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PubMed1994

Swine testis cells contain functional heparan sulfate but are defective in entry of herpes simplex virus.

Herpes simplex virus (HSV) enters and infects most cultured cells. We have found that swine testis cells (ST) produce yields of infectious HSV-1 up to four orders of magnitude lower than those of human embryonic lung (HEL) and HEp-2 cells because of a defect in virus entry. For ST cells, virus binding is reduced, DNA from input virus cannot be detected, and virus proteins are not synthesized. Polyethylene glycol treatment of ST cells after exposure to HSV allows viral entry, protein synthesis, and productive infection. Transfection of viral genomic DNA that bypasses the normal entry process produces similar yields of infectious virus from ST, HEL, and HEp-2 cells. Therefore, all three cell lines can support the HSV replicative cycle. Biochemical analyses and inhibition of sulfation by sodium chlorate treatment show that ST cells contain amounts and types of heparan sulfate (HS) similar to those of highly susceptible cells. HSV infection of sodium chlorate-treated HEL and ST cells indicates the presence of a second, non-HS receptor(s) on susceptible HEp-2 and HEL cells that is missing, or not functional, on poorly susceptible ST cells. We conclude that ST cells are defective in HSV entry, contain functional HS, but lack a functional non-HS receptor(s) required for efficient HSV-1 entry. Further, ST cells provide a novel resource that can be used to identify, isolate, and characterize an HSV non-HS receptor(s) and its role in the entry and tropism of this important human pathogen.

Animals↗
PubMed2005

A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells.

BACKGROUND: Connective tissue growth factor (CCN2) is upregulated in pancreatic fibrosis and desmoplastic pancreatic tumours. CCN2 interacts with integrin alpha5beta1 on pancreatic stellate cells (PSC) in which it stimulates fibrogenesis, adhesion, migration, and proliferation. AIM: To determine the structural domain(s) in CCN2 that interact with integrin alpha5beta1 to regulation PSC functions. METHODS: Primary activated rat PSC were tested for their adherence to isoforms of CCN2 comprising modules 1-4 (CCN2(1-4)), modules 3-4 (CCN2(3-4)), module 3 alone (CCN2(3)), or module 4 alone (CCN2(4)). Adhesion studies were performed in the presence of EDTA, divalent cations, anti-integrin alpha5beta1 antibodies, CCN2 synthetic peptides, or heparin, or after pretreatment of the cells with heparinase, chondroitinase, or sodium chlorate. CCN2 integrin alpha5beta1 binding was analysed in cell free systems. The ability of CCN2(1-4), CCN2(3-4), or CCN2(4) to stimulate PSC migration was evaluated in the presence of anti-integrin alpha5beta1 or heparin. RESULTS: PSC adhesion was stimulated by CCN2(1-4), CCN2(3-4), or CCN2(4) and supported by Mg2+ but not Ca2+. CCN2(4) supported PSC adhesion or migration were blocked by anti-integrin alpha5beta1 antibodies or by treatment of cells with heparinase or sodium chlorate. A direct interaction between CCN2(4) and integrin alpha5beta1 was demonstrated in cell free assays. The sequence GVCTDGR in module 4 mediated the binding between CCN2(4) and integrin alpha5beta1 as well as CCN2(4) mediated PSC adhesion and migration. CONCLUSIONS: A GVCTDGR sequence in module 4 of CCN2 is a novel integrin alpha5beta1 binding site that is essential for CCN2 stimulated functions in PSC and which represents a new therapeutic target in PSC mediated fibrogenesis.

Animals↗
PubMed2002

ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression.

