TY  - JOUR
AU  - Stojanović, Ivana D.
AU  - Popadić, Dušan
AU  - Vučković, Olivera
AU  - Harhaji-Trajković, Ljubica
AU  - Miljković, Đorđe
AU  - Trajković, Vladimir
PY  - 2004
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6009
AB  - The influence of a nucleoside analog 5-aza-2'-deoxycytidine (5-AzadC) on inducible nitric oxide synthase (iNOS)-dependent nitric oxide (NO) production in various rat cell types was investigated. In C6 astrocytoma cell line and primary astrocytes, 5-AzadC enhanced proinflammatory cytokine (IFN-gamma, TNF-alpha, IL-1)-triggered NO synthesis in a time- and dose-dependent manner. In contrast, 5-AzadC did not potentiate NO production in IFN-gamma-stimulated macrophages, fibroblasts, or endothelial cells. Blockade of transcription or translation in C6 cells abolished the observed effect, suggesting the iNOS gene expression, rather than its catalytic activity, as a target for the drug action. Accordingly, 5-AzadC upregulated IFN-gamma-induced expression of iNOS mRNA in C6 astrocytes. The effect of 5-AzadC on astrocyte NO release was blocked by the inhibitor of p44/42 mitogen activated protein kinase-dependent signaling. Finally, the observed stimulatory effect of 5-AzadC on iNOS expression was apparently independent of DNA demethylation, as DNA digestion with methylation-sensitive restriction enzyme HpaII showed that 5-AzadC failed to demethylate cellular DNA in conditions used for iNOS induction.
PB  - Elsevier B.V.
T2  - Brain Research
T1  - 5-Aza-2'-deoxycytidine stimulates inducible nitric oxide synthase induction in C6 astrocytoma cells
IS  - 1
VL  - 998
DO  - 10.1016/j.brainres.2003.11.014
SP  - 83
EP  - 90
ER  - 

@article{
author = "Stojanović, Ivana D. and Popadić, Dušan and Vučković, Olivera and Harhaji-Trajković, Ljubica and Miljković, Đorđe and Trajković, Vladimir",
year = "2004",
abstract = "The influence of a nucleoside analog 5-aza-2'-deoxycytidine (5-AzadC) on inducible nitric oxide synthase (iNOS)-dependent nitric oxide (NO) production in various rat cell types was investigated. In C6 astrocytoma cell line and primary astrocytes, 5-AzadC enhanced proinflammatory cytokine (IFN-gamma, TNF-alpha, IL-1)-triggered NO synthesis in a time- and dose-dependent manner. In contrast, 5-AzadC did not potentiate NO production in IFN-gamma-stimulated macrophages, fibroblasts, or endothelial cells. Blockade of transcription or translation in C6 cells abolished the observed effect, suggesting the iNOS gene expression, rather than its catalytic activity, as a target for the drug action. Accordingly, 5-AzadC upregulated IFN-gamma-induced expression of iNOS mRNA in C6 astrocytes. The effect of 5-AzadC on astrocyte NO release was blocked by the inhibitor of p44/42 mitogen activated protein kinase-dependent signaling. Finally, the observed stimulatory effect of 5-AzadC on iNOS expression was apparently independent of DNA demethylation, as DNA digestion with methylation-sensitive restriction enzyme HpaII showed that 5-AzadC failed to demethylate cellular DNA in conditions used for iNOS induction.",
publisher = "Elsevier B.V.",
journal = "Brain Research",
title = "5-Aza-2'-deoxycytidine stimulates inducible nitric oxide synthase induction in C6 astrocytoma cells",
number = "1",
volume = "998",
doi = "10.1016/j.brainres.2003.11.014",
pages = "83-90"
}

Stojanović, I. D., Popadić, D., Vučković, O., Harhaji-Trajković, L., Miljković, Đ.,& Trajković, V.. (2004). 5-Aza-2'-deoxycytidine stimulates inducible nitric oxide synthase induction in C6 astrocytoma cells. in Brain Research
Elsevier B.V.., 998(1), 83-90.
https://doi.org/10.1016/j.brainres.2003.11.014

Stojanović ID, Popadić D, Vučković O, Harhaji-Trajković L, Miljković Đ, Trajković V. 5-Aza-2'-deoxycytidine stimulates inducible nitric oxide synthase induction in C6 astrocytoma cells. in Brain Research. 2004;998(1):83-90.
doi:10.1016/j.brainres.2003.11.014 .

Stojanović, Ivana D., Popadić, Dušan, Vučković, Olivera, Harhaji-Trajković, Ljubica, Miljković, Đorđe, Trajković, Vladimir, "5-Aza-2'-deoxycytidine stimulates inducible nitric oxide synthase induction in C6 astrocytoma cells" in Brain Research, 998, no. 1 (2004):83-90,
https://doi.org/10.1016/j.brainres.2003.11.014 . .

TY  - JOUR
AU  - Drulović, Jelena
AU  - Popadić, Dušan
AU  - Mesaroš, Šarlota
AU  - Dujmović, Irena
AU  - Stojanović, Ivana D.
AU  - Miljković, Djordje
AU  - Stojsavljević, Nebojša
AU  - Pravica, Vera
AU  - Pekmezović, Tatjana
AU  - Bogdanović, Gradimir
AU  - Jarebinski, Mirjana
AU  - Mostarica Stojković, Marija
PY  - 2003
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5924
AB  - Tumor necrosis factor (TNF) alpha has been considered the prototypic cytopathogenic cytokine in multiple sclerosis (MS), but recently this cytokine has been shown to possess significant anti-inflammatory and neuroprotective effects in demyelinating diseases. It has been reported that the TNFalpha -308 polymorphism influences levels of TNFalpha production, and that the rare allele, TNF2, is associated with high TNFalpha production. We investigated the TNFalpha -308 polymorphism in 143 unrelated Serbian patients with MS and 123 ethnically matched, healthy individuals using the allele-specific restriction fragment length polymorphism polymerase chain reaction technique. The frequency of the TNF2 allele was significantly decreased in MS patients (14%) in comparison with controls (24%; p = 0.044). The TNF2 allele had no influence on disease behavior, since it was not associated with the course and severity of MS in this group of patients. The result suggests that in the Serbian population polymorphism at position -308 of TNFalpha or at an adjacent locus might have a role in MS susceptibility.
PB  - Basel: Krager AG
T2  - European Neurology
T1  - Decreased Frequency of the Tumor Necrosis Factor α –308 Allele in Serbian Patients with Multiple Sclerosis
IS  - 1
VL  - 50
DO  - 10.1159/000070855
SP  - 25
EP  - 29
ER  - 

@article{
author = "Drulović, Jelena and Popadić, Dušan and Mesaroš, Šarlota and Dujmović, Irena and Stojanović, Ivana D. and Miljković, Djordje and Stojsavljević, Nebojša and Pravica, Vera and Pekmezović, Tatjana and Bogdanović, Gradimir and Jarebinski, Mirjana and Mostarica Stojković, Marija",
year = "2003",
abstract = "Tumor necrosis factor (TNF) alpha has been considered the prototypic cytopathogenic cytokine in multiple sclerosis (MS), but recently this cytokine has been shown to possess significant anti-inflammatory and neuroprotective effects in demyelinating diseases. It has been reported that the TNFalpha -308 polymorphism influences levels of TNFalpha production, and that the rare allele, TNF2, is associated with high TNFalpha production. We investigated the TNFalpha -308 polymorphism in 143 unrelated Serbian patients with MS and 123 ethnically matched, healthy individuals using the allele-specific restriction fragment length polymorphism polymerase chain reaction technique. The frequency of the TNF2 allele was significantly decreased in MS patients (14%) in comparison with controls (24%; p = 0.044). The TNF2 allele had no influence on disease behavior, since it was not associated with the course and severity of MS in this group of patients. The result suggests that in the Serbian population polymorphism at position -308 of TNFalpha or at an adjacent locus might have a role in MS susceptibility.",
publisher = "Basel: Krager AG",
journal = "European Neurology",
title = "Decreased Frequency of the Tumor Necrosis Factor α –308 Allele in Serbian Patients with Multiple Sclerosis",
number = "1",
volume = "50",
doi = "10.1159/000070855",
pages = "25-29"
}

