| 1. |
- Aili, Ulrika, et al.
(författare)
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Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.
- 2010
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Ingår i: Cancer Research. - 1538-7445. ; 70:9, s. 3771-3779
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Tidskriftsartikel (refereegranskat)abstract
- Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.
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| 2. |
- Cheng, Fang, et al.
(författare)
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APP/APLP2 expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:30, s. 20871-20878
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Tidskriftsartikel (refereegranskat)abstract
- Anhydromannose (anMan)-containing heparan sulfate (HS) derived from the proteoglycan glypican-1 (Gpc-1) is generated in endosomes by an endogenously or ascorbate induced SNO-catalyzed reaction. Processing of the amyloid precursor protein (APP) and APP-like protein 2 (APLP2) by β- and γ-secretases into amyloid beta (Aβ) and Aβ-like peptides also takes place in these compartments. Moreover, anMan-containing HS suppresses the formation of toxic Aβ assemblies in vitro. We show by using deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody as well as 35S-labeling experiment that expression of APP/APLP2 is required for ascorbate-induced transport of HS from endosomes to the nucleus. Nuclear translocation was observed in wild-type mouse embryonic fibroblasts (Wt-MEF), Tg2576 MEF and N2a neuroblastoma cells but not in APP-/- and APLP2-/- MEF. Transfection of APP-/- cells with a vector encoding APP restored nuclear import of anMan-containing HS. In Wt-MEF and N2a neuroblastoma cells exposed to β- or γ-secretase inhibitors, nuclear translocation was greatly impeded, suggesting involvement of APP/APLP2 degradation products. In Tg2576 MEF, the β-inhibitor blocked transport but the γ- inhibitor did not. During chase in ascorbate-free medium, anMan-containing HS disappeared from the nuclei of Wt-MEF. Confocal immunofluorescence microscopy showed that they appeared in acidic, LC3-positive vesicles in keeping with an autophagosomal location. There was increased accumulation of anMan-containing HS in nuclei and cytosolic vesicles upon treatment with chloroquine indicating that HS was degraded in lysosomes. Manipulations of APP expression and processing may have deleterious effects upon HS function in the nucleus.
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| 3. |
- Cheng, Fang, et al.
(författare)
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Non-conserved, S-nitrosylated cysteines in glypican-1 react with N-unsubstituted glucosamines in heparan sulfate and catalyze deaminative cleavage.
- 2012
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 22:11, s. 1480-1485
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Tidskriftsartikel (refereegranskat)abstract
- The membrane lipid-anchored glypicans (heparan sulfate proteoglycans) are present in both vertebrates and invertebrates and serve as important modulators of growth factors and morphogens during development. Their core proteins are similar and consist of a large N-terminal domain comprising 14 evolutionary conserved cysteines and a C-terminal stalk carrying the heparan sulfate side-chains and the lipid anchor. Cysteines in glypican-1 can be S-nitrosylated but their positions have not been identified. The recently determined crystal structure of the N-terminal domain of glypican-1 has revealed that all the evolutionary conserved cysteines form intramolecular disulfide bonds. However, glypican-1 contains two more, non-conserved cysteines in the C-terminal stalk, located near the heparan sulfate attachment sites. We show here that the non-conserved cysteines are free thiols as a glypican-1 core protein containing the C-terminal stalk could be biotinylated by biotin-BMCC. After S-nitrosylation by using an NO-donor and copper ions, the glypican-1 core protein was retained on an affinity matrix substituted with heparan sulfate oligosaccharides containing N-unsubstituted glucosamines. The protein was displaced with 0.2 M glucosamine but also by 2 mM ascorbate. In the latter case, the heparan sulfate of the affinity matrix was simultaneously cleaved into fragments containing anhydromannose. We propose that the S-nitrosocysteine residues interact with closely located N-unsubstituted glucosamines in the heparan sulfate side-chains of the glypican-1 proteoglycan. Addition of ascorbate induces a series of reactions that eventually releases heparan sulfate fragments with reducing terminal anhydromannose, presumably without the formation of free nitric oxide.
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| 4. |
- Cheng, Fang, et al.