Transcription of specific skeletal muscle genes requires the expression of the muscle regulatory factor myogenin. To assess the role of the extracellular matrix (ECM) in skeletal muscle differentiation, the specific inhibitors of proteoglycan synthesis, sodium chlorate and beta-D-xyloside, were used. Treatment of cultured skeletal muscle cells with each inhibitor substantially abolished the expression of creatine kinase and alpha-dystroglycan. This inhibition was totally reversed by the addition of exogenous ECM. Myoblast treatment with each inhibitor affected the deposition and assembly of the ECM constituents glypican, fibronectin, and laminin. These treatments did not affect MyoD, MEF2A, and myogenin expression and nuclear localization. Differentiated myoblast treatment with RGDS peptides completely inhibited myogenesis without affecting the expression or nuclear localization of myogenin. Integrin-mediated signaling of focal adhesion kinase was partially inhibited by chlorate and beta-D-xyloside, an effect reversed by the addition of exogenous ECM gel. These results suggested that the expression of myogenin is not sufficient to successfully drive skeletal muscle formation and that ECM is required to complete the skeletal muscle differentiation process.

Animals↗
PubMed1982

Metabolism and pharmacokinetics of alternate drinking water disinfectants.

The chlorination of surface waters is known to elevate trihalomethanes; consequently, chlorine dioxide (ClO2) is being considered as an alternative disinfectant. The primary products resulting from ClO2 disinfection of waters are chlorites (ClO2-) and chlorates (ClO3-). Studies in rats revealed that ClO2 is converted to chloride (Cl-), ClO2- and ClO3-. ClO2- and ClO3- are excreted as Cl-, ClO2- and Cl-, ClO2-, ClO3-, respectively. Radioactivity was rapidly absorbed from the gastrointestinal tract following the administration of 36ClO2 orally, and the half-life for the elimination of 36Cl from the rat was 44 hr, corresponding to a rate constant of 0.016/hr. After 72 hr, radioactivity was highest in plasma, followed by kidney, lung, and stomach. 36Cl in plasma reached a peak at 2 hr and 1 hr after oral administration of 36ClO2- and 36ClO3-, respectively. 36Cl excretion was greatest 24 hr after the administration of 36ClO3-, but in the case of 36ClO2-, the excretion probably represented saturation of the biotransformation and excretion pathway. A low activity in packed cells compared to plasma was detected in chlorate ingestion, rather than an even distribution in chlorite treatment. Chloroform determinations in rat blood after one year indicated that chloroform was significantly higher than control in the 100 and 1000 mg/l. ClO2 groups. However, no significant values were observed in the 1 or 10 mg/l. ClO2 and ClO2 metabolites groups. ClO2 and its metabolites are eliminated from the body more rapidly than chlorine, and they do not appear to increase trihalomethane concentrations at low dosages.

Animals↗
PubMed2006

Reduction of Campylobacter jejuni on chicken wings by chemical treatments.

Eight chemicals, including glycerol monolaurate, hydrogen peroxide, acetic acid, lactic acid, sodium benzoate, sodium chlorate, sodium carbonate, and sodium hydroxide, were tested individually or in combination for their ability to inactivate Campylobacter jejuni at 4 degrees C in suspension. Results showed that treatment for up to 20 min with 0.01% glycerol monolaurate, 0.1% sodium benzoate, 50 or 100 mM sodium chlorate, or 1% lactic acid did not substantially (< or = 0.5 log CFU/ml) reduce C. jejuni populations but that 0.1 and 0.2% hydrogen peroxide for 20 min reduced C. jejuni populations by ca. 2.0 and 4.5 log CFU/ml, respectively. By contrast, treatments with 0.5, 1.0, 1.5, and 2.0% acetic acid, 25, 50, and 100 mM sodium carbonate, and 0.05 and 0.1 N sodium hydroxide reduced C. jejuni populations by >5 log CFU/ml within 2 min. A combination of 0.5% acetic acid plus 0.05% potassium sorbate or 0.5% acetic acid plus 0.05% sodium benzoate reduced C. jejuni populations by >5 log CFU/ml within 1 min; however, substituting 0.5% lactic acid for 0.5% acetic acid was not effective, with a reduction of C. jejuni of <0.5 log CFU/ml. A combination of acidic calcium sulfate, lactic acid, ethanol, sodium dodecyl sulfate, and polypropylene glycol (ACS-LA) also reduced C. jejuni in suspension by >5 log CFU/ml within 1 min. All chemicals or chemical combinations for which there was a >5-log/ml reduction of C. jejuni in suspension were further evaluated for C. jejuni inactivation on chicken wings. Treatments at 4 degrees C of 2% acetic acid, 100 mM sodium carbonate, or 0.1 N sodium hydroxide for up to 45 s reduced C. jejuni populations by ca. 1.4, 1.6, or 3.5 log CFU/g, respectively. Treatment with ACS-LA at 4 degrees C for 15 s reduced C. jejuni by >5 log CFU/g to an undetectable level. The ACS-LA treatment was highly effective in chilled water at killing C. jejuni on chicken and, if recycled, may be a useful treatment in chill water tanks for poultry processors to reduce campylobacters on poultry skin after slaughter.