Drulović, J., Popadić, D., Mesaroš, Š., Dujmović, I., Stojanović, I. D., Miljković, D., Stojsavljević, N., Pravica, V., Pekmezović, T., Bogdanović, G., Jarebinski, M.,& Mostarica Stojković, M.. (2003). Decreased Frequency of the Tumor Necrosis Factor α –308 Allele in Serbian Patients with Multiple Sclerosis. in European Neurology
Basel: Krager AG., 50(1), 25-29.
https://doi.org/10.1159/000070855

Drulović J, Popadić D, Mesaroš Š, Dujmović I, Stojanović ID, Miljković D, Stojsavljević N, Pravica V, Pekmezović T, Bogdanović G, Jarebinski M, Mostarica Stojković M. Decreased Frequency of the Tumor Necrosis Factor α –308 Allele in Serbian Patients with Multiple Sclerosis. in European Neurology. 2003;50(1):25-29.
doi:10.1159/000070855 .

Drulović, Jelena, Popadić, Dušan, Mesaroš, Šarlota, Dujmović, Irena, Stojanović, Ivana D., Miljković, Djordje, Stojsavljević, Nebojša, Pravica, Vera, Pekmezović, Tatjana, Bogdanović, Gradimir, Jarebinski, Mirjana, Mostarica Stojković, Marija, "Decreased Frequency of the Tumor Necrosis Factor α –308 Allele in Serbian Patients with Multiple Sclerosis" in European Neurology, 50, no. 1 (2003):25-29,
https://doi.org/10.1159/000070855 . .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Samardžić, Tatjana
AU  - Mostarica Stojković, Marija
AU  - Stošić-Grujičić, Stanislava
AU  - Popadić, Dušan
AU  - Trajković, Vladimir
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5994
AB  - Highly reactive gaseous free radical nitric oxide (NO), generated by astrocytes and infiltrating macrophages is implicated in
inflammatory destruction of brain tissue, including that occurring in multiple sclerosis. Therefore, the influence of immunosuppressive
drug leflunomide on inducible nitric oxide synthase (iNOS)-dependent NO production in rat astrocytes and macrophages was investigated.
Under the same cultivating conditions, leflunomide’s active metabolite A77 1726 caused a dose-dependent decrease of NO production in
IFN-g1LPS-stimulated primary astrocytes, but not in macrophages. While A77 1726 did not alter iNOS enzymatic activity, it markedly
suppressed IFN-g1LPS-triggered expression of iNOS mRNA in astrocytes. In the presence of transcription inhibitor actinomycin D, A77
1726 failed to inhibit astrocyte NO production, suggesting transcriptional regulation of iNOS by leflunomide. This assumption was further
supported by the ability of A77 1726 to inhibit IFN-g1LPS-induced expression of mRNA for an important iNOS transcription factor
IRF-1. PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), but not genistein, an unselective
protein tyrosine kinase inhibitor, completely mimicked cell type-specific inhibition of NO synthesis by A77 1726. Therefore, previously
described inhibition of MEK/MAP pathway by leflunomide could present a possible mechanism for A77 1726-mediated suppression of
iNOS activation in astrocytes. Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced
IFN-g1LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6. The ability to suppress iNOS induction in astrocytes
supports potential use of leflunomide in the treatment of multiple sclerosis and other NO-dependent inflammatory brain disorders.
PB  - Elsevier Science B.V.
T2  - Brain Research
T1  - Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes
IS  - 1-2
VL  - 889
DO  - 10.1016/s0006-8993(00)03181-4
SP  - 331
EP  - 338
ER  - 

