TY  - JOUR
AU  - Dragić, Milorad
AU  - Mihajlovic, Katarina
AU  - Adžić, Marija
AU  - Jakovljević, Marija
AU  - Zarić Kontić, Marina
AU  - Mitrović, Nataša
AU  - Laketa, Danijela
AU  - Lavrnja, Irena
AU  - Kipp, Markus
AU  - Grković, Ivana
AU  - Nedeljkovic, Nadezda
PY  - 2022
UR  - http://journals.sagepub.com/doi/10.1177/17590914221102068
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4984
AB  - Ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) hydrolyzes extracellular ATP to ADP, which is the ligand for P2Y1,12,13 receptors. The present study describes the distribution of NTPDase2 in adult rat brains in physiological conditions, and in hippocampal neurodegeneration induced by trimethyltin (TMT). The study also describes the regulation of NTPDase2 by inflammatory mediators in primary astrocytes and oligodendroglial cell line OLN93. In physiological conditions, NTPDase2 protein was most abundant in the hippocampus, where it was found in fibrous astrocytes and synaptic endings in the synaptic-rich hippocampal layers. In TMT-induced neurodegeneration, NTPDase2-mRNA acutely decreased at 2-dpi and then gradually recovered to the control level at 7-dpi and 21-dpi. As determined by immunohistochemistry and double immunofluorescence, the decrease was most pronounced in the dentate gyrus (DG), where NTPDase2 withdrew from the synaptic boutons in the polymorphic layer of DG, whereas the recovery of the expression was most profound in the subgranular layer. Concerning the regulation of NTPDase2 gene expression, proinflammatory cytokines IL-6, IL-1β, TNFα, and IFNγ negatively regulated the expression of NTPDase2 in OLN93 cells, while did not altering the expression in primary astrocytes. Different cell-intrinsic stressors, such as depletion of intracellular energy store, oxidative stress, endoplasmic reticulum stress, and activation of protein kinase C, also massively disturbed the expression of the NTPDase2 gene. Together, our results suggest that the expression and the activity of NTPDase2 transiently cease in neurodegeneration and brain injury, most likely as a part of the acute adaptive response designed to promote cell defense, survival, and recovery.
T2  - ASN Neuro
T1  - Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro.
VL  - 14
DO  - 10.1177/17590914221102068
SP  - 17590914221102068
ER  - 

@article{
author = "Dragić, Milorad and Mihajlovic, Katarina and Adžić, Marija and Jakovljević, Marija and Zarić Kontić, Marina and Mitrović, Nataša and Laketa, Danijela and Lavrnja, Irena and Kipp, Markus and Grković, Ivana and Nedeljkovic, Nadezda",
year = "2022",
abstract = "Ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) hydrolyzes extracellular ATP to ADP, which is the ligand for P2Y1,12,13 receptors. The present study describes the distribution of NTPDase2 in adult rat brains in physiological conditions, and in hippocampal neurodegeneration induced by trimethyltin (TMT). The study also describes the regulation of NTPDase2 by inflammatory mediators in primary astrocytes and oligodendroglial cell line OLN93. In physiological conditions, NTPDase2 protein was most abundant in the hippocampus, where it was found in fibrous astrocytes and synaptic endings in the synaptic-rich hippocampal layers. In TMT-induced neurodegeneration, NTPDase2-mRNA acutely decreased at 2-dpi and then gradually recovered to the control level at 7-dpi and 21-dpi. As determined by immunohistochemistry and double immunofluorescence, the decrease was most pronounced in the dentate gyrus (DG), where NTPDase2 withdrew from the synaptic boutons in the polymorphic layer of DG, whereas the recovery of the expression was most profound in the subgranular layer. Concerning the regulation of NTPDase2 gene expression, proinflammatory cytokines IL-6, IL-1β, TNFα, and IFNγ negatively regulated the expression of NTPDase2 in OLN93 cells, while did not altering the expression in primary astrocytes. Different cell-intrinsic stressors, such as depletion of intracellular energy store, oxidative stress, endoplasmic reticulum stress, and activation of protein kinase C, also massively disturbed the expression of the NTPDase2 gene. Together, our results suggest that the expression and the activity of NTPDase2 transiently cease in neurodegeneration and brain injury, most likely as a part of the acute adaptive response designed to promote cell defense, survival, and recovery.",
journal = "ASN Neuro",
title = "Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro.",
volume = "14",
doi = "10.1177/17590914221102068",
pages = "17590914221102068"
}

