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Latest Paper:
PLoS One. 2012 ;7 (2):e31205
22348056
Rafael Fernandes Zanin,
Elizandra Braganhol,
Letícia Scussel Bergamin,
Luís Felipe Ingrassia Campesato,
Alfeu Zanotto Filho,
José Cláudio Fonseca Moreira,
Fernanda Bueno Morrone,
Jean Sévigny,
Maria Rosa Chitolina Schetinger,
Angela Terezinha de Souza Wyse,
Ana Maria Oliveira Battastini
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
Macrophages are key elements in the inflammatory process, whereas depending on the micro-environmental stimulation they exhibit a pro-inflammatory (classical/M1) or an anti-inflammatory/reparatory (alternative/M2) phenotype. Extracellular ATP can act as a danger signal whereas adenosine generally serves as a negative feedback mechanism to limit inflammation. The local increase in nucleotides communication is controlled by ectonucleotidases, such as members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family and ecto-5'-nucleotidase/CD73 (ecto-5'-NT). In the present work we evaluated the presence of these enzymes in resident mice M1 (macrophages stimulated with LPS), and M2 (macrophages stimulated with IL-4) macrophages. Macrophages were collected by a lavage of the mice (6-8 weeks) peritoneal cavity and treated for 24 h with IL-4 (10 ng/mL) or LPS (10 ng/mL). Nitrite concentrations were measured using the Greiss reaction. Supernatants were harvested to determine cytokines and the ATPase, ADPase and AMPase activities were determined by the malachite green method and HPLC analysis. The expression of selected surface proteins was evaluated by flow cytometry. The results reveal that M1 macrophages presented a decreased ATP and AMP hydrolysis in agreement with a decrease in NTPDase1,-3 and ecto-5'-nucleotidase expression compared to M2. In contrast, M2 macrophages showed a higher ATP and AMP hydrolysis and increased NTPDase1,-3 and ecto-5'-nucleotidase expression compared to M1 macrophages. Therefore, macrophages of the M1 phenotype lead to an accumulation of ATP while macrophages of the M2 phenotype may rapidly convert ATP to adenosine. The results also showed that P1 and P2 purinoreceptors present the same mRNA profile in both phenotypes. In addition, M2 macrophages, which have a higher ATPase activity, were less sensitive to cell death. In conclusion, these changes in ectoenzyme activities might allow macrophages to adjust the outcome of the extracellular purinergic cascade in order to fine-tune their functions during the inflammatory set.
J Dent Res. 2011 Dec 14;:
22173326
Dental pulpal nerve fibers express ionotropic adenosine triphosphate (ATP) receptors, suggesting that ATP signaling participates in the process of dental nociception. In this study, we investigated if the principal enzymes responsible for extracellular ATP hydrolysis, namely, nucleoside triphosphate diphosphohydrolases (NTPDases), are present in human dental pulp. Immunohistochemical and immunofluorescence experiments showed that NTPDase2 was predominantly expressed in pulpal nerve bundles, Raschkow's nerve plexus, and in the odontoblast layer. NTPDase2 was expressed in pulpal Schwann cells, with processes accompanying the nerve fibers and projecting into the odontoblast layer. Odontoblasts expressed the gap junction protein, connexin43, which can form transmembrane hemichannels for ATP release. NTPDase2 was localized close to connexin43 within the odontoblast layer. These findings provide evidence for the existence of an apparatus for ATP release and degradation in human dental pulp, consistent with the involvement of ATP signaling in the process of dentin sensitivity and dental pain.
Michel Fausther,
Joanna Lecka,
Elwy Soliman,
Gilles Kauffenstein,
Julie Pelletier,
Nina Sheung,
Jonathan A Dranoff,
Jean Sevigny
1University of Arkansas.