Animals↗
PubMed2000

[Hand injuries caused by self-made bombs. Observations and reconstructoin techniques. Report of 7 cases].

The authors report on their experience of sodium chlorate bomb injuries of the hand observed in seven boys. The thumb was damaged in all cases. This digit was amputated in five cases, was totally saved in one case and partially saved in another case. In four cases, the preservation of damaged tissues in the emergency procedure allowed a secondary reconstruction of the thumb, thus making it possible to achieve a prehensile and sensitive hand. In these former four cases, a posterior interosseous flap was performed to ensure the primary or secondary skin coverage. In two cases, the major lesions necessitated an amputation at the radiocarpal level. In one of these two cases, coverage of the amputated stump by a free gracilis muscle flap made it possible to minimize the level of amputation and to wear a functional prosthesis. Sodium chlorate bombs are made with an unstable chemical mixture. These reactives provoke high-energy injuries with a short range of dispersion. The damages depend on the prehensile mode, which explains why the thumb and the index finger are always injured. These blast injuries were limited to the hand and the skin coverage could be done with a distally based posterior interosseous flap. In spite of the impressive lesions observed in such young patients, a conservative attitude could be taken in an emergency situation with the aim to perform further reconstructive procedures.

Adolescent↗
PubMed1992

Cell-associated proteoheparan sulfate mediates binding and uptake of thrombospondin in cultured porcine vascular endothelial cells.

[125I]Thrombospondin (TSP) binds to porcine endothelial cells in a specific, saturable and time-dependent fashion and is endocytosed by a receptor-mediated process. The N-terminal heparin-binding domain is necessary for the interaction with the cell surface. Binding and uptake is inhibited by heparin and to a much smaller extent by other vascular glycosaminoglycans. Chemical modification of lysine and arginine residues of TSP, but not treatment of the molecule with neuraminidase, resulted in a pronounced loss of binding at the cell surface. Treatment of cells with heparitinase but not with chondroitin ABC lyase caused inhibition of binding and uptake of TSP. Inhibition of sulfation of proteoglycans on the cell surface by chlorate leads to a dose and time-dependent inhibition of binding and degradation of TSP. In the presence of chlorate, newly synthesized TSP is not incorporated into the cell matrix but mainly released into the culture medium, whereas localization and incorporation of newly synthesized fibronectin is not altered. A cell surface proteoheparan sulfate was identified as TSP binding macromolecule by affinity chromatography. The data emphasize the role of heparan sulfate proteoglycan as a receptor-like molecule for the specific interaction with thrombospondin.

Animals↗
PubMed2004

Hydrogen-based, hollow-fiber membrane biofilm reactor for reduction of perchlorate and other oxidized contaminants.