(författare)
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Non-toxic amyloid beta formed in the presence of glypican-1 or its deaminatively generated heparan sulfate degradation products
- 2013
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 23:12, s. 1510-1519
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid beta (A beta) peptides (mainly A beta 40 and A beta 42), which are derived from the amyloid precursor protein (APP), can oligomerize into antibody A11-positive, neurotoxic species, believed to be involved in Alzheimer's disease. Interestingly, APP binds strongly to the heparan sulfate (HS) proteoglycan (PG) glypican-1 (Gpc-1) in vitro and both proteins are colocalized inside cells. In endosomes, APP is proteolytically processed to yield A beta peptides. The HS chains of S-nitrosylated (SNO) Gpc-1 PG are cleaved into anhydromannose (anMan)-containing di- and oligosaccharides by an NO-dependent reaction in the same compartments. Here, we have studied the toxicity of oligomers/aggregates of A beta 40 and A beta 42, as well as A beta 40/42 mixtures that were formed in the presence of immobilized Gpc-1 PG or immobilized HS oligosaccharides. Afterwards, A beta was displaced from the matrices, analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for A11 immunoreactivity, for effects on growth of mouse N2a neuroblastoma cells and for membrane leakage in rat cortical neurons. HS generally promoted and accelerated A beta multimerization into oligomers as well as larger aggregates that were mostly A11 positive and showed toxic effects. However, non-toxic A beta was formed in the presence of Gpc-1 PG or when anMan-containing HS degradation products were simultaneously generated. Both toxic and non-toxic A beta peptides were taken up by the cells but toxic forms appeared to enter the nuclei to a larger extent. The protection afforded by the presence of HS degradation products may reflect a normal intracellular function for the A beta peptides.
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| 5. |
- Cheng, Fang, et al.
(författare)
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Suppression of amyloid beta a11-immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, no-catalyzed degradation.
- 2011
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 286:31, s. 27559-27572
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta is generated from the copper- and heparan sulfate (HS)-binding amyloid precursor protein (APP) by proteolytic processing. APP supports S-nitrosylation of the HS-proteoglycan glypican-1 (Gpc-1). In the presence of ascorbate there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-SNO. We have investigated whether these oligosaccharides interact with amyolid beta during APP processing and plaque formation. anMan-Immunoreactivity was detected in amyloid plaques of Alzheimer (AD) and APP transgenic (Tg2576) mouse brains by immunofluorescence microscopy. APP/APP degradation products detected by antibodies to the C-terminus of APP, but not amyolid beta oligomers detected by the anti-amyloid beta A11 antibody, colocalized with anMan-immunoreactivity in Tg2576 fibroblasts. A 50-55-kDa anionic, SDS-stable, anMan- and amyloid beta-immunoreactive species was obtained from Tg2576 fibroblasts using immunoprecipitation with anti-APP (C-terminal). anMan-Containing HS oligo- and disaccharide preparations modulated or suppressed A11-immunoreactivity and oligomerization of amyloid beta 42 peptide in an in vitro assay. A11 immunoreactivity increased in Tg2576 fibroblasts when Gpc-1 autoprocessing was inhibited by U18666A, and decreased when Gpc-1 autoprocessing was stimulated by ascorbate. Neither overexpression of Gpc-1 in Tg2576 fibroblasts nor addition of copper ion and NO-donor to hippocampal slices from 3xTg-AD mice affected A11 immunoreactivity levels. However, A11 immunoreactivity was greatly suppressed by the subsequent addition of ascorbate. We speculate that temporary interaction between the amyolid beta domain and small, anMan-containing oligosaccharides may preclude formation of toxic amyloid beta oligomers. A portion of the oligosaccharides co-secrete with the amyloid beta peptides and are deposited in plaques. These results support the notion that inadequate supply of vitamin C could contribute to late onset AD in humans.
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| 6. |
- Fransson, Liselotte, et al.
(författare)
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beta-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome
- 2013
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Ingår i: Journal of Endocrinology. - : BioScientifica. - 0022-0795 .- 1479-6805. ; 219:3, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 mu g/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into beta-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.
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| 7. |
- Fransson, Liselotte, et al.
(författare)
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β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome
- 2013
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 219:3, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.
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| 8. |
- Hagman, Karl, et al.
(författare)
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On the potential roles of ticks and migrating birds in the ecology of West Nile virus
- 2014
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Ingår i: Infection Ecology & Epidemiology. - : Informa UK Limited. - 2000-8686 .- 2000-8686. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mosquitoes are the primary vectors of West Nile virus (WNV). Ticks have, however, been suggested to be potential reservoirs of WNV. In order to investigate their role in the spread of the virus, ticks, which had been collected from birds migrating northwards from Africa to Europe, were analyzed for the potential presence of WNV-RNA.METHODS: On the Mediterranean islands Capri and Antikythira a total of 14,824 birds were captured and investigated from which 747 ticks were collected.RESULTS AND CONCLUSION: Most of the identified ticks (93%) were nymphs and larvae of Hyalomma marginatum sensu lato, most of which were or appear to be Hyalomma rufipes. Of these ticks 729 were individually screened for WNV-RNA. None of the ticks was found to be WNV positive. Thus, there was no evidence that Hyalomma marginatum s.l. ticks play a role in the spread of WNV from Africa to Europe.
