: Methods and Protocols / [ed] Françoise Rédini, Springer, 2012, Vol. 836, no 3, p. 239-255Chapter in book (Refereed)
    Abstract [en]

    Proteoglycans are macromolecules expressed on the cell surfaces and in the extracellular matrix of most animal tissues (Annu Rev Biochem 68:729-777, 1999; Int Rev Cell Mol Biol 276:105-159, 2009). Heparan sulfate proteoglycans (HSPGs) are essential for animal development and homeostasis, and are involved in various pathological processes. The functions of HSPGs are largely exerted through interaction of the heparan sulfate (HS) side chains with different types of ligands, including diverse molecules such as cytokines, enzymes, and pathogens. One of the important roles of cell surface HSPGs is to mediate cytokine-induced cell signaling through interaction with growth factors (GFs) and their cognate receptors. A selective dependence of GFs for different structural features of HS has been demonstrated by applying cell models that are mutated variously in HS structure due to deficiency in enzymes involved in the biosynthesis of HS chains.

  • 47.
    Li, Jin-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodavsky, Israel
    Heparin, heparan sulfate and heparanase in inflammatory reactions2009In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 102, no 5, p. 823-828Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) proteoglycans at the cell surface and in the extracellular matrix of most animal tissues are essential in development and homeostasis, and are implicated in disease processes. Emerging evidence demonstrates the important roles of HS in inflammatory reactions, particularly in the regulation of leukocyte extravasation. Heparin, a classical anticoagulant, exhibits anti-inflammatory effects in animal models and in the clinic, presumably through interference with the functions of HS, as both polysaccharides share a high similarity in molecular structure. Apart of regulation during biosynthesis, the structures of HS and heparin are significantly modulated by heparanase, an endoglycosidase that is upregulated in a number of inflammatory conditions. Exploring the physiological roles of HS and heparin and the mode of heparanase action in modulating their functions during inflammation responses is of importance for future studies.

  • 48. Li, Lili
    et al.
    Wang, Bo
    Gao, Tianle
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hao, Jing-Xia
    Vlodavsky, Israel
    Wiesenfeld-Hallin, Zsuzsanna
    Xu, Xiao-Jun
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 511, no 1, p. 4-7Article in journal (Refereed)
    Abstract [en]

    Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.

  • 49.
    Lindahl, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Interactions Between Heparan Sulfate and Proteins—Design and Functional Implications2009In: International review of cell and molecular biology, ISSN 1937-6448, Vol. 276, p. 105-159Article, review/survey (Refereed)
    Abstract [en]

    Heparan sulfate (HS) proteoglycans at cell surfaces and in the extracellular matrix of most animal tissues are essential in development and homeostasis, and variously implicated in disease processes. Functions of HS polysaccharide chains depend on ionic interactions with a variety of proteins including growth factors and their receptors. Negatively charged sulfate and carboxylate groups are arranged in various types of domains, generated through strictly regulated biosynthetic reactions and with enormous potential for structural variability. The level of specificity of HS-protein interactions is assessed through binding experiments in vitro using saccharides of defined composition, signaling assays in cell culture, and targeted disruption of genes for biosynthetic enzymes followed by phenotype analysis. While some protein ligands appear to require strictly defined HS structure, others bind to variable saccharide domains without any apparent dependence on distinct saccharide sequence. These findings raise intriguing questions concerning the functional significance of regulation in HS biosynthesis.

  • 50.
    Lindahl, Ulf
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salmivirta, Markku
    Alaranta, Sakari
    Veromaa, Timo
    Emeis, Jef
    Roberts, Ian
    Taylor, Clare
    Oreste, Pasqua
    Zoppetti, Giorgio
    Naggi, Annamaria
    Torri, Giangiacomo
    Casu, Benito
    Generation of "neoheparin" from E. coli K5 capsular polysaccharide.2005In: J Med Chem, ISSN 0022-2623, Vol. 48, no 2, p. 349-52Article in journal (Refereed)
123 1 - 50 of 102
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf