TY  - CONF
AU  - Jeremić, Marija
AU  - Jovanović, Maja
AU  - Tovilović-Kovačević, Gordana
AU  - Harhaji-Trajković, Ljubica
AU  - Zogović, Nevena
AU  - Vukojević, Milica
AU  - Kostić, Vladimir
AU  - Marković, Ivanka D.
AU  - Trajković, Vladimir
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4450
AB  - Alpha-synuclein (ASYN) is regarded as one of the key culprits in
pathogenesis of synucleinopathies, including Parkinson’s disease,
and impaired regulation of autophagy is associated with the
ASYN aggregation. Autophagy is regulated by complex mechanisms,
including AMP activated protein kinase (AMPK), a key
energy sensor regulating cellular metabolism to maintain energy
homeostasis. The aim of our study was to investigate the role of
AMPK and autophagy in neurotoxic effect of secreted ASYN, as
well as dopamine-modified and nitrated recombinant wild-type
ASYN oligomers, on retinoic acid (RA)-differentiated SH-SY5Y
cells. The culture supernatant from neuroblastoma cells stably
expressing wt ASYN was collected and used as conditioned medium (CM). The presence of wt ASYN in CM was confirmed
by immunoblot, following lyophilisation. The CM, as well as
recombinant dopamine-modified or nitrated ASYN, all reduced
viability in differentiated SH-SY5Y cells. This decrease in viability
was accompanied by reduced AMPK activation, increased
conversion of LC3-I to LC3-II and increase in Beclin-1 level, as
demonstrated by immunoblot. Pharmacological activators of
AMPK and autophagy (metformin and AICAR) significantly
increased the cells’ viability in the presence of CM and modified
ASYN forms. Level of AMPK-activated pULK was reduced in
presence of CM, but pharmacological activators of AMPK
reversed that effect. Pharmacological inhibitors of autophagy,
further reduced cell viability in the presence of extracellular
ASYN. The shRNA-mediated LC3 downregulation, as well as
the RNA interference-mediated knockdown of ATG7 gene, both
important for autophagosome biogenesis/maturation, increased
sensitivity of SH-SY5Y cells to the extracellular ASYN-induced
toxicity. These data demonstrate the protective role of AMPK
and autophagy against the toxicity of extracellular ASYN, suggesting
that their modulation may be a promising neuroprotective
strategy in Parkinson’s disease.
PB  - Hoboken: Wiley
C3  - FEBS OpenBio
T1  - Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy
IS  - Supplement 1
VL  - 11
SP  - 463
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4450
ER  - 

@conference{
author = "Jeremić, Marija and Jovanović, Maja and Tovilović-Kovačević, Gordana and Harhaji-Trajković, Ljubica and Zogović, Nevena and Vukojević, Milica and Kostić, Vladimir and Marković, Ivanka D. and Trajković, Vladimir",
year = "2021",
abstract = "Alpha-synuclein (ASYN) is regarded as one of the key culprits in
pathogenesis of synucleinopathies, including Parkinson’s disease,
and impaired regulation of autophagy is associated with the
ASYN aggregation. Autophagy is regulated by complex mechanisms,
including AMP activated protein kinase (AMPK), a key
energy sensor regulating cellular metabolism to maintain energy
homeostasis. The aim of our study was to investigate the role of
AMPK and autophagy in neurotoxic effect of secreted ASYN, as
well as dopamine-modified and nitrated recombinant wild-type
ASYN oligomers, on retinoic acid (RA)-differentiated SH-SY5Y
cells. The culture supernatant from neuroblastoma cells stably
expressing wt ASYN was collected and used as conditioned medium (CM). The presence of wt ASYN in CM was confirmed
by immunoblot, following lyophilisation. The CM, as well as
recombinant dopamine-modified or nitrated ASYN, all reduced
viability in differentiated SH-SY5Y cells. This decrease in viability
was accompanied by reduced AMPK activation, increased
conversion of LC3-I to LC3-II and increase in Beclin-1 level, as
demonstrated by immunoblot. Pharmacological activators of
AMPK and autophagy (metformin and AICAR) significantly
increased the cells’ viability in the presence of CM and modified
ASYN forms. Level of AMPK-activated pULK was reduced in
presence of CM, but pharmacological activators of AMPK
reversed that effect. Pharmacological inhibitors of autophagy,
further reduced cell viability in the presence of extracellular
ASYN. The shRNA-mediated LC3 downregulation, as well as
the RNA interference-mediated knockdown of ATG7 gene, both
important for autophagosome biogenesis/maturation, increased
sensitivity of SH-SY5Y cells to the extracellular ASYN-induced
toxicity. These data demonstrate the protective role of AMPK
and autophagy against the toxicity of extracellular ASYN, suggesting
that their modulation may be a promising neuroprotective
strategy in Parkinson’s disease.",
publisher = "Hoboken: Wiley",
journal = "FEBS OpenBio",
title = "Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy",
number = "Supplement 1",
volume = "11",
pages = "463",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4450"
}

