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Guilhem Frescaline,
Thibault Bouderlique,
Leyya Mansoor,
Gilles Carpentier,
Brigitte Baroukh,
Fernando Sineriz,
Marina Trouillas,
Jean-Louis Saffar,
José Courty,
Jean-Jacques Lataillade, Dulce Papy-Garcia,
Albanese Patricia
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ABSTRACT: Tissue engineering approaches to stimulate bone formation currently combines bioactive scaffolds with osteocompetent human mesenchymal stem cells (hMSC). Moreover, osteogenic and angiogenic factors are required to promote differentiation and survival of hMSC through improved vascularization through the damaged extracellular matrix (ECM). Glycosaminoglycans (GAG) are ECM compounds acting as modulators of Heparin Binding Proteins (HBP) activities during bone development and regenerative processes. GAG mimetics have been proposed as ECM stabilizers and were previously described for their positive effects on bone formation and angiogenesis after local treatment. Here, we developed a strategy associating the GAG mimetic [OTR4120] with bone substitutes to optimize stem cell-based therapeutic products. We showed that [OTR4120] was able to potentiate proliferation, migration and osteogenic differentiation of hMSC in vitro. Its link to Tricalcic/Hydroxyapatite (TCP/HA) scaffolds improved their colonization by hMSC. Surprisingly, when these combinations were tested in an ectopic model of bone formation in immunodeficient mice, the GAG mimetic inhibit bone formation induced by hMSC and promoted an osteoclastic activity. Moreover the inflammatory response was modulated and the peri-implant vascularization stimulated. All together, these findings further support the ability of GAG mimetics to organize the local ECM to coordinate the host response toward the implanted biomaterial, and to inhibit abnormal bone formation process on subcutaneous ectopic site.
Tissue Engineering Part A 03/2013; · 4.64 Impact Factor
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ABSTRACT: During the neurodegenerative process in several brain diseases, oxidative stress is known to play important roles in disease severity and evolution. Although early events of stress, such as increased lipid peroxidation and decreased superoxide dismutase, are known to characterize early onsets of these diseases, little is known about the events that participate in maintaining the chronic evolving phase influencing the disease progression in neurons. Here, we used differentiated PC12 cells to identify premitochondrial and postmitochondrial events occurring during the oxidative stress cascade leading to apoptosis. Our data indicate that an acute and strong oxidative impulse (500 μM H(2) O(2) , 30 min) can induce, in this model, a 24-hr self-evolving stress, which advances from a premitochondrial phase characterized by lysosomes and cathepsin B and D translocations to cytosol and early mitochondrial membrane hyperpolarization. This phase lasts for about 5 hr and is followed by a postmitochondrial phase distinguished by mitochondrial membrane depolarization, reactive oxygen species increase, caspase-9 and caspase-3 activations, and apoptosis. Inhibition of cathepsins B and D suggests that cells can be protected at the premitochondrial phase of stress evolution and that new cathepsins regulators, such as glycosaminoglycans mimetics, can be considered as new therapeutic prototypes for neurodegeneration. Insofar as early oxidative stress markers have been related to the early onset of neurodegeneration, strategies protecting cells at the premitochondrial phase of oxidative stress may have important therapeutic applications. © 2012 Wiley Periodicals, Inc.
Journal of Neuroscience Research 11/2012; · 2.74 Impact Factor
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ABSTRACT: Iinteractions of biologically active proteins with sulfated glycans, particularly heparan sulfates (HS), are dependent on factors involving amounts and positions of the sulfate groups in the sugars chains. Although the importance of knowing the exact positions of the sulfate groups in particular HS sequences is well recognized, at present, approaches in this area are complex and still considered as a challenge. Here, we investigated the applicability of the 'Molecular Imprinting Technology' for the generation of imprinted polymers able to specifically recognize a model HS-like disaccharide. In order to advance on the applicability of this technology to the recognition of these complex sugars, we prepared a library of imprinted polymers to investigate the impact of the polymerization reaction conditions and stoichiometry on the generation of binding sites able to specifically recognize the model sulfated sugar. Our results show that imprinted polymers able to specifically bind HS-like saccharide can readily be obtained. This constitutes a suitable option for developing novel strategies directed to study fine sulfated sugars structures.
