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Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis.
Oskarsson ME, Singh K, Wang J, Vlodavsky I, Li JP, Westermark GT
(2015) J Biol Chem 290: 15121-32
MeSH Terms: Amyloid, Animals, Apoptosis, Base Sequence, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, DNA Primers, Glucuronidase, Heparan Sulfate Proteoglycans, Humans, Islet Amyloid Polypeptide, Islets of Langerhans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction
Show Abstract · Added June 6, 2017
Deposition of β cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mm glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that β cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of β cells.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
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18 MeSH Terms
Cells derived from young bone marrow alleviate renal aging.
Yang HC, Rossini M, Ma LJ, Zuo Y, Ma J, Fogo AB
(2011) J Am Soc Nephrol 22: 2028-36
MeSH Terms: Age Factors, Aging, Animals, Bone Marrow Transplantation, Cell Differentiation, Female, Fibrosis, Gene Expression, Glucuronidase, Kidney, Male, Mice, Mice, 129 Strain, Phenotype, Proto-Oncogene Proteins c-sis, Rejuvenation, S100 Calcium-Binding Protein A4, S100 Proteins, Serpin E2, Transforming Growth Factor beta1
Show Abstract · Added January 20, 2012
Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less β-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show β-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor β. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney.
2 Communities
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20 MeSH Terms
sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair.
Alfaro MP, Vincent A, Saraswati S, Thorne CA, Hong CC, Lee E, Young PP
(2010) J Biol Chem 285: 35645-53
MeSH Terms: Animals, Apoptosis, Bone Morphogenetic Proteins, Calcinosis, Cell Differentiation, Cell Proliferation, Cells, Cultured, Flow Cytometry, Fluorescent Antibody Technique, Glucuronidase, Green Fluorescent Proteins, Immunoblotting, Membrane Proteins, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Myocardial Infarction, Recombinant Fusion Proteins, Signal Transduction, Transfection, Wnt Proteins
Show Abstract · Added August 19, 2012
Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing.
3 Communities
4 Members
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24 MeSH Terms
Suppression of aging in mice by the hormone Klotho.
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M
(2005) Science 309: 1829-33
MeSH Terms: Aging, Animals, Blood Glucose, Cell Line, Cell Line, Tumor, Eating, Female, Glucuronidase, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Ligands, Longevity, Male, Membrane Proteins, Mice, Mice, Transgenic, Myoblasts, Oxygen Consumption, Peptide Fragments, Phosphorylation, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Cell Surface, Recombinant Proteins, Signal Transduction
Show Abstract · Added July 21, 2014
A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.
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26 MeSH Terms
Isoproterenol inhibition of isolated human neutrophil function.
Busse WW, Sosman JM
(1984) J Allergy Clin Immunol 73: 404-10
MeSH Terms: Anti-Inflammatory Agents, Cell Separation, Cyclic AMP, Epinephrine, Glucuronidase, Humans, Isoproterenol, Luminescent Measurements, Neutrophils, Superoxides, Zymosan
Show Abstract · Added March 5, 2014
The human PMN can contribute to the inflammatory response. Several neutrophil responses can be inhibited by agonists that increase the cellular levels of cyclic AMP. In the following article, we compared the effects of ISO on lysosomal beta-glucuronidase release, superoxide generation, and CL in isolated human PMNs. ISO inhibited the neutrophil CL response to opsonized zymosan in a dose-dependent fashion with maximal effects at 10(-4)M. ISO inhibition of CL was not enhanced by the addition of theophylline, nor was CL inhibited by the exogenous addition cyclic AMP except at a very high concentration of 10(-3)M. ISO also suppressed beta-glucuronidase release and superoxide generation in neutrophils during an incubation with opsonized zymosan particles. For ISO to inhibit beta-glucuronidase release and superoxide generation, theophylline (5 X 10(-4)M) was necessary. ISO effectively inhibits three neutrophil functions that are capable of causing tissue inflammation. Although ISO suppressed all three neutrophil responses, the inhibitory mechanisms appear to be variable.
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11 MeSH Terms
Interaction of artificial phospholipid membranes with isolated polymorphonuclear leucocytic granules.