Dragić, M., Mihajlovic, K., Adžić, M., Jakovljević, M., Zarić Kontić, M., Mitrović, N., Laketa, D., Lavrnja, I., Kipp, M., Grković, I.,& Nedeljkovic, N.. (2022). Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro.. in ASN Neuro, 14, 17590914221102068.
https://doi.org/10.1177/17590914221102068

Dragić M, Mihajlovic K, Adžić M, Jakovljević M, Zarić Kontić M, Mitrović N, Laketa D, Lavrnja I, Kipp M, Grković I, Nedeljkovic N. Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro.. in ASN Neuro. 2022;14:17590914221102068.
doi:10.1177/17590914221102068 .

Dragić, Milorad, Mihajlovic, Katarina, Adžić, Marija, Jakovljević, Marija, Zarić Kontić, Marina, Mitrović, Nataša, Laketa, Danijela, Lavrnja, Irena, Kipp, Markus, Grković, Ivana, Nedeljkovic, Nadezda, "Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro." in ASN Neuro, 14 (2022):17590914221102068,
https://doi.org/10.1177/17590914221102068 . .

TY  - JOUR
AU  - Brisevac, Dusica
AU  - Adzic, Marija
AU  - Laketa, Danijela
AU  - Parabucki, Ana
AU  - Milosevic, Milena
AU  - Lavrnja, Irena
AU  - Bjelobaba, Ivana
AU  - Sevigny, Jean
AU  - Kipp, Markus
AU  - Nedeljkovic, Nadezda
PY  - 2015
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2349
AB  - Extracellular ATP (eATP) acts as a danger-associated molecular pattern
   which induces reactive response of astrocytes after brain insult,
   including morphological remodeling of astrocytes, proliferation,
   chemotaxis, and release of proinflammatory cytokines. The responses
   induced by eATP are under control of ecto-nucleotidases, which catalyze
   sequential hydrolysis of ATP to adenosine. In the mammalian brain,
   ecto-nucleotidases comprise three enzyme families: ecto-nucleoside
   triphosphate diphosphohydrolases 1-3 (NTPDase1-3), ecto-nucleotide
   pyrophosphatase/phospodiesterases 1-3 (NPP1-3), and ecto-5'-nucleotidase
   (eN), which crucially determine ATP/adenosine ratio in the pericellular
   milieu. Altered expression of ecto-nucleotidases has been demonstrated
   in several experimental models of human brain dysfunctions. In the
   present study, we have explored the pattern of NTPDase1-3, NPP1-3, and
   eN expression by cultured cortical astrocytes challenged with 1 mmol/L
   ATP (eATP). At the transcriptional level, eATP upregulated expression of
   NTPDase1, NTPDase2, NPP2, and eN, while, at translational and functional
   levels, these were paralleled only by the induction of NTPDase2 and eN.
   Additionally, eATP altered membrane topology of eN, from clusters
   localized in membrane domains to continuous distribution along the cell
   membrane. Our results suggest that eATP, by upregulating NTPDase2 and eN
   and altering the enzyme membrane topology, affects local kinetics of ATP
   metabolism and signal transduction that may have important roles in the
   process related to inflammation and reactive gliosis.
T2  - Journal of Molecular Neuroscience
T1  - Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate
 Diphosphohydrolase 2 and Ecto-5'-Nucleotidase by Rat Cortical Astrocytes
 In Vitro
IS  - 3
VL  - 57
DO  - 10.1007/s12031-015-0601-y
SP  - 452
EP  - 462
ER  - 