@article{
author = "Miljković, Đorđe and Samardžić, Tatjana and Mostarica Stojković, Marija and Stošić-Grujičić, Stanislava and Popadić, Dušan and Trajković, Vladimir",
year = "2001",
abstract = "Highly reactive gaseous free radical nitric oxide (NO), generated by astrocytes and infiltrating macrophages is implicated in
inflammatory destruction of brain tissue, including that occurring in multiple sclerosis. Therefore, the influence of immunosuppressive
drug leflunomide on inducible nitric oxide synthase (iNOS)-dependent NO production in rat astrocytes and macrophages was investigated.
Under the same cultivating conditions, leflunomide’s active metabolite A77 1726 caused a dose-dependent decrease of NO production in
IFN-g1LPS-stimulated primary astrocytes, but not in macrophages. While A77 1726 did not alter iNOS enzymatic activity, it markedly
suppressed IFN-g1LPS-triggered expression of iNOS mRNA in astrocytes. In the presence of transcription inhibitor actinomycin D, A77
1726 failed to inhibit astrocyte NO production, suggesting transcriptional regulation of iNOS by leflunomide. This assumption was further
supported by the ability of A77 1726 to inhibit IFN-g1LPS-induced expression of mRNA for an important iNOS transcription factor
IRF-1. PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), but not genistein, an unselective
protein tyrosine kinase inhibitor, completely mimicked cell type-specific inhibition of NO synthesis by A77 1726. Therefore, previously
described inhibition of MEK/MAP pathway by leflunomide could present a possible mechanism for A77 1726-mediated suppression of
iNOS activation in astrocytes. Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced
IFN-g1LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6. The ability to suppress iNOS induction in astrocytes
supports potential use of leflunomide in the treatment of multiple sclerosis and other NO-dependent inflammatory brain disorders.",
publisher = "Elsevier Science B.V.",
journal = "Brain Research",
title = "Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes",
number = "1-2",
volume = "889",
doi = "10.1016/s0006-8993(00)03181-4",
pages = "331-338"
}

Miljković, Đ., Samardžić, T., Mostarica Stojković, M., Stošić-Grujičić, S., Popadić, D.,& Trajković, V.. (2001). Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes. in Brain Research
Elsevier Science B.V.., 889(1-2), 331-338.
https://doi.org/10.1016/s0006-8993(00)03181-4

Miljković Đ, Samardžić T, Mostarica Stojković M, Stošić-Grujičić S, Popadić D, Trajković V. Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes. in Brain Research. 2001;889(1-2):331-338.
doi:10.1016/s0006-8993(00)03181-4 .

Miljković, Đorđe, Samardžić, Tatjana, Mostarica Stojković, Marija, Stošić-Grujičić, Stanislava, Popadić, Dušan, Trajković, Vladimir, "Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes" in Brain Research, 889, no. 1-2 (2001):331-338,
https://doi.org/10.1016/s0006-8993(00)03181-4 . .

TY  - JOUR
AU  - Trajković, Vladimir
AU  - Janković, Vladimir
AU  - Badovinac, Vladimir
AU  - Samardžić, Tamara
AU  - Maksimović-Ivanić, Danijela
AU  - Popadić, Dušan
PY  - 1999
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3823
AB  - The effects of immunosuppressant cyclosporin A (CsA) on nitric oxide (NO) production and inducible NO synthase (iNOS) activity in murine L929 fibroblasts were investigated. IFN-gamma-induced NO production in L929 cells was mediated through an iNOS-dependent L-arginine-NO pathway, since it was abrogated by a selective inhibitor of iNOS, aminoguanidine. CsA applied simultaneously with IFN-gamma caused a dose-dependent reduction of NO synthesis in L929 cells. However, CsA did not influence the enzymatic activity of iNOS, since it failed to affect NO production in cells in which iNOS had already been induced with IFN-gamma and any further induction was blocked by the protein-synthesis inhibitor cycloheximide. IFN-gamma-triggered expression of mRNA for interferon regulatory factor-1 was not reduced by CsA-treatment, suggesting that this iNOS transcription factor is not a target in CsA-mediated inhibition of NO synthesis. Finally, FK506 was not able to mimic the inhibitory effect of CsA on NO production in L929 cells, indicating the calcineurin-independent mechanism of CsA action. These results indicate that CsA suppresses NO synthesis in L929 cells independent of calcineurin inhibition, and interfering with intracellular pathways involved in the iNOS induction, rather than inhibiting its enzymatic activity.
PB  - New Jerswy: Wiley-VCH Verlag GmbH & Co
T2  - Scandinavian Journal of Immunology
T1  - Cyclosporin A suppresses the induction of nitric oxide synthesis in interferon-gamma-treated L929 fibroblasts
IS  - 2
VL  - 49
DO  - 10.1046/j.1365-3083.1999.00468.x
SP  - 126
EP  - 130
ER  - 

