| 1. |
- Gantner, Carlos W., et al.
(author)
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Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease
- 2020
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In: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 26:4, s. 5-526
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Journal article (peer-reviewed)abstract
- Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.
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| 2. |
- Beckman, Marie, et al.
(author)
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Activation of cathepsin D by glycosaminoglycans
- 2009
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In: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 276:24, s. 7343-7352
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Journal article (peer-reviewed)abstract
- We have previously shown that heparin can increase the activity of the proenzyme form of Alzheimer's beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Cathepsin D (CD) is a member of the aspartic protease family and has sequence similarity to BACE1. Therefore, we examined whether heparin and other glycosaminoglycans (GAGs) can influence the activity of CD. Heparin and other GAGs were found to stimulate the activity of recombinant proCD. Desulfation of heparin almost abolished the stimulation, indicating that sulfate groups were important for the stimulatory effect. In addition, the stimulation was dependent on the length of the GAG chain, as larger GAGs were more potent in their ability to stimulate proCD than shorter fragments. In the presence of heparin, limited autocatalytic proteolysis of the proenzyme was increased, suggesting that heparin increases the activity of proCD by accelerating the conversion of proCD, which has little activity, to pseudoCD, an active form lacking residues 1-26 of the prodomain. Furthermore, the activity of spleen-derived mature CD, which lacks the entire 44 amino acid residue prodomain, was also increased by heparin, indicating that the catalytic domain of CD contains at least one region to which GAGs bind and stimulate enzyme activity. Because heparin also stimulated the activity of pseudoCD, proenzyme activation was probably accelerated by the interaction of heparin with the catalytic domain of pseudoCD. However, it is possible that heparin may also activate the proenzyme directly. On the basis of this study, we propose that GAGs may regulate CD activity in vivo.
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| 3. |
- Kathiresan, Sekar, et al.
(author)
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Common variants at 30 loci contribute to polygenic dyslipidemia
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 56-65
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Journal article (peer-reviewed)abstract
- Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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| 4. |
- Khanna, Mayank, et al.
(author)
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Is host heparanase required for the rapid spread of heparan sulfate binding viruses?
- 2019
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In: Virology. - : Elsevier BV. - 0042-6822 .- 1096-0341. ; 529, s. 1-6
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Nyberg, Kicki, 2000, et al.
(author)
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The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus.
- 2004
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In: Antiviral research. - : Elsevier BV. - 0166-3542. ; 63:1, s. 15-24
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Journal article (peer-reviewed)abstract
- Although a number of sulfated polysaccharides have been shown to inhibit infection of cells by herpes simplex virus (HSV), little is known about their effects on the cell-to-cell spread of the virus. These compounds act by inhibiting the virus binding to cells, and their antiviral potencies usually increase with increasing molecular weight and sulfation density. We report that the low molecular weight HS-mimetic, PI-88, which is a mixture of highly sulfated mannose-containing di- to hexa-saccharides, inhibited HSV infection of cells and cell-to-cell spread of HSV-1 and HSV-2. Compared to a relatively large heparin polysaccharide, PI-88 demonstrated weaker inhibition of HSV infectivity but more efficient reduction of cell-to-cell spread of HSV. A tetrasaccharide fraction of PI-88 was the minimum fragment necessary to inhibit HSV-1 infectivity, while a trisaccharide was sufficient to reduce cell-to-cell spread. A reduction in HSV lateral spread was also observed in cells incubated with another low molecular weight compound, pentosan polysulfate but not with much larger polysaccharide chondroitin sulfate E. Some differences as regards the effects of PI-88, heparin, protamine, poly-L-lysine and sodium chlorate on intercellular spread of HSV-1 and HSV-2 were found. We conclude that structurally different sulfated oligosaccharides are preferred for inhibition of HSV infectivity and the cell-to-cell spread. The latter was efficiently inhibited by a relatively small but densely sulfated PI-88 oligosaccharide, very likely due to the capability of the compound to access the narrow intercellular space.
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| 6. |
- Poon, Ivan K H, et al.
(author)
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Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage
- 2009
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 424:Part 1, s. 27-37
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Journal article (peer-reviewed)abstract
- The plasminogen/plasmin system is involved in a variety of normal physiological and pathological processes, including tissue remodelling, angiogenesis and tumour metastasis. Plasminogen activators and receptors for plasminogen/plasminogen activators are essential for the processing of plasminogen to form the active serine protease plasmin. Plasmin can in turn positively or negatively regulate further plasminogen activation via plasmin-mediated cleavage of receptors and activators. HRG (histidine-rich glycoprotein), a relatively abundant (approx. 100-150 microg/ml) plasma glycoprotein, has a multi-domain structure that can interact with many ligands, including Zn2+, heparin, HS (heparan sulfate) and plasminogen. HRG has been shown to function as an adaptor molecule to tether plasminogen to GAG (glycosaminoglycan)-bearing surfaces and to regulate plasminogen activation via various mechanisms. As HRG itself is sensitive to plasmin cleavage, the present study examines in detail the cleavage of human HRG by plasmin and the effect of this cleavage on various functions of HRG. HRG fragments, generated by plasmin cleavage, are held together by disulfide linkages and are not released from the molecule under non-reducing conditions. Plasmin-mediated cleavage partially inhibited HRG binding to cell surface HS, but enhanced HRG binding to necrotic cells and to plasminogen. However, both intact and plasmin-cleaved HRG enhanced the binding of plasminogen to heparin-coated surfaces to a similar extent. Furthermore, the presence of heparin, Zn2+ or acidic pH was found to protect HRG from plasmin cleavage. Thus proteolytic cleavage of HRG by plasmin may provide a feedback mechanism to regulate the effects of HRG on the plasminogen/plasmin system and other functions of HRG.
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