Ectonucleotidases modulate purinergic signaling by hydrolyzing ATP to adenosine. Here we characterized the impact of the cellular distribution of hepatic ectonucleotidases, namely NTPDase1/CD39, NTPDase2/CD39L1, NTPDase8 and ecto-5'-nucleotidase/CD73, and of their specific biochemical properties, on the levels of P1 and P2 receptor agonists, with an emphasis on adenosine-producing CD73. Immunostaining and enzyme histochemistry showed that the distribution of CD73 (protein and AMPase activity) overlaps partially with those of NTPDase1, 2 and 8 (protein levels and ATPase and ADPase activities) in normal rat liver. CD73 is expressed in fibroblastic cells located underneath vascular endothelial cells and smooth muscle cells, which both express NTPDase1, in portal spaces in a distinct fibroblast population next to NTPDase2-positive portal fibroblasts, and in bile canaliculi, together with NTPDase8. In fibrotic rat livers, CD73 protein expression and activity are redistributed but still overlap with the NTPDases mentioned. The ability of the observed combinations of ectonucleotidases to generate adenosine over time was evaluated by reverse-phase HPLC with the recombinant rat enzymes at high "inflammatory"(500 μM) and low "physiological"(1 μM) ATP concentrations. Overall, ATP was rapidly converted to adenosine by the NTPDase1+CD73 combination, but not by the NTPDase2+CD73 combination. In the presence of NTPDase8 and CD73, ATP was sequentially dephosphorylated to the CD73 inhibitor ADP, and next to AMP, thus resulting in a delayed formation of adenosine. In conclusion, the specific cellular co-compartmentalization of CD73 with hepatic NTPDases is not redundant and may lead to the differential activation of P1 and P2 receptors, under normal and fibrotic conditions.
Purinergic Signal. 2011 Oct 30;:
22038661
Elizandra Braganhol,
Rafael F Zanin,
Andressa Bernardi,
Leticia S Bergamin,
Angelica R Cappellari,
Luis F Campesato,
Fernanda B Morrone,
Maria M Campos,
João B Calixto,
Maria Isabel A Edelweiss,
Márcia R Wink,
Jean Sévigny,
Simon C Robson,
Ana Maria O Battastini
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, RS, Brazil.
Gliomas are the most common and devastating type of primary brain tumor. Many non-neoplastic cells, including immune cells, comprise the tumor microenvironment where they create a milieu that appears to dictate cancer development. ATP and the phosphohydrolytic products ADP and adenosine by activating P2 and P1 receptors may participate in these interactions among malignant and immune cells. Purinergic receptor-mediated cell communication is closely regulated by ectonucleotidases, such as by members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, which hydrolyze extracellular nucleotides. We have shown that gliomas, unlike astrocytes, exhibit low NTPDase activity. Furthermore, ATP induces glioma cell proliferation and the co-administration of apyrase decreases progression of injected cells in vivo. We have previously shown that NTPDase2 reconstitution dramatically increases tumor growth in vivo. Here we evaluated whether NTPDase2 reconstitution to gliomas modulates systemic inflammatory responses. We observed that NTPDase2 overexpression modulated pro-inflammatory cytokine production and platelet reactivity. Additionally, pathological alterations in the lungs were observed in rats bearing these tumors. Our results suggest that disruption of purinergic signaling via ADP accumulation creates an inflammatory state that may promote tumor spread and dictate clinical progression.