@article{
author = "Brisevac, Dusica and Adzic, Marija and Laketa, Danijela and Parabucki, Ana and Milosevic, Milena and Lavrnja, Irena and Bjelobaba, Ivana and Sevigny, Jean and Kipp, Markus and Nedeljkovic, Nadezda",
year = "2015",
abstract = "Extracellular ATP (eATP) acts as a danger-associated molecular pattern
   which induces reactive response of astrocytes after brain insult,
   including morphological remodeling of astrocytes, proliferation,
   chemotaxis, and release of proinflammatory cytokines. The responses
   induced by eATP are under control of ecto-nucleotidases, which catalyze
   sequential hydrolysis of ATP to adenosine. In the mammalian brain,
   ecto-nucleotidases comprise three enzyme families: ecto-nucleoside
   triphosphate diphosphohydrolases 1-3 (NTPDase1-3), ecto-nucleotide
   pyrophosphatase/phospodiesterases 1-3 (NPP1-3), and ecto-5'-nucleotidase
   (eN), which crucially determine ATP/adenosine ratio in the pericellular
   milieu. Altered expression of ecto-nucleotidases has been demonstrated
   in several experimental models of human brain dysfunctions. In the
   present study, we have explored the pattern of NTPDase1-3, NPP1-3, and
   eN expression by cultured cortical astrocytes challenged with 1 mmol/L
   ATP (eATP). At the transcriptional level, eATP upregulated expression of
   NTPDase1, NTPDase2, NPP2, and eN, while, at translational and functional
   levels, these were paralleled only by the induction of NTPDase2 and eN.
   Additionally, eATP altered membrane topology of eN, from clusters
   localized in membrane domains to continuous distribution along the cell
   membrane. Our results suggest that eATP, by upregulating NTPDase2 and eN
   and altering the enzyme membrane topology, affects local kinetics of ATP
   metabolism and signal transduction that may have important roles in the
   process related to inflammation and reactive gliosis.",
journal = "Journal of Molecular Neuroscience",
title = "Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate
 Diphosphohydrolase 2 and Ecto-5'-Nucleotidase by Rat Cortical Astrocytes
 In Vitro",
number = "3",
volume = "57",
doi = "10.1007/s12031-015-0601-y",
pages = "452-462"
}

Brisevac, D., Adzic, M., Laketa, D., Parabucki, A., Milosevic, M., Lavrnja, I., Bjelobaba, I., Sevigny, J., Kipp, M.,& Nedeljkovic, N.. (2015). Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate
 Diphosphohydrolase 2 and Ecto-5'-Nucleotidase by Rat Cortical Astrocytes
 In Vitro. in Journal of Molecular Neuroscience, 57(3), 452-462.
https://doi.org/10.1007/s12031-015-0601-y

Brisevac D, Adzic M, Laketa D, Parabucki A, Milosevic M, Lavrnja I, Bjelobaba I, Sevigny J, Kipp M, Nedeljkovic N. Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate
 Diphosphohydrolase 2 and Ecto-5'-Nucleotidase by Rat Cortical Astrocytes
 In Vitro. in Journal of Molecular Neuroscience. 2015;57(3):452-462.
doi:10.1007/s12031-015-0601-y .

Brisevac, Dusica, Adzic, Marija, Laketa, Danijela, Parabucki, Ana, Milosevic, Milena, Lavrnja, Irena, Bjelobaba, Ivana, Sevigny, Jean, Kipp, Markus, Nedeljkovic, Nadezda, "Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate
 Diphosphohydrolase 2 and Ecto-5'-Nucleotidase by Rat Cortical Astrocytes
 In Vitro" in Journal of Molecular Neuroscience, 57, no. 3 (2015):452-462,
https://doi.org/10.1007/s12031-015-0601-y . .

TY  - JOUR
AU  - Brisevac, Dusica
AU  - Bajić, Aleksandar
AU  - Bjelobaba, Ivana
AU  - Milosević, Milena B
AU  - Stojiljković, Mirjana B
AU  - Beyer, Cordian
AU  - Clarner, Tim
AU  - Kipp, Markus
AU  - Nedeljković, Nadezda N
PY  - 2013
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/958
AB  - Nucleoside triphosphate diphosphohydrolases (NTPDases) are ecto-enzymes catalyzing the first step of sequential hydrolysis of extracellular ATP to adenosine, as the final product. Among eight members of NTPDase family, NTPDases1-3 have been shown to be expressed in the brain. Although altered NTPDase expression has been observed in relation to cell death and reactive gliosis in several experimentally induced neuropathologies, regulators of NTPDases expression and function are largely unknown. The present study explored the effects of several inflammatory factors (i.e., INF-gamma, TNF-alpha, LPS, peroxide, and glutamate) on NTPDase1-3 activity and expression by cultured cortical astrocytes. We were able to demonstrate that INF-gamma and TNF-alpha increased both ATP and ADP hydrolysis, while LPS specifically increased ATP hydrolysis. Consistent with the observed enhanced nucleotidase activity, INF-gamma induced the upregulation of NTPDase1 at the mRNA and protein level. Furthermore, we were able to demonstrate that INF-gamma and TNF-alpha decreased the relative abundance of dominant astrocytic NTPDase2 in favor of NTPDase1. In summary, these results suggest that INF-gamma, TNF-alpha, and LPS may be relevant in vivo regulators of NTPDase expression in neuropathologies associated with neuroinflammation.
T2  - Journal of Molecular Neuroscience
T1  - Expression of Ecto-Nucleoside Triphosphate Diphosphohydrolase1-3 (NTPDase1-3) by Cortical Astrocytes After Exposure to Pro-inflammatory Factors In Vitro
IS  - 3
VL  - 51
SP  - 23
EP  - 879
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_958
ER  - 