Jeremić, M., Jovanović, M., Tovilović-Kovačević, G., Harhaji-Trajković, L., Zogović, N., Vukojević, M., Kostić, V., Marković, I. D.,& Trajković, V.. (2021). Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy. in FEBS OpenBio
Hoboken: Wiley., 11(Supplement 1), 463.
https://hdl.handle.net/21.15107/rcub_ibiss_4450

Jeremić M, Jovanović M, Tovilović-Kovačević G, Harhaji-Trajković L, Zogović N, Vukojević M, Kostić V, Marković ID, Trajković V. Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy. in FEBS OpenBio. 2021;11(Supplement 1):463.
https://hdl.handle.net/21.15107/rcub_ibiss_4450 .

Jeremić, Marija, Jovanović, Maja, Tovilović-Kovačević, Gordana, Harhaji-Trajković, Ljubica, Zogović, Nevena, Vukojević, Milica, Kostić, Vladimir, Marković, Ivanka D., Trajković, Vladimir, "Neurotoxic effect of extracellular alpha-synuclein can be alleviated by AMPK and autophagy" in FEBS OpenBio, 11, no. Supplement 1 (2021):463,
https://hdl.handle.net/21.15107/rcub_ibiss_4450 .

TY  - CONF
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Ćirić, Darko
AU  - Martinović, Tamara
AU  - Jovanović, Maja
AU  - Isaković, Aleksandra
AU  - Marković, Ivanka
AU  - Zogović, Nevena
AU  - Foretz, Mark
AU  - Rabanal-Ruiz, Yoana
AU  - Korolchuk, Viktor
AU  - Trajković, Vladimir
PY  - 2019
UR  - https://www.fens.org/news-activities/fens-and-societies-calendar/meeting-event/fens-regional-meeting-2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6357
AB  - We investigated the effect of excitotoxic glutamate on nutrient starvation-induced autophagy, a process of lysosome-mediated degradation of cellular macromolecules and organelles. Incubation of SH-SY5Y human neuroblastoma cell line in glucose/amino acid/serum-free Hank Balanced Salt solution synergized with glutamate in causing energy stress and excitotoxic necrosis. Glutamate inhibited starvation-induced autophagy, as demonstrated by decreased intracellular acidification, lower LC3 punctuation, reduced conversion of LC3-I to LC3-II, reduced expression of autophagy activators beclin-1 and ATG5, increased
levels of the selective autophagic target NBR1, and decline in the number of autophagic vesicles observed by transmission electron microscopy. NMDA antagonist memantine restored LC3B-II accumulation in starved cells exposed to glutamate, indicating that glutamate exerts its inhibitory role on autophagy by activating NMDA receptors. The modulation of mTOR, the negative regulator of autophagy, was not responsible for glutamate-mediated autophagy inhibition during starvation. On the other hand, glutamate downregulated starvation-induced activation of the intracellular energy sensor AMP-activated protein
kinase (AMPK). This was associated with reduced mRNA expression of autophagy transcription factors FOXO3 and ATF4, as well as molecules involved in autophagy process (ULK1, ATG13, FIP200, ATG14, beclin-1, ATG5, ATG12, SQSTM1). The ability of glutamate to repress transcription of autophagy genes in starved cells was partly mediated by AMPK downregulation. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, rescued cells from glutamate-mediated excitoxicity. These data indicate that transcriptional inhibition of AMPK-dependent autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
PB  - Belgrade : Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Autophagy regulation and its role in glutamate excitotoxicity during nutrient stress
SP  - 144
EP  - 144
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6357
ER  - 