Mol Ecol Resour. 2011 Sep 27;:
21951598
F Keith Barker,
James J Bell,
Steven M Bogdanowicz,
S L Bonatto,
Frank Cezilly,
Sarah M Collins,
Christine Dubreuil,
Matthew J Dufort,
Cyril Eraud,
Reiko Fuseya,
E A Heap,
N Jacobsen,
M Madders,
R McEwing,
Andrew P Michel,
F Mougeot,
R S Ogden,
Lucia C Orantes,
A S Othman,
Eric Parent,
P Pulido-Santacruz,
Rachel Rioux-Paré,
M F Roberts,
R Rosazlina,
Takashi Sakamoto,
Pelayo Salinas De-León,
Jean-Marie Sévigny,
Philippe St-Onge,
J Terraube,
R E Tingay,
Réjean Tremblay,
Seiichi Watanabe,
Rémi A Wattier
Molecular Ecology Resources Editorial Office, 6270 University Blvd, Vancouver, BC, V6T 1Z4, Canada Department of Ecology, Evolution, and Behavior, University of Minnesota, 100 Ecology Building, 1987 Upper Buford Circle, St. Paul, MN 55108, USA Bell Museum of Natural History, University of Minnesota, 100 Ecology Building, 1987 Upper Buford Circle, St. Paul, MN 55108, USA Centre for Marine Environmental and Economic Research, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand Department of Ecology & Evolutionary Biology, Cornell University, E149 Corson Hall, Ithaca, NY 14853, USA Laboratório de Biologia Genômica e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul. Av. Ipiranga, 6681, CEP 90619-900, Porto Alegre, RS - Brazil Equipe Ecologie Evolutive, Université de Bourgogne, UMR CNRS 5561 Biogéosciences, 6 boulevard Gabriel, 21000 Dijon, France Office National de la Chasse et de la Faune Sauvage, Direction des Etudes et de la Recherche, CNERA Avifaune migratrice, Station de Chizé, Carrefour de la Canauderie, 79 360 Villiers-en-Bois, France National Research Institute of Fisheries Engineering, Fisheries Research Agency, 7620-7, Hasaki, Kamisu, Ibaraki 314-0408, Japan WildGenes, Royal Zoological Society of Scotland, Corstorphine Road, Edinburgh EH12 6TS, UK Natural Research Ltd, Brathens Business Park, Hill of Brathens, Glassel, Banchory, Aberdeenshire AB31 4BY, UK Department of Agronomy and Ecology, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 21 DK 1958 Frederiksberg C, Denmark Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Ave., Wooster, OH 44691, USA IREC (CSIC-UCLM-JCCM), Ronda de Toledo s/n, 13005, Ciudad Real, Spain Estación Experimental de Zonas Áridas (EEZA-CSIC), Ctra. de Sacramento s/n La Cañada de San Urbano, 04120 Almería, Spain School of Biological Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia Pêches et Océans Canada, Institut Maurice-Lamontagne 850 Route de la Mer, Mont-Joli, QC, Canada, G5H 3Z4 Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, 4-5-7 Konan, Minato, Tokyo 108-8477, Japan Institut des Sciences de la Mer, Université du Québec à Rimouski 310 Allée des Ursulines, Rimouski, QC, Canada G5L 3A1.
This article documents the addition of 112 microsatellite marker loci and 24 pairs of single nucleotide polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Agelaius phoeniceus, Austrolittorina cincta, Circus cyaneus, Circus macrourus, Circus pygargus, Cryptocoryne × purpurea Ridl. nothovar. purpurea, Mya arenaria, Patagioenas squamosa, Prochilodus mariae, Scylla serrata and Scytalopus speluncae. These loci were cross-tested on the following species: Cryptocoryne × purpurea nothovar. purpurea, Cryptocoryne affinis, Cryptocoryne ciliata, Cryptocoryne cordata var. cordata, Cryptocoryne elliptica, Cryptocoryne griffithii, Cryptocoryne minima, Cryptocoryne nurii and Cryptocoryne schulzei. This article also documents the addition of 24 sequencing primer pairs and 24 allele-specific primers or probes for Aphis glycines.
J Cell Physiol. 2011 Sep 6;:
21898410
J B Noronha-Matos,
M A Costa,
M T Magalhães-Cardoso,
F Ferreirinha,
J Pelletier,
R Freitas,
J M Neves,
J Sévigny,
P Correia-de-Sá
Laboratório de Farmacologia e Neurobiologia, UMIB, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal.