Many oxidized pollutants, such as nitrate, perchlorate, bromate, and chlorinated solvents, can be microbially reduced to less toxic or less soluble forms. For drinking water treatment, an electron donor must be added. Hydrogen is an ideal electron donor, as it is non-toxic, inexpensive, and sparsely soluble. We tested a hydrogen-based, hollow-fiber membrane biofilm reactor (MBfR) for reduction of perchlorate, bromate, chlorate, chlorite, chromate, selenate, selenite, and dichloromethane. The influent included 5 mg/L nitrate or 8 mg/L oxygen as a primary electron accepting substrate, plus 1 mg/L of the contaminant. The mixed-culture reactor was operated at a pH of 7 and with a 25 minute hydraulic detention time. High recirculation rates provided completely mixed conditions. The objective was to screen for the reduction of each contaminant. The tests were short-term, without allowing time for the reactor to adapt to the contaminants. Nitrate and oxygen were reduced by over 99 percent for all tests. Removals for the contaminants ranged from a minimum of 29% for chlorate to over 95% for bromate. Results show that the tested contaminants can be removed as secondary substrates in an MBfR, and that the MBfR may be suitable for treating these and other oxidized contaminants in drinking water.

Biofilms↗
PubMed1991

Coupling of N-deacetylation and N-sulfation in a Chinese hamster ovary cell mutant defective in heparan sulfate N-sulfotransferase.

The coordination of N-deacetylation and N-sulfation of heparan sulfate was examined in wild-type Chinese hamster ovary cells and mutant pgsE-606. This mutant expresses about 3-fold less N-sulfotransferase activity, which causes the proportion of N-sulfated GlcN residues in heparan sulfate to decline from 39 to 21% of total GlcN (Bame, K.J., and Esko, J.D. (1989) J. Biol. Chem. 264, 8059-8065). In this report, we show that microsomes from pgsE-606 cells have about twice the N-deacetylase activity found in microsomes from wild-type cells. However, N-deacetylation in vivo was actually depressed since heparan sulfate preparations from the mutant contained very few unsubstituted GlcN residues and 2-fold less N-sulfated GlcN residues. Treatment of mutant cells with chlorate, a general inhibitor of sulfation, depressed adenosine 3'-phosphate-5'-phosphosulfate pools more than 10-fold and further reduced the extent of N-sulfation from 21% to less than 6% of total GlcN. Unsubstituted GlcN residues accumulated under these conditions to the extent that N-sulfated residues declined. Thus, N-deacetylation remained depressed in the mutant in the presence of chlorate. These findings show that N-deacetylation is regulated in vivo and support the idea that the activity of N-deacetylase may be linked to N-sulfotransferase.

Acetylation↗
PubMedDate not supplied

[Potable water in Local Health Area 12 from 1980 to 1987].

This research work deals with the problem of the pollution of both public and industrial water supplies in a local health authority area (U.S.S.L.) in Lombardy. This is an area of approximately 120 square kilometres which, for the most part, does not as yet have a public sewage system purification plant. As a result, almost all effluent enters the local watercourses which have developed physico-chemical characteristics similar to those of sewage, thus creating very serious health risks for the inhabitants of the area. Our study deals especially with the hydrological characteristics of the area which possesses two water-tables, one above the other. The lower of these two water-tables has a particularly large supply in the source areas of the rivers. Following this our study presents data concerning the wells in the area, their position, methods of excavation, depth, stratigraphy and capacity of water-supply. Since 1980, all wells have had regular four-monthly or six-monthly microbiological and chemical tests. Special attention has been paid to the levels of ammonia, nitric and nitrous acid, pH, sulphates, electrical conductivity, chlorides, chromium and chlorate solvents. During 1986-87, one investigation was carried out on the presence of Cu, Pb, Ni, F, Cd, Al, hydrocarbons and tensioactive substances. The main pollutants were discovered to be chlorohydrocarbons and nitrates. The chlorohydrocarbons come from textile factories and metallurgical and mechanical industries which discharge these substances into the drainage system either as the result of accidents of because or inadequate depuration. The source of the nitrates is, for the most part, domestic although a small proportion is also due to agriculture. As a result of the discovery of this pollution of the water-tables, a programme of preventive checks has been introduced for all the industries which use chlorate solvents. The purpose of these checks is to identify the methods of use and of disposal of these substances. A more satisfactory discharge of industrial effluent has been achieved by at least some of the firms in the area with a consequent reduction both in illegal discharge and in pollution of the water-tables.