Talanta 09/2012; 99:833-9. · 3.79 Impact Factor
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Journal of Neuroscience Research 08/2012; · 2.74 Impact Factor
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ABSTRACT: Pleiotrophin, also known as heparin affin regulatory peptide (HARP), is a growth factor expressed in various tissues and cell lines. In this work, HARP was tested for its capacity to modulate the anticoagulant activity of heparin and heparan sulphate mimetics (OTR4120). We used both in vitro and in vivo assays. HARP was found to be differently effective for neutralization of the anticoagulant activity of the mimetic heparan sulphate (OTR4120) and heparin in purified system and human plasma. HARP was shown to compete with both antithrombin and thrombin for binding to heparin and to OTR4120, respectively. In the presence of OTR4120, the V(max) was constant and the calculated maximum velocity was 1.56 U/min; the thrombin Km value (0.011 nM) was affected by HARP concentrations. The Km (HARP) value was 0.085 nM, which is consistent with high affinity of HARP to OTR4120. Under the same conditions, initial velocity patterns for antithrombin-heparin were determined in the presence or in the absence of HARP. The antithrombin value Km (0.022 nM) was affected by HARP (0.077 nM). HARP exhibits efficacy equivalent to or greater than protamine. Interestingly, intraperitoneally administered HARP decreased the anticoagulant activity of heparin and of OTR4120 in mice. Taken together, these data provide the first evidence for a physiological role of HARP in the modulation of anticoagulant activity of heparin and heparin-like material.
Basic & Clinical Pharmacology & Toxicology 06/2012; 111(5):296-302. · 2.18 Impact Factor
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ABSTRACT: Successful use of stem cell-based therapeutic products is conditioned by transplantation of optimized cells in permissive microenvironment. Mesenchymal stem cell (MSC) fates are tightly regulated by humoral factors, cellular interactions and extracellular matrix (ECM) components, such as glycosaminoglycans (GAG), which are complex polysaccharides with structural heterogeneity. During osteogenesis, a temporally controlled expression of particular GAG species is required to interact with specific growth promoting and differentiating factors to regulate their biological activities. As a comparative tool to study natural GAG, we used structurally and functionally related synthetic GAG mimetics. One of these compounds [OTR(4120)] was previously shown to stimulate bone repair in rat models. Here, we demonstrate that structurally distinct GAG mimetics stimulate differentially clonogenicity, proliferation, migration and osteogenic phenotype of MSC in vitro, according to their specific chemical signature, underlying the role of sulfate and acetyl groups in specific interactions with heparin binding factors (HBF). These effects are dependent on FGF-2 interactions since they are inhibited by a FGF receptor 1 signaling pathway blocker. These data suggest that the in vivo [OTR(4120)] bone regenerative effect could be due to its ability to induce MSC migration and osteogenic differentiation. To conclude, we provide evidences showing that GAG mimetics may have great interest for bone regeneration therapy and represent an alternative to exogenous growth factor treatments to optimize potential therapeutic properties of MSC.
Stem cell research 03/2012; 8(2):180-92. · 3.39 Impact Factor
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ABSTRACT: Glycosaminoglycans (GAGs) are essential components of the extracellular matrix, the natural environment from which cell behavior is regulated by a number or tissue homeostasis guarantors including growth factors. Because most heparin-binding growth factor activities are regulated by GAGs, structural and functional alterations of these polysaccharides may consequently affect the integrity of tissues during critical physiological and pathological processes. Here, we investigated whether the aging process can induce changes in the myocardial GAG composition in rats and whether these changes can affect the activities of particular heparin-binding growth factors known to sustain cardiac tissue integrity. Our results showed an age-dependent increase of GAG levels in the left ventricle. Biochemical and immunohistological studies pointed out heparan sulfates (HS) as the GAG species that increased with age. ELISA-based competition assays showed altered capacities of the aged myocardial GAGs to bind FGF-1, FGF-2, and VEGF but not HB EGF. Mitogenic assays in cultured cells showed an age-dependent decrease of the elderly GAG capacities to potentiate FGF-2 whereas the potentiating effect on VEGF(165) was increased, as confirmed by augmented angiogenic cell proliferation in Matrigel plugs. Moreover, HS disaccharide analysis showed considerably altered 6-O-sulfation with modest changes in N- and 2-O-sulfations. Together, these findings suggest a physiological significance of HS structural and functional alterations during aging. This can be associated with an age-dependent decline of the extracellular matrix capacity to efficiently modulate not only the activity of resident or therapeutic growth factors but also the homing of resident or therapeutic cells.
