TY  - CONF
AU  - Zeković, Janko
AU  - Vidičević Novaković, Sašenka
AU  - Tasić, Jelena
AU  - Stanojević, Željka
AU  - Milovanović, Andona
AU  - Tomonjić, Nina
AU  - Petričević, Saša
AU  - Zogović, Nevena
AU  - Tovilović-Kovačević, Gordana
AU  - Trajković, Vladimir
AU  - Isaković, Aleksandra
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5839
AB  - Introduction: Cuprizone is a copper chelating agent rensposible for toxic
demyelination. Although its mechanism of demyelination is not fully elucidated, its
toxicity is thought to result, at least partially, from induced autophagy.
The Aim: To examine the effect of cuprizone on autophagy markers in different
neural structures in rats with the assessment of behavior in the open field test.
Material and Methods: This study was performed on 16 female DA rats, 6 weeks
old.The control group (n=8) did not receive cuprizone, while the experimental group
(n=8) received food with 0.6% cuprizone content during 7 weeks. Afterwards,
locomotion and anxiety-like behavior were assessed in the open field test. Imunoblot
technique was performed on: cortex, corpus callosum, cerebellum and spinal cord, in
order to examine the markers of autophagy signaling pathway: pUlk, p62, Beclin1,
LC3II, pAMPK, pmTOR and pRaptor.
Results: Cuprizone-fed animals had a reduced locomotor activity and exhibited an
anxiety-like behavior. In the cortex, p62 and pAMPK were decreased, while pmTOR
tended to be lower. In the corpus callosum, pULK was increased and pmTOR was
decreased. LC3II tended to be increased, while pAMPK tended to be decreased. In the
cerebellum, pAMPK was reduced, while pmTOR was increased. In the spinal cord,
Beclin1 and pRaptor were decreased, while pmTOR, pAMPK, LC3II, p62 tended to
be decreased.
Conclusion: Long-term use of cuprizone leads to impaired locomotor activity and

anxiety-like behavior. Cuprizone-induced damage is most likely due to AMPK-
independent autophagy in the cortex and corpus callosum, while autophagy is

probably inhibited in the cerebellum and spinal cord.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - Effects of cuprizone-induced demyelination on autophagy markers in different neural structures with the evaluation of behavior in rats
SP  - 80
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5839
ER  - 

@conference{
author = "Zeković, Janko and Vidičević Novaković, Sašenka and Tasić, Jelena and Stanojević, Željka and Milovanović, Andona and Tomonjić, Nina and Petričević, Saša and Zogović, Nevena and Tovilović-Kovačević, Gordana and Trajković, Vladimir and Isaković, Aleksandra",
year = "2023",
abstract = "Introduction: Cuprizone is a copper chelating agent rensposible for toxic
demyelination. Although its mechanism of demyelination is not fully elucidated, its
toxicity is thought to result, at least partially, from induced autophagy.
The Aim: To examine the effect of cuprizone on autophagy markers in different
neural structures in rats with the assessment of behavior in the open field test.
Material and Methods: This study was performed on 16 female DA rats, 6 weeks
old.The control group (n=8) did not receive cuprizone, while the experimental group
(n=8) received food with 0.6% cuprizone content during 7 weeks. Afterwards,
locomotion and anxiety-like behavior were assessed in the open field test. Imunoblot
technique was performed on: cortex, corpus callosum, cerebellum and spinal cord, in
order to examine the markers of autophagy signaling pathway: pUlk, p62, Beclin1,
LC3II, pAMPK, pmTOR and pRaptor.
Results: Cuprizone-fed animals had a reduced locomotor activity and exhibited an
anxiety-like behavior. In the cortex, p62 and pAMPK were decreased, while pmTOR
tended to be lower. In the corpus callosum, pULK was increased and pmTOR was
decreased. LC3II tended to be increased, while pAMPK tended to be decreased. In the
cerebellum, pAMPK was reduced, while pmTOR was increased. In the spinal cord,
Beclin1 and pRaptor were decreased, while pmTOR, pAMPK, LC3II, p62 tended to
be decreased.
Conclusion: Long-term use of cuprizone leads to impaired locomotor activity and

anxiety-like behavior. Cuprizone-induced damage is most likely due to AMPK-
independent autophagy in the cortex and corpus callosum, while autophagy is

probably inhibited in the cerebellum and spinal cord.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "Effects of cuprizone-induced demyelination on autophagy markers in different neural structures with the evaluation of behavior in rats",
pages = "80",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5839"
}