Industrial Waste↗
PubMed1996

Undersulfation of glycosaminoglycans reduces the proliferation of a leukemia cell line in vitro.

Leukemia represents the clonal expansion of an individual cell lineage of the hematopoietic system at a specific point of its maturation and development. This dysregulated expansion of cells is often accompanied by altered adherence to the bone marrow microenvironment and abnormalities in endogenous cytokine production by neoplastic cells. Proteoglycans (PGs) synthesized by neoplastic cells may interact with extracellular matrix (ECM) molecules and/or locally produced cytokines. It is believed that these events may be mediated by the glycosaminoglycan (GAG) moiety of PGs such as heparan or chondroitin sulfate, and depends on its charge. The strength of GAG-cytokine binding may be determined by the extent of sulfation of the GAG chains. The synthesis, metabolism and biological role of PGs in hematopoietic malignancies have not been clearly defined. In order to study how alterations of GAGs in leukemic cells may alter cellular behavior, we treated the murine myeloid leukemic cell line WeHi-3B with sodium chlorate. This drug reduces the sulfation of GAGs, since chlorate is a potent inhibitor of sulfate adenylyltransferase. The undersulfated GAGs produced by WeHi-3B cells were not efficient in controlling the mitotic rate of the cells, since a decrease in cell proliferation was observed in vitro. These data suggest that the complexes formed by GAGs with ECM components and/or cytokines may have an important role in the induction of leukemic cell proliferation. It is possible that the stimulatory activity elicited by this binding may be dependent upon the organization of these complexes.

Extracellular Matrix↗
PubMed1997

Is the sensitivity of cells for FGF-1 and FGF-2 regulated by cell surface heparan sulfate proteoglycans?

We have examined the importance of cell surface heparan sulfate proteoglycans (HSPG) in fibroblast growth factor (FGF) signaling. 3T3 cells grown under conventional conditions were much more sensitive to FGF-2 compared to FGF-1. However, cells were equally sensitive to FGF-1 and FGF-2 using conditions which reduced the effect of endogenous HSPG. Addition of heparin, or treatment with chlorate, an inhibitor of proteoglycan sulfation, resulted in enhanced or reduced growth factor response, respectively, and eliminated the differences between FGF-1 and FGF-2. HSPGs isolated from trypsin digests of 3T3 cells had a much higher affinity for FGF-2 compared to that for FGF-1 when analyzed by affinity chromatography. Glycosaminoglycan chains or core protein fragments derived from the HSPG failed to show the same high apparent affinity for FGF-2, suggesting that an intact proteoglycan structure was important for the high FGF-2 affinity. Addition of HSPG ectodomains, isolated from cultured 3T3 cells or produced as recombinant molecules, to chlorate-treated cultures of 3T3 cells inhibited the mitogenic activity of FGF-2 and eliminated the effect of heparin as a potentiator of either growth factor. These results support the idea that the cell-associated HSPG is an integral component of the FGF signaling system and in 3T3 cells contributes to the increased sensitivity of these cells to FGF-2 compared to FGF-1. Since isolated ectodomains of HSPG inhibited rather than stimulated the mitogenic response of the FGFs, the proper anchoring of the HSPG in the cell membrane appears to be important for a stimulatory effect.

3T3 Cells↗
PubMed1997

Effect of sodium chloride, chlorite, and perchlorate on the hypochlorite-induced peroxidation of phospholipid liposomes.

The abilities of sodium hypochlorite (NaClO), chlorite (NaClO2), chlorate (NaClO3), and perchlorate (NaClO4) to initiate lipid peroxidation (LP) in liposomes formed from unsaturated phosphatidylcholine were compared. It was shown that only NaClO induced an intensive accumulation of LP products (thiobarbituric acid-reactive substances and diene conjugates) in the liposomes as a result of their co-incubation. The other oxochlorates produced no similar effects and did not affect the hypochlorite-induced LP. This indicates that the observed hypochlorite-induced LP does not result from the presence of chlorite, chlorate, or perchlorate anion admixtures in the medium.