This study aimed at investigating the expression and function of uracil nucleotide-sensitive receptors (P2Y(2), P2Y(4) and P2Y(6)) on osteogenic differentiation of human bone marrow stromal cells (BMSCs) in culture. Bone marrow specimens were obtained from postmenopausal female patients (68±5 years old, n=18) undergoing total hip arthroplasty. UTP and UDP (100 µM) facilitated osteogenic differentiation of the cells measured as increases in alkaline phosphatase (ALP) activity, without affecting cell proliferation. Uracil nucleotides concentration-dependently increased [Ca(2+)](i) in BMSCs; their effects became less evident with time (7>21 days) of the cells in culture. Selective activation of P2Y(6) receptors with the stable UDP analogue, PSB 0474, mimicked the effects of both UTP and UDP, whereas UTPγS was devoid of effect. Selective blockade of P2Y(6) receptors with MRS 2578 prevented [Ca(2+)](i) rises and osteogenic differentiation caused by UDP at all culture time points. BMSCs are immunoreactive against P2Y(2), P2Y(4) and P2Y(6) receptors. While the expression of P2Y(6) receptors remained fairly constant (7∼21 days), P2Y(2) and P2Y(4) became evident only in less proliferative and more differentiated cultures (7<21 days). The rate of extracellular UTP and UDP inactivation was higher in less proliferative and more differentiated cell populations. Immunoreactivity against NTPDase1,-2 and -3 rises as cells differentiate (7<21 days). Data show that uracil nucleotides are important regulators of osteogenic cells differentiation predominantly through the activation of UDP-sensitive P2Y(6) receptors coupled to increases in [Ca(2+)](i). Endogenous actions of uracil nucleotides may be balanced through specific NTPDases determining whether osteoblast progenitors are driven into proliferation or differentiation. J. Cell. Physiol. © 2011 Wiley-Liss, Inc.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Nucleotide-activated P2X channels and P2Y metabotropic receptors participate in nociceptive signaling. Agonist availability is regulated by nucleoside triphosphate diphosphohydrolase-1 (NTPDase1),-2,-3, and -8, a family of enzymes that hydrolyze extracellular ATP to generate ADP (a P2Y agonist) and AMP. They provide a major source of extracellular AMP, the substrate for adenosine production by ecto-5'-nucleotidase (NT5E), and thereby regulate adenosine (P1) receptor signaling. NTPDases vary in their efficiency of tri- and diphosphate hydrolysis; therefore, which family members are expressed impacts nucleotide availability and half-life. This study employed enzyme activity histochemistry to examine the distribution of ATPase activity and immunohistochemistry for NTPDase1, 2, 3, and 8 in dorsal root ganglion (DRG) and spinal cord. Nucleotidase activity was robust in spinal dorsal horn, confirming that nociceptive pathways are a major site of nucleotide transmission. In DRG, extensive staining revealed ATPase activity in a subset of neurons and in non-neuronal cells. mRNA for NTPDase1-3, but not NTPDase8, was detected in lumbar DRG and spinal cord. Immunoreactivity for NTPDase3 closely matched the distribution of ATPase activity, labeling DRG central projections in the dorsal root and superficial dorsal horn, as well as intrinsic spinal neurons concentrated in lamina II. In DRG, NTPDase3 co-localized with markers of nociceptors and with NT5E. In addition, labeling of a subset of larger-diameter neurons in DRG was consistent with intense staining of Meissner corpuscle afferents in glabrous skin. Merkel cells and terminal Schwann cells of hair follicle afferents were also labeled, but the axons themselves were negative. We propose that NTPDase3 is a key regulator of nociceptive signaling that also makes an unexpected contribution to innocuous tactile sensation.