Zeković, J., Vidičević Novaković, S., Tasić, J., Stanojević, Ž., Milovanović, A., Tomonjić, N., Petričević, S., Zogović, N., Tovilović-Kovačević, G., Trajković, V.,& Isaković, A.. (2023). Effects of cuprizone-induced demyelination on autophagy markers in different neural structures with the evaluation of behavior in rats. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 80.
https://hdl.handle.net/21.15107/rcub_ibiss_5839

Zeković J, Vidičević Novaković S, Tasić J, Stanojević Ž, Milovanović A, Tomonjić N, Petričević S, Zogović N, Tovilović-Kovačević G, Trajković V, Isaković A. Effects of cuprizone-induced demyelination on autophagy markers in different neural structures with the evaluation of behavior in rats. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:80.
https://hdl.handle.net/21.15107/rcub_ibiss_5839 .

Zeković, Janko, Vidičević Novaković, Sašenka, Tasić, Jelena, Stanojević, Željka, Milovanović, Andona, Tomonjić, Nina, Petričević, Saša, Zogović, Nevena, Tovilović-Kovačević, Gordana, Trajković, Vladimir, Isaković, Aleksandra, "Effects of cuprizone-induced demyelination on autophagy markers in different neural structures with the evaluation of behavior in rats" in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):80,
https://hdl.handle.net/21.15107/rcub_ibiss_5839 .

TY  - JOUR
AU  - Mandić, Miloš
AU  - Misirkić Marjanović, Maja
AU  - Vučićević, Ljubica
AU  - Jovanović, Maja
AU  - Bošnjak, Mihajlo
AU  - Perović, Vladimir
AU  - Ristić, Biljana
AU  - Ćirić, Darko
AU  - Harhaji-Trajković, Ljubica
AU  - Trajković, Vladimir
PY  - 2022
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0024320522001813
UR  - http://www.ncbi.nlm.nih.gov/pubmed/35304128
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4947
AB  - We investigated the mechanisms and the role of autophagy in the differentiation of HL-60 human acute myeloid leukemia cells induced by protein kinase C (PKC) activator phorbol myristate acetate (PMA). PMA-triggered differentiation of HL-60 cells into macrophage-like cells was confirmed by cell-cycle arrest accompanied by elevated expression of macrophage markers CD11b, CD13, CD14, CD45, EGR1, CSF1R, and IL-8. The induction of autophagy was demonstrated by the increase in intracellular acidification, accumulation/punctuation of autophagosome marker LC3-II, and the increase in autophagic flux. PMA also increased nuclear translocation of autophagy transcription factors TFEB, FOXO1, and FOXO3, as well as the expression of several autophagy-related (ATG) genes in HL-60 cells. PMA failed to activate autophagy inducer AMP-activated protein kinase (AMPK) and inhibit autophagy suppressor mechanistic target of rapamycin complex 1 (mTORC1). On the other hand, it readily stimulated the phosphorylation of mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) via a protein kinase C-dependent mechanism. Pharmacological or genetic inhibition of ERK or JNK suppressed PMA-triggered nuclear translocation of TFEB and FOXO1/3, ATG expression, dissociation of pro-autophagic beclin-1 from its inhibitor BCL2, autophagy induction, and differentiation of HL-60 cells into macrophage-like cells. Pharmacological or genetic inhibition of autophagy also blocked PMA-induced macrophage differentiation of HL-60 cells. Therefore, MAP kinases ERK and JNK control PMA-induced macrophage differentiation of HL-60 leukemia cells through AMPK/mTORC1-independent, TFEB/FOXO-mediated transcriptional and beclin-1-dependent post-translational activation of autophagy.
PB  - Elsevier Inc.
T2  - Life Sciences
T1  - MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.
VL  - 297
DO  - 10.1016/j.lfs.2022.120481
SP  - 120481
ER  - 