Animals↗
PubMed1998

Evidence for sulfate modification of H-2Dd on N-linked carbohydrate(s): possible involvement in Ly-49A interaction.

Murine class I molecules are ligands for Ly-49 molecules, a family of regulatory receptors expressed on murine NK cells. Since soluble sulfated mono- and polysaccharides interfere with the interaction of Ly-49A, a C-type lectin, and its class I ligand, Dd, it is possible that the oligosaccharides on class I molecules are sulfated and participate in Ly-49A binding. In this report, we show that H-2Dd expressed by activated T cells and various tumor cell lines is sulfated, as demonstrated by immunoprecipitation of Dd following Na235SO4 labeling. The 35SO4(-2) label on Dd expressed by a representative tumor cell, NZB1.1, is removed by peptide N-glycosidase F, but is resistant to endoglycosidase H treatment, indicating that the sulfate group is located on mature N-linked oligosaccharides. Two-dimensional SDS-PAGE analysis revealed that all major mature glycosylation variants of the Dd expressed by NZB1.1 are sulfated. Sodium chlorate, a potent inhibitor of ATP-sulfurylase, which prevents the formation of the sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate, inhibited metabolic sulfation of Dd. NZB1.1 binds isolated Ly-49A immobilized on solid phase through an interaction by cell surface Dd, since cell adhesion was blocked by Abs directed against Dd or Ly-49A. Treatment of the Dd-expressing NZB1.1 tumor cells with sodium chlorate reduced their ability to bind immobilized Ly-49A, particularly when Ly-49A density was limiting. These results provide evidence for sulfation of H-2Dd oligosaccharide moieties, and suggest a role for this posttranslational modification in the interaction of Dd with Ly-49A.

Animals↗
PubMed1996

Evidence that fibroblast growth factors 1 and 4 participate in regulation of cardiogenesis.

Previous studies in this laboratory have indicated that the early embryonic chick heart depends on fibroblast growth factor-2 (FGF-2; bFGF), sequentially utilized in paracrine and autocrine fashion, for its growth and development (Sugi and Lough, [1995] Dev. Biol. 168-567-574). This view emanated from immunohistochemical detection of FGF-like antigens in endoderm cells at stage 6, and later in the early myocardium at stage 9+ (Parlow et al. [1991] Dev. Biol. 146:139-147). To identify other members of the FGF family that are expressed by these cells, we have used peptide-generated antisera that specifically recognize FGFs 1 and 4. Like FGF-2, FGFs 1 and 4 were exclusively detected in the endoderm at stage 5+ and later in the myocardium, appearing as punctate cytoplasmic deposits. However, whereas FGF-2 is first detected at stage 9+, FGFs 1 and 4 did not appear until stages 11 and 15, respectively. Expression of all FGFs peaked at stages 18-24, decreasing thereafter in parallel with reduced myocardial cell proliferation. To determine these isoproteins' ability to facilitate the completion of terminal cardiac myocyte differentiation, stage 5+ precardiac mesoderm was cultured in defined medium with purified FGFs. Like FGF-2, as little as 5-10 ng/ml FGF-1 or FGF-4 supported the proliferation and differentiation of precardiac myoblasts, resulting in the formation of a vesicle containing an adherent multilayer of synchronously contractile cells. Evidence that this represented FGF receptor-mediated signaling rather than a nonspecific effect of exogenous FGF was indicated by the ability of sodium chlorate to inhibit FGF-mediated cardiogenesis. These findings are consistent with the hypothesis that, like FGF-2, FGFs 1 and 4 participate in the regulation of early heart development via paracrine and autocrine mechanisms.

Animals↗
PubMedDate not supplied

Evaluation of chlorinated by-products in drinking waters of Central Friuli (Italy).