@conference{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Ćirić, Darko and Martinović, Tamara and Jovanović, Maja and Isaković, Aleksandra and Marković, Ivanka and Zogović, Nevena and Foretz, Mark and Rabanal-Ruiz, Yoana and Korolchuk, Viktor and Trajković, Vladimir",
year = "2019",
abstract = "We investigated the effect of excitotoxic glutamate on nutrient starvation-induced autophagy, a process of lysosome-mediated degradation of cellular macromolecules and organelles. Incubation of SH-SY5Y human neuroblastoma cell line in glucose/amino acid/serum-free Hank Balanced Salt solution synergized with glutamate in causing energy stress and excitotoxic necrosis. Glutamate inhibited starvation-induced autophagy, as demonstrated by decreased intracellular acidification, lower LC3 punctuation, reduced conversion of LC3-I to LC3-II, reduced expression of autophagy activators beclin-1 and ATG5, increased
levels of the selective autophagic target NBR1, and decline in the number of autophagic vesicles observed by transmission electron microscopy. NMDA antagonist memantine restored LC3B-II accumulation in starved cells exposed to glutamate, indicating that glutamate exerts its inhibitory role on autophagy by activating NMDA receptors. The modulation of mTOR, the negative regulator of autophagy, was not responsible for glutamate-mediated autophagy inhibition during starvation. On the other hand, glutamate downregulated starvation-induced activation of the intracellular energy sensor AMP-activated protein
kinase (AMPK). This was associated with reduced mRNA expression of autophagy transcription factors FOXO3 and ATF4, as well as molecules involved in autophagy process (ULK1, ATG13, FIP200, ATG14, beclin-1, ATG5, ATG12, SQSTM1). The ability of glutamate to repress transcription of autophagy genes in starved cells was partly mediated by AMPK downregulation. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, rescued cells from glutamate-mediated excitoxicity. These data indicate that transcriptional inhibition of AMPK-dependent autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Autophagy regulation and its role in glutamate excitotoxicity during nutrient stress",
pages = "144-144",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6357"
}

Vučićević, L., Misirkić Marjanović, M., Ćirić, D., Martinović, T., Jovanović, M., Isaković, A., Marković, I., Zogović, N., Foretz, M., Rabanal-Ruiz, Y., Korolchuk, V.,& Trajković, V.. (2019). Autophagy regulation and its role in glutamate excitotoxicity during nutrient stress. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade : Serbian Neuroscience Society., 144-144.
https://hdl.handle.net/21.15107/rcub_ibiss_6357

Vučićević L, Misirkić Marjanović M, Ćirić D, Martinović T, Jovanović M, Isaković A, Marković I, Zogović N, Foretz M, Rabanal-Ruiz Y, Korolchuk V, Trajković V. Autophagy regulation and its role in glutamate excitotoxicity during nutrient stress. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:144-144.
https://hdl.handle.net/21.15107/rcub_ibiss_6357 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Ćirić, Darko, Martinović, Tamara, Jovanović, Maja, Isaković, Aleksandra, Marković, Ivanka, Zogović, Nevena, Foretz, Mark, Rabanal-Ruiz, Yoana, Korolchuk, Viktor, Trajković, Vladimir, "Autophagy regulation and its role in glutamate excitotoxicity during nutrient stress" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):144-144,
https://hdl.handle.net/21.15107/rcub_ibiss_6357 .

TY  - CONF
AU  - Dulovic, M.
AU  - Jovanovic, M.
AU  - Harhaji-Trajković, Ljubica
AU  - Stefanis, L.
AU  - Xilouri, M.
AU  - Kostic, V.
AU  - Trajkovic, V.
AU  - Markovic, I.
PY  - 2014
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2155
C3  - European Neuropsychopharmacology
T1  - The protective role of AMPK and Akt in neurotoxicity caused by
 intracellular and extracellular alpha-synuclein accumulation in vitro
IS  - 2
VL  - 24
SP  - S641
EP  - S642
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_2155
ER  - 

@conference{
author = "Dulovic, M. and Jovanovic, M. and Harhaji-Trajković, Ljubica and Stefanis, L. and Xilouri, M. and Kostic, V. and Trajkovic, V. and Markovic, I.",
year = "2014",
journal = "European Neuropsychopharmacology",
title = "The protective role of AMPK and Akt in neurotoxicity caused by
 intracellular and extracellular alpha-synuclein accumulation in vitro",
number = "2",
volume = "24",
pages = "S641-S642",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_2155"
}

Dulovic, M., Jovanovic, M., Harhaji-Trajković, L., Stefanis, L., Xilouri, M., Kostic, V., Trajkovic, V.,& Markovic, I.. (2014). The protective role of AMPK and Akt in neurotoxicity caused by
 intracellular and extracellular alpha-synuclein accumulation in vitro. in European Neuropsychopharmacology, 24(2), S641-S642.
https://hdl.handle.net/21.15107/rcub_ibiss_2155

Dulovic M, Jovanovic M, Harhaji-Trajković L, Stefanis L, Xilouri M, Kostic V, Trajkovic V, Markovic I. The protective role of AMPK and Akt in neurotoxicity caused by
 intracellular and extracellular alpha-synuclein accumulation in vitro. in European Neuropsychopharmacology. 2014;24(2):S641-S642.
https://hdl.handle.net/21.15107/rcub_ibiss_2155 .