@article{
author = "Brisevac, Dusica and Bajić, Aleksandar and Bjelobaba, Ivana and Milosević, Milena B and Stojiljković, Mirjana B and Beyer, Cordian and Clarner, Tim and Kipp, Markus and Nedeljković, Nadezda N",
year = "2013",
abstract = "Nucleoside triphosphate diphosphohydrolases (NTPDases) are ecto-enzymes catalyzing the first step of sequential hydrolysis of extracellular ATP to adenosine, as the final product. Among eight members of NTPDase family, NTPDases1-3 have been shown to be expressed in the brain. Although altered NTPDase expression has been observed in relation to cell death and reactive gliosis in several experimentally induced neuropathologies, regulators of NTPDases expression and function are largely unknown. The present study explored the effects of several inflammatory factors (i.e., INF-gamma, TNF-alpha, LPS, peroxide, and glutamate) on NTPDase1-3 activity and expression by cultured cortical astrocytes. We were able to demonstrate that INF-gamma and TNF-alpha increased both ATP and ADP hydrolysis, while LPS specifically increased ATP hydrolysis. Consistent with the observed enhanced nucleotidase activity, INF-gamma induced the upregulation of NTPDase1 at the mRNA and protein level. Furthermore, we were able to demonstrate that INF-gamma and TNF-alpha decreased the relative abundance of dominant astrocytic NTPDase2 in favor of NTPDase1. In summary, these results suggest that INF-gamma, TNF-alpha, and LPS may be relevant in vivo regulators of NTPDase expression in neuropathologies associated with neuroinflammation.",
journal = "Journal of Molecular Neuroscience",
title = "Expression of Ecto-Nucleoside Triphosphate Diphosphohydrolase1-3 (NTPDase1-3) by Cortical Astrocytes After Exposure to Pro-inflammatory Factors In Vitro",
number = "3",
volume = "51",
pages = "23-879",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_958"
}

Brisevac, D., Bajić, A., Bjelobaba, I., Milosević, M. B., Stojiljković, M. B., Beyer, C., Clarner, T., Kipp, M.,& Nedeljković, N. N.. (2013). Expression of Ecto-Nucleoside Triphosphate Diphosphohydrolase1-3 (NTPDase1-3) by Cortical Astrocytes After Exposure to Pro-inflammatory Factors In Vitro. in Journal of Molecular Neuroscience, 51(3), 23-879.
https://hdl.handle.net/21.15107/rcub_ibiss_958

Brisevac D, Bajić A, Bjelobaba I, Milosević MB, Stojiljković MB, Beyer C, Clarner T, Kipp M, Nedeljković NN. Expression of Ecto-Nucleoside Triphosphate Diphosphohydrolase1-3 (NTPDase1-3) by Cortical Astrocytes After Exposure to Pro-inflammatory Factors In Vitro. in Journal of Molecular Neuroscience. 2013;51(3):23-879.
https://hdl.handle.net/21.15107/rcub_ibiss_958 .

Brisevac, Dusica, Bajić, Aleksandar, Bjelobaba, Ivana, Milosević, Milena B, Stojiljković, Mirjana B, Beyer, Cordian, Clarner, Tim, Kipp, Markus, Nedeljković, Nadezda N, "Expression of Ecto-Nucleoside Triphosphate Diphosphohydrolase1-3 (NTPDase1-3) by Cortical Astrocytes After Exposure to Pro-inflammatory Factors In Vitro" in Journal of Molecular Neuroscience, 51, no. 3 (2013):23-879,
https://hdl.handle.net/21.15107/rcub_ibiss_958 .