Drinkable water supplied by aqueducts undergoes preliminar potabilization which, in Italy, is mainly accomplished by chlorine addition. The bactericidal action involved in this process is always accompanied by chlorination and oxidation of organic species (mainly humic and fulvic acids) naturally present in treated waters, so that many disinfection by-products (DBPs) are formed, such as trihalomethanes (THMs) and halo-acetic acids (HAA), which can represent a chemical risk for public health. The aim of this study was the monitoring of DBPs in drinking water disinfected by chlorination, supplied by four different aqueducts of Central Friuli (Italy). DBP evaluations were performed in water samples consisting of both input and output of disinfection plants. The results of analytical determinations were worked out to provide the THM and HAA parameters for disinfected waters, while in feeding waters the following different conventional parameters were adopted: (i) trihalomethanes formation potential (THMFP), (ii) halo-acetic acids formation potential (HAAFP) and (iii) UV absorbance at 254 nm (UV254). The quite moderate content of chlorinated products found in all samples considered highlighted the excellent quality of potabilized waters available in Central Friuli. Moreover, our results confirmed that the majority of DBPs formed when chlorine is used for water disinfection consists of THMs, while chlorites and chlorates prevailed when potabilization is accomplished by using chlorine dioxide. Finally, simple UV254 monitoring turned out to be a profitable approach for the determination of chlorinated by-products only when THMs prevail among DBPs.

Chlorates↗
PubMed2003

Localisation of specific heparan sulfate proteoglycans during the proliferative phase of brain development.

Early brain development is characterised by the proliferation of neural precursor cells. Several families of signalling molecules such as the fibroblast growth factors (FGFs) and Wnts are known to play important roles in this early phase of brain development. Accumulating evidence demonstrates that signalling of these molecules requires the presence of heparan sulfate chains attached to a proteoglycan core protein (HSPG). However, the specific identity of the HSPG components in the developing brain is unknown. To determine which HSPGs might be involved at this early phase, we analysed the expression of the major cell surface HSPG families in the developing brain at a time of most active proliferation. Syndecan-1 and glypican-4 were the most highly expressed in the developing brain during the time of peak proliferation and localise to ventricular regions of the brain, where the precursor cells are proliferating. Syndecan-4, although less abundant, also localises to cells in the ventricular zone. We have also examined HSPG involvement in brain development using cultures of embryonic neural precursor cells. We find that FGF2 stimulation of proliferation is inhibited in the presence of sodium chlorate, an inhibitor of heparan sulfate synthesis, and is rescued by addition of exogenous heparan sulfate. These data support a requirement for heparan sulfate in FGF signalling for proliferation of brain precursor cells. The expression of these specific HSPGs within the proliferative zone of the brain suggests that they may be involved in regulation of early brain development, such as FGF-stimulated proliferation.

Animals↗
PubMed2003

Proteoglycans are potent modulators of the biological responses of eosinophils to chemokines.

Chemokines play critical roles in governing the recruitment and activation of eosinophils at sites of allergic inflammation, particularly the asthmatic lung. However, we know little of how chemokine function is regulated post-translationally. Proteoglycans, consisting of a core protein and glycosaminoglycan (GAG) side chains, are cell surface molecules and components of the extracellular matrix that are able to bind chemokines, whilst heparin is a GAG with therapeutic value in asthma. We examined whether soluble GAG could alter the actions of chemokines in assays of eosinophil activation. Heparin inhibited intracellular calcium flux, respiratory burst and chemotactic responses of eosinophils to CCL11, but not to the chemoattractant C5a, and inhibited binding of CCL11 to CCR3. Heparin also inhibited eosinophil stimulation by CCL11, CCL24, CCL7, CCL13 and CCL5 to differing degrees, which broadly correlated with their relative affinities for heparin. Heparan sulfate and dermatan sulfate, but not chondroitin sulfate, also inhibited the actions of CCL11 and CCL13 in assays of cellular shape change and chemotaxis. Following treatment with the sulfation inhibitor chlorate or proteoglycanases, no inhibition of CCL11-induced activity was observed using either eosinophils or a CCR3-expressing transfectant cell line. This suggests that cell surface proteoglycans are not necessary for signaling via CCR3. However, the GAG context in which chemokines are expressed is likely to represent an important level of regulation of allergic inflammation.

Calcium↗