Dulovic, M., Jovanovic, M., Harhaji-Trajković, Ljubica, Stefanis, L., Xilouri, M., Kostic, V., Trajkovic, V., Markovic, I., "The protective role of AMPK and Akt in neurotoxicity caused by
 intracellular and extracellular alpha-synuclein accumulation in vitro" in European Neuropsychopharmacology, 24, no. 2 (2014):S641-S642,
https://hdl.handle.net/21.15107/rcub_ibiss_2155 .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Marković, Miloš
AU  - Trajković, Vladimir
PY  - 2004
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6012
AB  - The focus of this review is the influence of an immunosuppressive xenobiotic drug mycophenolic acid on the induction of nitric oxide production in various cell types. The potential therapeutic significance of the cell-specific fine-tuning of nitric oxide release by mycophenolic acid, as well as the mechanisms behind the drug action are discussed.
PB  - Bentham Science Publishers Ltd.
T2  - Mini-Reviews in Medicinal Chemistry
T1  - Inducible nitric oxide synthase inhibition by mycophenolic acid
IS  - 7
VL  - 4
DO  - 10.2174/1389557043403585
SP  - 741
EP  - 746
ER  - 

@article{
author = "Miljković, Đorđe and Marković, Miloš and Trajković, Vladimir",
year = "2004",
abstract = "The focus of this review is the influence of an immunosuppressive xenobiotic drug mycophenolic acid on the induction of nitric oxide production in various cell types. The potential therapeutic significance of the cell-specific fine-tuning of nitric oxide release by mycophenolic acid, as well as the mechanisms behind the drug action are discussed.",
publisher = "Bentham Science Publishers Ltd.",
journal = "Mini-Reviews in Medicinal Chemistry",
title = "Inducible nitric oxide synthase inhibition by mycophenolic acid",
number = "7",
volume = "4",
doi = "10.2174/1389557043403585",
pages = "741-746"
}

Miljković, Đ., Marković, M.,& Trajković, V.. (2004). Inducible nitric oxide synthase inhibition by mycophenolic acid. in Mini-Reviews in Medicinal Chemistry
Bentham Science Publishers Ltd.., 4(7), 741-746.
https://doi.org/10.2174/1389557043403585

Miljković Đ, Marković M, Trajković V. Inducible nitric oxide synthase inhibition by mycophenolic acid. in Mini-Reviews in Medicinal Chemistry. 2004;4(7):741-746.
doi:10.2174/1389557043403585 .

Miljković, Đorđe, Marković, Miloš, Trajković, Vladimir, "Inducible nitric oxide synthase inhibition by mycophenolic acid" in Mini-Reviews in Medicinal Chemistry, 4, no. 7 (2004):741-746,
https://doi.org/10.2174/1389557043403585 . .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Samardzić, Tatjana
AU  - Drakulić, Danijela
AU  - Stošić-Grujičić, Stanislava
AU  - Trajković, Vladimir
PY  - 2002
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6000
AB  - Mycophenolic acid (MPA) and A77 1726, the active components of the immunosuppressants mycophenolate mophetil and leflunomide, respectively, in a dose-dependent manner inhibited interferon (IFN)-gamma/LPS-induced interleukin (IL)-6 release in confluent cultures of mouse L929 fibrosarcoma cells. In addition, both drugs markedly reduced the production of the free radical gas nitric oxide (NO), without affecting the viability of L929 cells. The inhibitors of NO synthase, aminoguanidine and L-NMMA, but not L-NMMA inactive counterpart D-NMMA, mimicked the effects of A77 1726 and MPA on IL-6 generation in L929 fibroblasts. Furthermore, NO-releasing substance SNP completely reverted IL-6 accumulation in L929 cultures treated with A77 1726, while only partial recovery of IL-6 production was observed in the presence of MPA. MPA, but not A77 1726, significantly suppressed NO-independent IL-6 release triggered by cAMP-elevating agent rolipram. Thus, while A77 1726 effect on IL-6 production was mediated through concomitant reduction of NO synthesis, MPA action was mainly independent of the interference with NO generation. Finally, both agents inhibited IFN-gamma/LPS-triggered IL-6 production in mouse primary fibroblasts, but not in mouse peritoneal macrophages, indicating cell-specificity of this novel anti-inflammatory action of A77 1726 and MPA.
PB  - Elsevier
T2  - Cytokine
T1  - Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms
IS  - 4
VL  - 19
DO  - 10.1006/cyto.2002.0885
SP  - 181
EP  - 186
ER  - 