@article{
author = "Mandić, Miloš and Misirkić Marjanović, Maja and Vučićević, Ljubica and Jovanović, Maja and Bošnjak, Mihajlo and Perović, Vladimir and Ristić, Biljana and Ćirić, Darko and Harhaji-Trajković, Ljubica and Trajković, Vladimir",
year = "2022",
abstract = "We investigated the mechanisms and the role of autophagy in the differentiation of HL-60 human acute myeloid leukemia cells induced by protein kinase C (PKC) activator phorbol myristate acetate (PMA). PMA-triggered differentiation of HL-60 cells into macrophage-like cells was confirmed by cell-cycle arrest accompanied by elevated expression of macrophage markers CD11b, CD13, CD14, CD45, EGR1, CSF1R, and IL-8. The induction of autophagy was demonstrated by the increase in intracellular acidification, accumulation/punctuation of autophagosome marker LC3-II, and the increase in autophagic flux. PMA also increased nuclear translocation of autophagy transcription factors TFEB, FOXO1, and FOXO3, as well as the expression of several autophagy-related (ATG) genes in HL-60 cells. PMA failed to activate autophagy inducer AMP-activated protein kinase (AMPK) and inhibit autophagy suppressor mechanistic target of rapamycin complex 1 (mTORC1). On the other hand, it readily stimulated the phosphorylation of mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) via a protein kinase C-dependent mechanism. Pharmacological or genetic inhibition of ERK or JNK suppressed PMA-triggered nuclear translocation of TFEB and FOXO1/3, ATG expression, dissociation of pro-autophagic beclin-1 from its inhibitor BCL2, autophagy induction, and differentiation of HL-60 cells into macrophage-like cells. Pharmacological or genetic inhibition of autophagy also blocked PMA-induced macrophage differentiation of HL-60 cells. Therefore, MAP kinases ERK and JNK control PMA-induced macrophage differentiation of HL-60 leukemia cells through AMPK/mTORC1-independent, TFEB/FOXO-mediated transcriptional and beclin-1-dependent post-translational activation of autophagy.",
publisher = "Elsevier Inc.",
journal = "Life Sciences",
title = "MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.",
volume = "297",
doi = "10.1016/j.lfs.2022.120481",
pages = "120481"
}

Mandić, M., Misirkić Marjanović, M., Vučićević, L., Jovanović, M., Bošnjak, M., Perović, V., Ristić, B., Ćirić, D., Harhaji-Trajković, L.,& Trajković, V.. (2022). MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.. in Life Sciences
Elsevier Inc.., 297, 120481.
https://doi.org/10.1016/j.lfs.2022.120481

Mandić M, Misirkić Marjanović M, Vučićević L, Jovanović M, Bošnjak M, Perović V, Ristić B, Ćirić D, Harhaji-Trajković L, Trajković V. MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.. in Life Sciences. 2022;297:120481.
doi:10.1016/j.lfs.2022.120481 .

Mandić, Miloš, Misirkić Marjanović, Maja, Vučićević, Ljubica, Jovanović, Maja, Bošnjak, Mihajlo, Perović, Vladimir, Ristić, Biljana, Ćirić, Darko, Harhaji-Trajković, Ljubica, Trajković, Vladimir, "MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells." in Life Sciences, 297 (2022):120481,
https://doi.org/10.1016/j.lfs.2022.120481 . .

TY  - JOUR
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Ćirić, Darko
AU  - Martinović, Tamara
AU  - Jovanović, Maja
AU  - Isaković, Aleksandra
AU  - Marković, Ivanka
AU  - Šaponjić, Jasna
AU  - Foretz, Marc
AU  - Rabanal-Ruiz, Yoana
AU  - Korolchuk, Viktor I.
AU  - Trajković, Vladimir
PY  - 2020
UR  - http://link.springer.com/10.1007/s00018-019-03356-2
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3528
AB  - We investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
T2  - Cellular and Molecular Life Sciences
T1  - Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.
VL  - 77
DO  - 10.1007/s00018-019-03356-2
SP  - 3383
EP  - 3399
ER  - 

@article{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Ćirić, Darko and Martinović, Tamara and Jovanović, Maja and Isaković, Aleksandra and Marković, Ivanka and Šaponjić, Jasna and Foretz, Marc and Rabanal-Ruiz, Yoana and Korolchuk, Viktor I. and Trajković, Vladimir",
year = "2020",
abstract = "We investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.",
journal = "Cellular and Molecular Life Sciences",
title = "Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.",
volume = "77",
doi = "10.1007/s00018-019-03356-2",
pages = "3383-3399"
}

Vučićević, L., Misirkić Marjanović, M., Ćirić, D., Martinović, T., Jovanović, M., Isaković, A., Marković, I., Šaponjić, J., Foretz, M., Rabanal-Ruiz, Y., Korolchuk, V. I.,& Trajković, V.. (2020). Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.. in Cellular and Molecular Life Sciences, 77, 3383-3399.
https://doi.org/10.1007/s00018-019-03356-2

Vučićević L, Misirkić Marjanović M, Ćirić D, Martinović T, Jovanović M, Isaković A, Marković I, Šaponjić J, Foretz M, Rabanal-Ruiz Y, Korolchuk VI, Trajković V. Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.. in Cellular and Molecular Life Sciences. 2020;77:3383-3399.
doi:10.1007/s00018-019-03356-2 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Ćirić, Darko, Martinović, Tamara, Jovanović, Maja, Isaković, Aleksandra, Marković, Ivanka, Šaponjić, Jasna, Foretz, Marc, Rabanal-Ruiz, Yoana, Korolchuk, Viktor I., Trajković, Vladimir, "Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells." in Cellular and Molecular Life Sciences, 77 (2020):3383-3399,
https://doi.org/10.1007/s00018-019-03356-2 . .

TY  - JOUR
AU  - Jovanović-Tucović, Maja
AU  - Harhaji-Trajković, Ljubica
AU  - Dulović, Marija
AU  - Tovilović-Kovačević, Gordana
AU  - Zogović, Nevena
AU  - Jeremić, Marija
AU  - Mandić, Miloš
AU  - Kostić, Vladimir
AU  - Trajković, Vladimir
AU  - Marković, Ivanka
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0014299919306296?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3482
AB  - We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.
T2  - European Journal of Pharmacology
T1  - AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.
VL  - 863
DO  - 10.1016/j.ejphar.2019.172677
SP  - 172677
ER  - 

@article{
author = "Jovanović-Tucović, Maja and Harhaji-Trajković, Ljubica and Dulović, Marija and Tovilović-Kovačević, Gordana and Zogović, Nevena and Jeremić, Marija and Mandić, Miloš and Kostić, Vladimir and Trajković, Vladimir and Marković, Ivanka",
year = "2019",
abstract = "We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.",
journal = "European Journal of Pharmacology",
title = "AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.",
volume = "863",
doi = "10.1016/j.ejphar.2019.172677",
pages = "172677"
}

Jovanović-Tucović, M., Harhaji-Trajković, L., Dulović, M., Tovilović-Kovačević, G., Zogović, N., Jeremić, M., Mandić, M., Kostić, V., Trajković, V.,& Marković, I.. (2019). AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.. in European Journal of Pharmacology, 863, 172677.
https://doi.org/10.1016/j.ejphar.2019.172677

Jovanović-Tucović M, Harhaji-Trajković L, Dulović M, Tovilović-Kovačević G, Zogović N, Jeremić M, Mandić M, Kostić V, Trajković V, Marković I. AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.. in European Journal of Pharmacology. 2019;863:172677.
doi:10.1016/j.ejphar.2019.172677 .