Journal of Biological Chemistry 02/2012; 287(14):11363-73. · 4.77 Impact Factor
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ABSTRACT: Lewy bodies and Lewy neurites, neuropathological hallmarks of several neurological diseases, are mainly made of filamentous
assemblies of α-synuclein. However, other macromolecules including Tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase,
and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase
is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes, but its role in Parkinson disease
is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological
conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small
angle x-ray scattering, circular dichroism, and fluorescence microscopy. Aggregation proceeds through the formation of short
rod-like oligomers, which elongates in one dimension. Heparan sulfate was also capable of inducing glyceraldehyde-3-phosphate
dehydrogenase aggregation, but chondroitin sulfates A, B, and C together with dextran sulfate had a negligible effect. Aided
with molecular docking simulations, a putative binding site on the protein is proposed providing a rational explanation for
the structural specificity of heparin and heparan sulfate. Finally, it is demonstrated that in vitro the early oligomers present in the glyceraldehyde-3-phosphate dehydrogenase fibrillation pathway promote α-synuclein aggregation.
Taking into account the toxicity of α-synuclein prefibrillar species, the heparin-induced glyceraldehyde-3-phosphate dehydrogenase
early oligomers might come in useful as a novel therapeutic strategy in Parkinson disease and other synucleinopathies.
Journal of Biological Chemistry 01/2012; 287(4):2398-2409. · 4.77 Impact Factor
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ABSTRACT: Lewy bodies and Lewy neurites, neuropathological hallmarks of several neurological diseases, are mainly made of filamentous assemblies of α-synuclein. However, other macromolecules including Tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase, and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes, but its role in Parkinson disease is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small angle x-ray scattering, circular dichroism, and fluorescence microscopy. Aggregation proceeds through the formation of short rod-like oligomers, which elongates in one dimension. Heparan sulfate was also capable of inducing glyceraldehyde-3-phosphate dehydrogenase aggregation, but chondroitin sulfates A, B, and C together with dextran sulfate had a negligible effect. Aided with molecular docking simulations, a putative binding site on the protein is proposed providing a rational explanation for the structural specificity of heparin and heparan sulfate. Finally, it is demonstrated that in vitro the early oligomers present in the glyceraldehyde-3-phosphate dehydrogenase fibrillation pathway promote α-synuclein aggregation. Taking into account the toxicity of α-synuclein prefibrillar species, the heparin-induced glyceraldehyde-3-phosphate dehydrogenase early oligomers might come in useful as a novel therapeutic strategy in Parkinson disease and other synucleinopathies.
Journal of Biological Chemistry 12/2011; 287(4):2398-409. · 4.77 Impact Factor
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ABSTRACT: Glycosaminoglycans (GAGs) are major extracellular matrix components known to tightly regulate cell behavior by interacting with tissue effectors as trophic factors and other heparin binding proteins. Alterations of GAGs structures might thus modify the nature and extent of these interactions and alter tissue integrity. Here, we studied levels and composition of GAGs isolated from adult and aged human hippocampus and investigated if their changes can influence the function of important trophic factors and the Aβ42 peptide toxicity. Biochemical analyses showed that heparan sulfates are increased in the aged hippocampus. Moreover, GAGs from aged hippocampus showed altered capacities to regulate trophic factor activities without changing their capacities to protect cells from Aβ42 toxicity, compared to adult hippocampus GAGs. Structural alterations in GAGs from elderly were suggested by differential transcripts levels of key biosynthetic enzymes. C5-epimerase and 2-OST expressions were decreased while NDST-2 and 3-OST-4 were increased; in contrast, heparanase expression was unchanged. Results suggest that alteration of GAGs in hippocampus of aged subjects could participate to tissue impairment during aging.
Neurobiology of aging 10/2011; 33(5):1005.e11-22. · 5.94 Impact Factor
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ABSTRACT: ReGeneraTing Agents (RGTAs) are biodegradable polymers engineered to mimic heparan-sulfate in the extracellular matrix of damaged tissue. RGTAs improve tissue healing in several animal models by stabilizing and protecting heparin-binding growth factors and matrix proteins. RGTA restores the normal matrix architecture and supports tissue regeneration. In this study, the authors evaluated the effects of RGTA on epidermal repair and dermal remodeling in a rat burn model.
Deep second-degree burns were induced in 156 hairless rats, of which half (n = 78) received topical and intramuscular RGTA immediately after the burn followed by intramuscular RGTA weekly for 1 month. The controls (n = 78) received saline according to the same protocol. Rats were killed starting on each day of the first week and on days 14, 28, 60, 120, 240, and 365. The burns were evaluated by photography, histology, and immunohistochemistry.