@article{
author = "Trajković, Vladimir and Janković, Vladimir and Badovinac, Vladimir and Samardžić, Tamara and Maksimović-Ivanić, Danijela and Popadić, Dušan",
year = "1999",
abstract = "The effects of immunosuppressant cyclosporin A (CsA) on nitric oxide (NO) production and inducible NO synthase (iNOS) activity in murine L929 fibroblasts were investigated. IFN-gamma-induced NO production in L929 cells was mediated through an iNOS-dependent L-arginine-NO pathway, since it was abrogated by a selective inhibitor of iNOS, aminoguanidine. CsA applied simultaneously with IFN-gamma caused a dose-dependent reduction of NO synthesis in L929 cells. However, CsA did not influence the enzymatic activity of iNOS, since it failed to affect NO production in cells in which iNOS had already been induced with IFN-gamma and any further induction was blocked by the protein-synthesis inhibitor cycloheximide. IFN-gamma-triggered expression of mRNA for interferon regulatory factor-1 was not reduced by CsA-treatment, suggesting that this iNOS transcription factor is not a target in CsA-mediated inhibition of NO synthesis. Finally, FK506 was not able to mimic the inhibitory effect of CsA on NO production in L929 cells, indicating the calcineurin-independent mechanism of CsA action. These results indicate that CsA suppresses NO synthesis in L929 cells independent of calcineurin inhibition, and interfering with intracellular pathways involved in the iNOS induction, rather than inhibiting its enzymatic activity.",
publisher = "New Jerswy: Wiley-VCH Verlag GmbH & Co",
journal = "Scandinavian Journal of Immunology",
title = "Cyclosporin A suppresses the induction of nitric oxide synthesis in interferon-gamma-treated L929 fibroblasts",
number = "2",
volume = "49",
doi = "10.1046/j.1365-3083.1999.00468.x",
pages = "126-130"
}

Trajković, V., Janković, V., Badovinac, V., Samardžić, T., Maksimović-Ivanić, D.,& Popadić, D.. (1999). Cyclosporin A suppresses the induction of nitric oxide synthesis in interferon-gamma-treated L929 fibroblasts. in Scandinavian Journal of Immunology
New Jerswy: Wiley-VCH Verlag GmbH & Co., 49(2), 126-130.
https://doi.org/10.1046/j.1365-3083.1999.00468.x

Trajković V, Janković V, Badovinac V, Samardžić T, Maksimović-Ivanić D, Popadić D. Cyclosporin A suppresses the induction of nitric oxide synthesis in interferon-gamma-treated L929 fibroblasts. in Scandinavian Journal of Immunology. 1999;49(2):126-130.
doi:10.1046/j.1365-3083.1999.00468.x .

Trajković, Vladimir, Janković, Vladimir, Badovinac, Vladimir, Samardžić, Tamara, Maksimović-Ivanić, Danijela, Popadić, Dušan, "Cyclosporin A suppresses the induction of nitric oxide synthesis in interferon-gamma-treated L929 fibroblasts" in Scandinavian Journal of Immunology, 49, no. 2 (1999):126-130,
https://doi.org/10.1046/j.1365-3083.1999.00468.x . .