TY  - JOUR
AU  - Brisevac, Dusica
AU  - Bjelobaba, Ivana
AU  - Bajić, Aleksandar
AU  - Clarner, Tim
AU  - Stojiljković, Mirjana B
AU  - Beyer, Cordian
AU  - Anđus, Pavle R
AU  - Kipp, Markus
AU  - Nedeljković, Nadezda N
PY  - 2012
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1098
AB  - Ecto-5'-nucleotidase (e-5NT) is a cell-surface located, rate-limiting enzyme in the extracellular metabolism of ATP, catalyzing the final step of the conversion of AMP to adenosine. Since this enzyme shifts the balance from pro-inflammatory ATP to anti-inflammatory adenosine, it is considered to be an important regulator of inflammation. Although up-regulation of e-5NT was repeatedly reported in several in vivo models of brain injury, the regulation of its expression and function remains largely unknown. We have studied effects of several pro-inflammatory factors, namely, bacterial endotoxin lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), glutamate (Glu) and hydrogen peroxide (H2O2) on e-5NT (i) activity, (ii) mRNA expression and (iii) membrane protein abundance in primary cultured cortical astrocytes. We are clearly able to demonstrate a stimulus-specific regulation of the e-5NT pathway. IFN-gamma, LPS, Glu and H2O2 decrease, while TNF-alpha increases e-5NT activity. The analysis of e-5NT gene expression and e-5NT membrane protein levels revealed that tested factors regulate e-5NT at different levels and by employing different mechanisms. In summary, we provide evidence that e-5NT activity is tightly regulated in a stimulus-specific manner. (C) 2012 Elsevier Ltd. All rights reserved.
T2  - Neurochemistry International
T1  - Regulation of ecto-5 '-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors
IS  - 5
VL  - 61
SP  - 406
EP  - 688
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1098
ER  - 

@article{
author = "Brisevac, Dusica and Bjelobaba, Ivana and Bajić, Aleksandar and Clarner, Tim and Stojiljković, Mirjana B and Beyer, Cordian and Anđus, Pavle R and Kipp, Markus and Nedeljković, Nadezda N",
year = "2012",
abstract = "Ecto-5'-nucleotidase (e-5NT) is a cell-surface located, rate-limiting enzyme in the extracellular metabolism of ATP, catalyzing the final step of the conversion of AMP to adenosine. Since this enzyme shifts the balance from pro-inflammatory ATP to anti-inflammatory adenosine, it is considered to be an important regulator of inflammation. Although up-regulation of e-5NT was repeatedly reported in several in vivo models of brain injury, the regulation of its expression and function remains largely unknown. We have studied effects of several pro-inflammatory factors, namely, bacterial endotoxin lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), glutamate (Glu) and hydrogen peroxide (H2O2) on e-5NT (i) activity, (ii) mRNA expression and (iii) membrane protein abundance in primary cultured cortical astrocytes. We are clearly able to demonstrate a stimulus-specific regulation of the e-5NT pathway. IFN-gamma, LPS, Glu and H2O2 decrease, while TNF-alpha increases e-5NT activity. The analysis of e-5NT gene expression and e-5NT membrane protein levels revealed that tested factors regulate e-5NT at different levels and by employing different mechanisms. In summary, we provide evidence that e-5NT activity is tightly regulated in a stimulus-specific manner. (C) 2012 Elsevier Ltd. All rights reserved.",
journal = "Neurochemistry International",
title = "Regulation of ecto-5 '-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors",
number = "5",
volume = "61",
pages = "406-688",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1098"
}

Brisevac, D., Bjelobaba, I., Bajić, A., Clarner, T., Stojiljković, M. B., Beyer, C., Anđus, P. R., Kipp, M.,& Nedeljković, N. N.. (2012). Regulation of ecto-5 '-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors. in Neurochemistry International, 61(5), 406-688.
https://hdl.handle.net/21.15107/rcub_ibiss_1098

Brisevac D, Bjelobaba I, Bajić A, Clarner T, Stojiljković MB, Beyer C, Anđus PR, Kipp M, Nedeljković NN. Regulation of ecto-5 '-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors. in Neurochemistry International. 2012;61(5):406-688.
https://hdl.handle.net/21.15107/rcub_ibiss_1098 .

Brisevac, Dusica, Bjelobaba, Ivana, Bajić, Aleksandar, Clarner, Tim, Stojiljković, Mirjana B, Beyer, Cordian, Anđus, Pavle R, Kipp, Markus, Nedeljković, Nadezda N, "Regulation of ecto-5 '-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors" in Neurochemistry International, 61, no. 5 (2012):406-688,
https://hdl.handle.net/21.15107/rcub_ibiss_1098 .