Coagulation necrosis involved the entire epidermis and superficial adnexa. Compared with the controls, speed of epidermal repair, as assessed between days 3 and 7 based on cell-layer number and anticytokeratin-14 staining, was faster in the RGTA group; and the zone of stasis, as assessed based on secondary vascular lesions in the dermis, was smaller. On day 7, reepithelialization was complete in both groups. On days 14 and 28, the remodeled dermal zone was smaller in the RGTA group.
RGTA accelerated epidermal repair and protected the dermis from secondary effects of heat as quantified by zone-of-stasis size and extent of dermal remodeling.
Plastic and reconstructive surgery 02/2011; 127(2):541-50. · 2.74 Impact Factor
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ABSTRACT: Bexarotene, (LGD1069, Targretin), is an antitumoral agent used as chemotherapy in the treatment of cutaneous T-cell lymphoma. Therapy with bexarotene is accompanied by adverse events, such as, bleeding, hemorrhage, and coagulopathy
In order to design applications for bexarotene, it was very important to gain an understanding of how bexarotene inhibits blood clotting
We investigated the interaction between bexarotene or vehicle alone, and coagulation factors or blood cells. We used both in vitro and in vivo assays. Anticoagulant activity of bexarotene or vehicle was assessed by clotting time tests (TT, RT, APTT, and PT). Coagulation factors activity was measured by adding diluted test plasma to artificially prepared factor-deficient plasma. Direct interactions between bexarotene and factor Xa were studied by chromogenic substrate assay. A mouse model was used to investigate in vivo effects of the drug on blood system and for evaluation of clinical hematology and organ pathology.
Increases in clotting times (prothrombin time and activated thromboplastin time) occurred with bexarotene in in vitro and in vivo experiments. We detected no significant influence of bexarotene on factors II, V, VII, VIII, XI and XII, while factor IX and factors X were affected. Bexarotene exerts anticoagulant effects and acts mainly as a direct factor IX and factor X inhibitor. On the contrary, the vehicle is remarkably inert toward the coagulation system. The number of blood cells was unaffected in mice treated with bexarotene or with the vehicle.
Monitoring of the coagulation factors profile should be considered in cancer patients receiving bexarotene, particularly those with a known diagnosis of coagulation factors deficient.
Cancer Chemotherapy and Pharmacology 01/2011; 68(4):847-54. · 2.83 Impact Factor
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Yasunori Ikeda,
Saïd Charef,
Mohand-Ouidir Ouidja,
Véronique Barbier-Chassefière,
Fernando Sineriz,
Arlette Duchesnay,
Hemalata Narasimprakash,
Isabelle Martelly,
Patrick Kern,
Denis Barritault,
Emmanuel Petit, Dulce Papy-Garcia
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ABSTRACT: Biologically active oligosaccharides related to glycosaminoglycans are accumulating increased attention because of their therapeutic potential and for their value in mechanistic studies. Heparan mimetics (HMs) are a family of dextran based polymer known to mimic the properties of glycosaminoglycans, and particularly those of heparan sulfates, as to interact with heparin binding proteins. HMs have shown to stimulate tissue repair in various animal models. Here, we use different methods to depolymerize HMs in order to produce a library of related oligosaccharides and study their biological activities. Since HMs were resistant to endoglycanases activities, depolymerization was achieved by chemical approaches. In vitro biological studies showed that HM oligosaccharides can differentially potentiate FGF-2 mitogenic and antithrombotic activities. In vivo, a selected oligosaccharide (H-dp12) showed to be able to regenerate tissue almost as well as the related polymeric product. The very low anticoagulant activity and high biological activity of low mass oligosaccharides give to these products a new therapeutic potential.