Jovanović-Tucović, Maja, Harhaji-Trajković, Ljubica, Dulović, Marija, Tovilović-Kovačević, Gordana, Zogović, Nevena, Jeremić, Marija, Mandić, Miloš, Kostić, Vladimir, Trajković, Vladimir, Marković, Ivanka, "AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy." in European Journal of Pharmacology, 863 (2019):172677,
https://doi.org/10.1016/j.ejphar.2019.172677 . .

TY  - JOUR
AU  - Stamenković, Marina
AU  - Janjetović, Kristina
AU  - Paunović, Verica
AU  - Ćirić, Darko
AU  - Kravić-Stevović, Tamara
AU  - Trajković, Vladimir
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0014299919304923?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3448
AB  - We performed a comparative analysis of molecular cytotoxic mechanisms of lysosomal autophagy inhibitors bafilomycin A1, chloroquine, and ammonium chloride in B16 mouse melanoma cells. All agents caused oxidative stress, mitochondrial depolarization, and caspase-dependent apoptotic death, which was not affected by genetic inactivation of autophagy. Cathepsin inhibition reduced only the cytotoxicity of chloroquine, indicating its ability to cause lysosomal membrane permeabilization. Bafilomycin reduced the mRNA levels of anti-apoptotic Bcl-2, while chloroquine and ammonium chloride increased the mRNA expression of pro-apoptotic Pten and Puma, as well as anti-apoptotic Bcl-xL. Ammonium chloride additionally increased the mRNA expression of pro-apoptotic Bim and p53. All three agents decreased the activity of mechanistic target of rapamycin (mTOR) and increased the activation of p38 mitogen-activated protein kinase (MAPK). Chloroquine and ammonium chloride additionally stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), respectively, while only bafilomycin increased the phosphorylation of the energy sensor AMP-activated protein kinase (AMPK). mTOR activator leucine did not affect the cytotoxicity of lysosomal inhibitors. p38 MAPK inhibitor SB203580 reduced the cytotoxicity of bafilomycin but increased that of chloroquine and ammonium chloride. The pharmacological inhibition of ERK1/2, JNK, and AMPK potentiated the cytotoxicity of chloroquine, ammonium chloride, and bafilomycin, respectively. The observed mechanistic differences were associated with antagonistic interactions of lysosomal inhibitors in B16 cell killing. In conclusion, all investigated lysosomal inhibitors cause autophagy-independent mitochondrial dysfunction and apoptotic death, but differ in the ability to affect lysosomal permeabilization, balance between pro- and anti-apoptotic molecules of Bcl-2 family, and MAPK/AMPK signaling.
T2  - European Journal of Pharmacology
T1  - Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors.
VL  - 859
DO  - 10.1016/j.ejphar.2019.172540
SP  - 172540
ER  - 