Filip Kukulski,
Fariborz Bahrami,
Fethia Ben Yebdri,
Joanna Lecka,
Mireia Martín-Satué,
Sébastien A Lévesque,
Jean Sévigny
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec (pavillon Centre Hospitalier de l'Université Lava), Québec City, Québec G1V 4G2, Canada. Filip.Kukulski@crchul.ulaval.ca
The ectonucleotidase NTPDase1 (CD39) terminates P2 receptor activation by the hydrolysis of extracellular nucleotides (i.e., the P2 receptor ligands). In agreement with that role, exacerbated inflammation has been observed in NTPDase1-deficient mice. In this study, we extend these observations by showing that inhibition of NTPDase1 markedly increases IL-8 production by TLR-stimulated human neutrophils. First, immunolabeling of human blood neutrophils and neutrophil-like HL60 cells displayed the expression of NTPDase1 protein, which correlated with the hydrolysis of ATP at their surface. NTPDase1 inhibitors (e.g., NF279 and ARL 67156) as well as NTPDase1-specific small interfering RNAs markedly increased IL-8 production in neutrophils stimulated with LPS and Pam(3)CSK(4)(agonists of TLR4 and TLR1/2, respectively) but not with flagellin (TLR5) and gardiquimod (TLR7 and 8). This increase in IL-8 release was due to the synergy between TLRs and P2 receptors. Indeed, ATP was released from neutrophils constitutively and accumulated in the medium upon NTPDase1 inhibition by NF279. Likewise, both human blood neutrophils and neutrophil-like HL60 cells produced IL-8 in response to exogenous nucleotides, ATP being the most potent inducer. In agreement, P2Y(2) receptor knockdown in neutrophil-like HL60 cells markedly decreased LPS- and Pam(3)CSK(4)-induced IL-8 production. In line with these in vitro results, injection of LPS in the air pouches of NTPDase1-deficient mice triggered an increased production of the chemokines MIP-2 and keratinocyte-derived chemokine (i.e., the rodent counterparts of human IL-8) compared with that in wild-type mice. In summary, NTPDase1 controls IL-8 production by human neutrophils via the regulation of P2Y(2) activation.
Adv Pharmacol. 2011 ;61 :263-99
21586362
Cit:1
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Québec, Canada.
P2 receptors that are activated by extracellular nucleotides (e.g., ATP, ADP, UTP, UDP, Ap(n)A) and P1 receptors activated by adenosine control a diversity of biological processes. The activation of these receptors is tightly regulated by ectoenzymes that metabolize their ligands. This review presents these enzymes as well as their roles in the regulation of P2 and P1 receptor activation. We focus specifically on the role of ectoenzymes in processes of our interest, that is, inflammation, vascular tone, and neurotransmission. An update on the development of ectonucleotidase inhibitors is also presented.
G P Cognato,
F C Vuaden,
L E B Savio,
B Bellaver,
E Casali,
M R Bogo,
D O G Souza,
J Sévigny,
C D Bonan
Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Avenida Ramiro Barcelos, 2600 Anexo, 90035-000 Porto Alegre, Rio Grande do Sul, Brazil.
Studies have shown that seizures in young animals lead to later cognitive deficits. There is evidence that long-term potentiation (LTP) and long-term depression (LTD) might contribute to the neural basis for learning and memory mechanism and might be modulated by ATP and/or its dephosphorylated product adenosine produced by a cascade of cell-surface transmembrane enzymes, such as E-NTPDases (ecto-nucleoside triphosphate diphosphohydrolases) and ecto-5'-nucleotidase. Thus, we have investigated if hippocampal ecto-nucleotidase activities are altered at different time periods after one episode of seizure induced by kainic acid (KA) in 7 days old rats. We also have evaluated if 90 day-old rats previously submitted to seizure induced by KA at 7 days of age presented cognitive impairment in Y-maze behavior task. Our results have shown memory impairment of adult rats (Postnatal day 90) previously submitted to one single seizure episode in neonatal period (Postnatal day 7), which is accompanied by an increased ATP hydrolysis in hippocampal synaptosomes. The metabolism of ATP evaluated by HPLC confirmed that ATP hydrolysis was faster in adult rats treated with KA in neonatal period than in controls. Surprisingly, the mRNA and protein levels as seen by PCR and Western blot, respectively, were not altered by the KA administration in early age. Since we have found an augmented hydrolysis of ATP and this nucleotide seems to be important to LTP induction, we could assume that impairment of memory and learning observed in adult rats which have experienced a convulsive episode in postnatal period may be a consequence of the increased ATP hydrolysis. These findings correlate the purinergic signaling to the cognitive deficits induced by neonatal seizures and contribute to a better understanding about the mechanisms of seizure-induced memory dysfunction.
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