Biomaterials 10/2010; 32(3):769-76. · 7.40 Impact Factor
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ABSTRACT: The aim of this study was to investigate the development of an oral dextran derivative OTR4120. Pharmacokinetics (PK) parameters of OTR4120 were determined after treatment with intravenous injection (i.v.) at dose 5 mg/kg, intraperitoneal injection (i.p.) at dose 50 mg/kg or oral administration at dose 70 mg/kg. To study distribution at dose 70 mg/kg after oral administration, OTR4120 was given by gavage to mice. In ex vivo experiments, SDS-PAGE showed that plasma of mice treated orally at dose 70 mg/kg induced the formation of covalently linked complexes between antithrombin III and thrombin. OTR4120 were absorbed and metabolized following oral administration. OTR4120 given i.v., i.p. and oral had relatively small volume of distribution 0.95 L/kg and 4.68 L/kg respectively, plasma clearance was 45, 520 and 514 ml/h per kg after i.v., i.p. or oral administration respectively. Short elimination half-life was 80 min after i.p. administration and 383 min after oral administration. OTR4120 was distributed in the spleen and kidney and accumulated there over a long period, whereas the OTR4120 levels in liver were negligible a 24 hours after oral administration. Food do not change the oral bioavailability of OTR4120 in mice, AUC, C(max) and T(max) of OTR4120 were not significantly different when mice received the oral dose with food compared with under fasting conditions. This work presents another therapeutic agents administration way using dextran delivery system.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 09/2010; 64(9):627-32. · 2.24 Impact Factor
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ABSTRACT: Heparan sulfate mimetic polymers promotes tissue repair when injected locally in doses of 1-2mg/kg by various routes. These biopolymers, have been extensively studied for their diverse biological activities. However, there is no detailed report investigating the toxicity of OTR4120. In this study, the acute and subchronic (30 days) toxicity of varying levels of OTR4120 was investigated in mice after intraperitoneal administration. The results showed that no significant toxicological changes were observed when 50mg/kg body weight per day OTR4120 was administered to mice. But when the dose was increased to 60 and 70 mg/kg body weight per day, the clotting time was significantly prolonged. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were reduced female and male at dose 70 mg/kg body weight per day. These blood biochemistry data suggest that OTR4120 have a hepatoprotective effect. Based on these results, it can be concluded that the no adverse effect level of OTR4120 is 50 mg/kg body weight per day.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2010; 48(7):1965-8. · 2.99 Impact Factor
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ABSTRACT: Glycosaminoglycans (GAG) are sulfated polysaccharides that play an important role in regulating cell functions. GAG mimetics called RGTAs (for ReGeneraTing Agents) have been shown to stimulate tissue repair. In particular they accelerate myogenesis, in part via their heparin-mimetic property towards growth factors. RGTAs also increase activity of calcium-dependent intracellular protease suggesting an effect on calcium cellular homeostasis. This effect was presently investigated on myoblasts in vitro using one member of the RGTA family molecule named OTR4120. We have shown that OTR4120 or heparin induced transient increases of intracellular calcium concentration ([Ca(2+)]i) in pre-fusing myoblasts from both mouse SolD7 cell line and rat skeletal muscle satellite cells grown in primary culture by mobilising sarcoplasmic reticulum store. This [Ca(2+)]i was not mediated by ryanodine receptors but instead resulted from stimulation of the Inositol-3 phosphate-phospholipase C activation pathway. OTR4120-induced calcium transient was not mediated through an ATP, nor a tyrosine kinase, nor an acetylcholine receptor but principally through serotonin 5-HT2A receptor. This original finding shows that the GAG mimetic can induce calcium signal through serotonin receptors and the IP3 pathway may be relevant to its ability to favour myoblast differentiation. It supports a novel and unexpected function of GAGs in the regulation of calcium homeostasis.
Matrix biology: journal of the International Society for Matrix Biology 02/2010; 29(4):317-29. · 3.56 Impact Factor
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Veronique Friand,
Oualid Haddad, Dulce Papy-Garcia,
Hanna Hlawaty,
Roger Vassy,
Yamina Hamma-Kourbali,
Gerard-Yves Perret,
Jose Courty,
Françoise Baleux,
Olivier Oudar,
Liliane Gattegno,
Angela Sutton,
Nathalie Charnaux
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ABSTRACT: We have recently reported that the CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 induces proliferation, migration, and invasion of the Huh7 human hepatoma cells through its G-protein-coupled receptor CXCR4 and that glycosaminoglycans (GAGs) are involved in these events. Here, we demonstrate by surface plasmon resonance that the chemokine binds to GAG mimetics obtained by grafting carboxylate, sulfate or acetate groups onto a dextran backbone. We also demonstrate that chemically modified dextrans inhibit SDF-1/CXCL12-mediated in vitro chemotaxis and anchorage-independent cell growth in a dose-dependent manner. The binding of GAG mimetics to the chemokine and their effects in modulating the SDF-1/CXCL12 biological activities are mainly related to the presence of sulfate groups. Furthermore, the mRNA expression of enzymes involved in heparan sulfate biosynthesis, such as exostosin-1 and -2 or N-deacetylase N-sulfotransferases remained unchanged, but heparanase mRNA and protein expressions in Huh7 cells were decreased upon GAG mimetic treatment. Moreover, decreasing heparanase-1 mRNA levels by RNA interference significantly reduced SDF-1/CXCL12-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Therefore, we suggest that GAG mimetic effects on SDF-1/CXCL12-mediated hepatoma cell chemotaxis may rely on decreased heparanase expression, which impairs SDF-1/CXCL12's signaling. Altogether, these data suggest that GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and may affect heparanase expression, leading to reduced SDF-1/CXCL12 mediated in vitro chemotaxis and growth of hepatoma cells.