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| 9. |
- Malmström, Eva-Maj, et al.
(författare)
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Influence of prolonged unilateral cervical muscle contraction on head repositioning - Decreased overshoot after a 5-min static muscle contraction task.
- 2010
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Ingår i: Manual Therapy. - : Elsevier BV. - 1356-689X. ; 15, s. 229-234
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Tidskriftsartikel (refereegranskat)abstract
- The ability to reproduce a specified head-on-trunk position can be an indirect test of cervical proprioception. This ability is affected in subjects with neck pain, but it is unclear whether and how much pain or continuous muscle contraction factors contribute to this effect. We studied the influence of a static unilateral neck muscle contraction task (5 min of lateral flexion at 30% of maximal voluntary contraction) on head repositioning ability in 20 subjects (10 women, 10 men; mean age 37 years) with healthy necks. Head repositioning ability was tested in the horizontal plane with 30 degrees target and neutral head position tests; head position was recorded by Zebris((R)), an ultrasound-based motion analyser. Head repositioning ability was analysed for accuracy (mean of signed differences between introduced and reproduced positions) and precision (standard deviation of the differences). Accuracy of head repositioning ability increased significantly after the muscle contraction task, as the normal overshoot was reduced. An average overshoot of 7.1 degrees decreased to 4.6 degrees after the muscle contraction task for the 30 degrees target and from 2.2 degrees to 1.4 degrees for neutral head position. The increased accuracy was most pronounced for movements directed towards the activated side. Hence, prolonged unilateral neck muscle contraction may increase the sensitivity of cervical proprioceptors.
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| 10. |
- Petrov, Miroslav, 1971-, et al.
(författare)
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High-Speed Steam Turbine Systems For Small-Scale Power Generation Applications
- 2012
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Ingår i: Proceedings of the 20th International Conference on Nuclear Engineering collocated with the ASME 2012 Power Conference. - : ASME Press. - 9780791844960 ; , s. 651-657
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Konferensbidrag (refereegranskat)abstract
- Energy utilization from low-grade fuels of either fossil or renewable origin, or from medium-temperature heat sources such as solar, industrial waste heat, or small nuclear reactors, for small-scale power generation via steam cycles, can be reasonably enhanced by a simple technology shift. This study evaluates the technical feasibility of a compact power generation package comprising a steam turbine directly coupled to a high-speed alternator delivering around 8 - 12 MW of electrical power. Commercial or research-phase high-speed electrical generators at MW-scale are reviewed, and a basic thermodynamic design and flow-path analysis of a steam turbine able to drive such a generator is attempted. High-speed direct drives are winning new grounds due to their abilities to be speed-controlled and to avoid the gearbox otherwise typical for small system drivetrains. These two features may offer a reasonable advantage to conventional drives in terms of higher reliability and better economy. High-speed alternators with related power electronics are nowadays becoming increasingly available for the MW-size market. A generic 8 to 12 MW synchronous alternator running respectively at 15,000 to 10,000 rpm, have been used as a reference for evaluating the fundamental design of a directly coupled steam turbine prime mover. The moderate steam parameter concept suits well for converting mid-temperature thermal energy into electrical power with the help of low-tech steam cycles, allowing for distributed electricity production at reasonable costs and efficiency. Steam superheat temperatures below 350 degrees C (660 degrees F) at pressures of maximum 20 bar would keep the steam volumetric flow sufficiently high in order to restrain the turbine losses typical for small-scale turbines, while helping also with simpler certification and safety procedures and using primarily established technology and standard components. The proposed steam turbines designs and their characteristics thereof have been evaluated by computer simulations using the in-house code ProSteam and its sub-procedures AXIAL and VaxCalc, by courtesy of Siemens Industrial Turbomachinery and its steam turbine division located in Finspong, Sweden. The first results from this study show that high-speed steam turbines of the proposed size and type are possible to design and manufacture based on conventional components, and can be expected to deliver a very satisfactory performance at variable power output.
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