@article{
author = "Miljković, Đorđe and Samardzić, Tatjana and Drakulić, Danijela and Stošić-Grujičić, Stanislava and Trajković, Vladimir",
year = "2002",
abstract = "Mycophenolic acid (MPA) and A77 1726, the active components of the immunosuppressants mycophenolate mophetil and leflunomide, respectively, in a dose-dependent manner inhibited interferon (IFN)-gamma/LPS-induced interleukin (IL)-6 release in confluent cultures of mouse L929 fibrosarcoma cells. In addition, both drugs markedly reduced the production of the free radical gas nitric oxide (NO), without affecting the viability of L929 cells. The inhibitors of NO synthase, aminoguanidine and L-NMMA, but not L-NMMA inactive counterpart D-NMMA, mimicked the effects of A77 1726 and MPA on IL-6 generation in L929 fibroblasts. Furthermore, NO-releasing substance SNP completely reverted IL-6 accumulation in L929 cultures treated with A77 1726, while only partial recovery of IL-6 production was observed in the presence of MPA. MPA, but not A77 1726, significantly suppressed NO-independent IL-6 release triggered by cAMP-elevating agent rolipram. Thus, while A77 1726 effect on IL-6 production was mediated through concomitant reduction of NO synthesis, MPA action was mainly independent of the interference with NO generation. Finally, both agents inhibited IFN-gamma/LPS-triggered IL-6 production in mouse primary fibroblasts, but not in mouse peritoneal macrophages, indicating cell-specificity of this novel anti-inflammatory action of A77 1726 and MPA.",
publisher = "Elsevier",
journal = "Cytokine",
title = "Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms",
number = "4",
volume = "19",
doi = "10.1006/cyto.2002.0885",
pages = "181-186"
}

Miljković, Đ., Samardzić, T., Drakulić, D., Stošić-Grujičić, S.,& Trajković, V.. (2002). Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms. in Cytokine
Elsevier., 19(4), 181-186.
https://doi.org/10.1006/cyto.2002.0885

Miljković Đ, Samardzić T, Drakulić D, Stošić-Grujičić S, Trajković V. Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms. in Cytokine. 2002;19(4):181-186.
doi:10.1006/cyto.2002.0885 .

Miljković, Đorđe, Samardzić, Tatjana, Drakulić, Danijela, Stošić-Grujičić, Stanislava, Trajković, Vladimir, "Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms" in Cytokine, 19, no. 4 (2002):181-186,
https://doi.org/10.1006/cyto.2002.0885 . .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Samardžić, Tatjana
AU  - Stojanović, Ivana D.
AU  - Mostarica Stojković, Marija
AU  - Trajković, Vladimir
PY  - 2002
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5921
AB  - Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamam (IFN-gamma)  lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDHdependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma  LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor- (TNF-) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis
PB  - Hoboken: Wiley
T2  - Glia
T1  - Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes
IS  - 3
VL  - 39
DO  - 10.1002/glia.10089
SP  - 247
EP  - 255
ER  - 

@article{
author = "Miljković, Đorđe and Samardžić, Tatjana and Stojanović, Ivana D. and Mostarica Stojković, Marija and Trajković, Vladimir",
year = "2002",
abstract = "Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamam (IFN-gamma)  lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDHdependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma  LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor- (TNF-) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis",
publisher = "Hoboken: Wiley",
journal = "Glia",
title = "Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes",
number = "3",
volume = "39",
doi = "10.1002/glia.10089",
pages = "247-255"
}

Miljković, Đ., Samardžić, T., Stojanović, I. D., Mostarica Stojković, M.,& Trajković, V.. (2002). Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes. in Glia
Hoboken: Wiley., 39(3), 247-255.
https://doi.org/10.1002/glia.10089

Miljković Đ, Samardžić T, Stojanović ID, Mostarica Stojković M, Trajković V. Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes. in Glia. 2002;39(3):247-255.
doi:10.1002/glia.10089 .

Miljković, Đorđe, Samardžić, Tatjana, Stojanović, Ivana D., Mostarica Stojković, Marija, Trajković, Vladimir, "Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes" in Glia, 39, no. 3 (2002):247-255,
https://doi.org/10.1002/glia.10089 . .

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 . .