Hawiger J, Collins RD, Horn RG, Koenig MG
(1969) Nature 222: 276-8
MeSH Terms: Animals, Cytoplasmic Granules, Glucuronidase, Glycoside Hydrolases, Leukocytes, Lysosomes, Membranes, Artificial, Microscopy, Electron, Phagocytosis, Phospholipids, Rabbits, Stimulation, Chemical
Added December 10, 2013
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12 MeSH Terms
Activation of lysosomal enzymes in polymorphonuclear leukocytic granules: the role of phospholipid-protein interaction.
Hawiger J, Hawiger A, Koenig MG
(1972) Yale J Biol Med 45: 42-8
MeSH Terms: Acid Phosphatase, Animals, Cell-Free System, Cytoplasmic Granules, Electrophoresis, Disc, Enzyme Activation, Glucuronidase, Hexosaminidases, Leukocytes, Lysosomes, Membranes, Artificial, Models, Biological, Muramidase, Peroxidases, Phospholipids, Phosphorus, Protein Binding, Proteins, Rabbits
Added December 10, 2013
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19 MeSH Terms
Dynamic changes in the membrane of leukocyte lysosomes detected with fluorescent probe and accompanied by release of lysosomal enzymes.
Hawiger J, Timmons S
(1973) Biochem Biophys Res Commun 55: 1278-84
MeSH Terms: Anilino Naphthalenesulfonates, Animals, Glucuronidase, Hexosaminidases, Hydrogen-Ion Concentration, Leukocytes, Lysosomes, Membranes, Rabbits, Spectrometry, Fluorescence
Added December 10, 2013
0 Communities
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10 MeSH Terms
Activation and release of lysosomal enzymes from isolated leukocytic granules by liposomes. A proposed model for degranulation in polymorphonuclear leukocytes.
Hawiger J, Horn RG, Koenig MG, Collins RD
(1969) Yale J Biol Med 42: 57-70
MeSH Terms: Animals, Cattle, Cell-Free System, Centrifugation, Cytoplasmic Granules, Enzyme Activation, Fluorides, Glucuronates, Glucuronidase, Glycoside Hydrolases, Histocytochemistry, Hydrogen-Ion Concentration, Leukocytes, Lysosomes, Membranes, Membranes, Artificial, Microscopy, Electron, Phagocytosis, Phosphatidylcholines, Phosphatidylethanolamines, Phosphatidylinositols, Phospholipids, Protamines, Serum Albumin, Solubility, Vibration
Added December 10, 2013
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26 MeSH Terms
Release of prostaglandin D2 into human airways during acute antigen challenge.
Murray JJ, Tonnel AB, Brash AR, Roberts LJ, Gosset P, Workman R, Capron A, Oates JA
(1986) N Engl J Med 315: 800-4
MeSH Terms: Antigens, Asthma, Bronchi, Bronchial Provocation Tests, Gas Chromatography-Mass Spectrometry, Glucuronidase, Humans, Hydroxyeicosatetraenoic Acids, Male, Mites, Prostaglandin D2, Prostaglandins D, Pulmonary Alveoli, Therapeutic Irrigation
Show Abstract · Added December 10, 2013
Among the many possible mediators of the early asthmatic response, prostaglandin D2, a bronchoconstrictor, is the principal cyclooxygenase metabolite of arachidonic acid that is released upon the activation of mast cells and is also synthesized by human alveolar macrophages. We performed bronchoalveolar lavage in five patients with chronic stable asthma, before and up to nine minutes after local provocative challenge with Dermatophagoides pteronyssinus. The lavage fluid was analyzed for products of arachidonic acid metabolism. Prostaglandin D2 levels in all five patients rose an average of 150-fold, from less than 8 to 332 +/- 114 pg per milliliter (mean +/- SEM; P less than 0.050), after local instillation of the antigen. Levels of 15-hydroxyeicosatetraenoic acid, which may also have a role in the pulmonary allergic response, were detectable in lavage fluid before challenge and increased after provocation with the antigen in four of the five patients. The activity of beta-glucuronidase, an enzyme released by macrophages and mast cells upon stimulation, tended to increase in the lavage fluid after provocation in all patients. These studies provide evidence that the release of prostaglandin D2 into the airways is an early event after the instillation of D. pteronyssinus in patients who are sensitive to this antigen.
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14 MeSH Terms