Glycobiology 09/2009; 19(12):1511-24. · 3.58 Impact Factor
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ABSTRACT: Glycosaminoglycans (GAG) are major components of bone marrow extracellular matrix because they have the property to interact with cells and growth factors in hematopoietic niches. In this study, we investigated the effect of two different chemically defined GAG mimetics on mobilization of hematopoietic stem and progenitor cells (HSPCs) in mice peripheral blood.
Mobilization was achieved by intraperitoneal injection of GAG mimetics. Mobilized cells were characterized phenotypically by reverse transcription polymerase chain reaction and fluorescence-activated cell sorting analysis and functionally by colony-forming cell, cobblestone area-forming cell and long-term culture-initiating cell assays in vitro. Radioprotection assays were performed to confirm the functionality of primitive hematopoietic cells in vivo. Involvement of stromal-derived factor-1 (SDF-1) and matrix metalloproteinase-9 (MMP-9) were investigated.
GAG mimetics treatment induces hyperleukocytosis and mobilization of HSPC. They synergize with the effects of granulocyte colony-stimulating factor or AMD3100 on hematopoietic progenitors mobilization. Reconstitution of lethally irradiated recipient mice with peripheral blood mononuclear cells from GAG mimetic-treated donor mice improves engraftment and survival. BiAcore studies indicate that the mimetics interact directly with SDF-1. In addition, GAG mimetics-induced mobilization is associated with increased levels of pro- and active MMP-9 from bone marrow cells and increased level of SDF-1 in peripheral blood. Finally, mobilization is partially inhibited by co-injection with anti-SDF-1 antibody.
This study demonstrates that GAG mimetics induce efficient mobilization of HSPCs, associated with an activation of pro-MMP-9 and a modification in the SDF-1 concentration gradient between bone marrow and peripheral blood. We suggest that structural features of GAGs can modify the nature of mobilized cells.
Experimental hematology 07/2009; 37(9):1072-83. · 3.11 Impact Factor
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ABSTRACT: A heparan sulfate disaccharide analog was synthesized by a multistep route. This synthesis was designed in such a way that one intermediate could be selectively deprotected to provide versatility during both synthesis and homologation of heparan sulfate related polysaccharides. Non-covalent imprinted polymers were prepared by using the synthesized disaccharide as a template and a primary amine functionalized acrylate as the key functional monomer suitable for specific sulfated sugar recognition. The binding of related sugars to the imprinted and non-imprinted polymers and the binding of template to the chemically modified polymers have been also investigated.
Carbohydrate Research 04/2008; 343(4):587-95. · 2.33 Impact Factor
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Mohand-Ouidir Ouidja,
Emmanuel Petit,
Marie-Emmanuelle Kerros,
Yasunori Ikeda,
Christophe Morin,
Gilles Carpentier,
Denis Barritault,
Jeanne Brugère-Picoux,
Jean-Philippe Deslys,
Karim Adjou, Dulce Papy-Garcia
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ABSTRACT: Polysulfated molecules, as the family of heparan mimetics (HMs) and pentosan polysulfate, are considered among the more promising drugs used in experimental models of prion diseases. Regardless of their therapeutic potential, structure-function studies on these polyanions are still missing. Here, we report the syntheses of a library of HMs of different molecular sizes, containing various sulfation and carboxylation levels, and substituted or not by different hydrophobic cores. The HMs capacities to inhibit the accumulation of PrPres in chronically infected cells (ScGT1-7) and their PrPc binding abilities were examined. Our results showed that an optimal size and sulfation degree are needed for optimum activity, that incorporation of hydrophobic moieties increases compounds efficacy and that the presence of carboxymethyl moieties decreases it. These structural features should be considered on the modelling of polyanionic compounds for optimum anti-prion activities and for advancing in the understanding the mechanisms involved in their biological actions.
Biochemical and Biophysical Research Communications 12/2007; 363(1):95-100. · 2.48 Impact Factor