@article{
author = "Stamenković, Marina and Janjetović, Kristina and Paunović, Verica and Ćirić, Darko and Kravić-Stevović, Tamara and Trajković, Vladimir",
year = "2019",
abstract = "We performed a comparative analysis of molecular cytotoxic mechanisms of lysosomal autophagy inhibitors bafilomycin A1, chloroquine, and ammonium chloride in B16 mouse melanoma cells. All agents caused oxidative stress, mitochondrial depolarization, and caspase-dependent apoptotic death, which was not affected by genetic inactivation of autophagy. Cathepsin inhibition reduced only the cytotoxicity of chloroquine, indicating its ability to cause lysosomal membrane permeabilization. Bafilomycin reduced the mRNA levels of anti-apoptotic Bcl-2, while chloroquine and ammonium chloride increased the mRNA expression of pro-apoptotic Pten and Puma, as well as anti-apoptotic Bcl-xL. Ammonium chloride additionally increased the mRNA expression of pro-apoptotic Bim and p53. All three agents decreased the activity of mechanistic target of rapamycin (mTOR) and increased the activation of p38 mitogen-activated protein kinase (MAPK). Chloroquine and ammonium chloride additionally stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), respectively, while only bafilomycin increased the phosphorylation of the energy sensor AMP-activated protein kinase (AMPK). mTOR activator leucine did not affect the cytotoxicity of lysosomal inhibitors. p38 MAPK inhibitor SB203580 reduced the cytotoxicity of bafilomycin but increased that of chloroquine and ammonium chloride. The pharmacological inhibition of ERK1/2, JNK, and AMPK potentiated the cytotoxicity of chloroquine, ammonium chloride, and bafilomycin, respectively. The observed mechanistic differences were associated with antagonistic interactions of lysosomal inhibitors in B16 cell killing. In conclusion, all investigated lysosomal inhibitors cause autophagy-independent mitochondrial dysfunction and apoptotic death, but differ in the ability to affect lysosomal permeabilization, balance between pro- and anti-apoptotic molecules of Bcl-2 family, and MAPK/AMPK signaling.",
journal = "European Journal of Pharmacology",
title = "Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors.",
volume = "859",
doi = "10.1016/j.ejphar.2019.172540",
pages = "172540"
}

Stamenković, M., Janjetović, K., Paunović, V., Ćirić, D., Kravić-Stevović, T.,& Trajković, V.. (2019). Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors.. in European Journal of Pharmacology, 859, 172540.
https://doi.org/10.1016/j.ejphar.2019.172540

Stamenković M, Janjetović K, Paunović V, Ćirić D, Kravić-Stevović T, Trajković V. Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors.. in European Journal of Pharmacology. 2019;859:172540.
doi:10.1016/j.ejphar.2019.172540 .

Stamenković, Marina, Janjetović, Kristina, Paunović, Verica, Ćirić, Darko, Kravić-Stevović, Tamara, Trajković, Vladimir, "Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors." in European Journal of Pharmacology, 859 (2019):172540,
https://doi.org/10.1016/j.ejphar.2019.172540 . .

TY  - JOUR
AU  - Tovilović-Kovačević, Gordana
AU  - Krstić Milošević, Dijana
AU  - Vinterhalter, Branka
AU  - Toljić, Mina
AU  - Perović, Vladimir
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
AU  - Zogović, Nevena
PY  - 2018
UR  - https://www.sciencedirect.com/science/article/pii/S0944711318300874?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3125
AB  - BACKGROUND Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds. HYPOTHESIS/PURPOSE The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1—derived from untransformed roots, E2—derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3—derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined. METHODS The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting. RESULTS E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (β-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress. CONCLUSION These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma.
T2  - Phytomedicine
T1  - Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line
VL  - 47
DO  - 10.1016/J.PHYMED.2018.03.052
SP  - 151
EP  - 160
ER  - 

@article{
author = "Tovilović-Kovačević, Gordana and Krstić Milošević, Dijana and Vinterhalter, Branka and Toljić, Mina and Perović, Vladimir and Trajković, Vladimir and Harhaji-Trajković, Ljubica and Zogović, Nevena",
year = "2018",
abstract = "BACKGROUND Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds. HYPOTHESIS/PURPOSE The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1—derived from untransformed roots, E2—derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3—derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined. METHODS The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting. RESULTS E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (β-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress. CONCLUSION These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma.",
journal = "Phytomedicine",
title = "Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line",
volume = "47",
doi = "10.1016/J.PHYMED.2018.03.052",
pages = "151-160"
}

Tovilović-Kovačević, G., Krstić Milošević, D., Vinterhalter, B., Toljić, M., Perović, V., Trajković, V., Harhaji-Trajković, L.,& Zogović, N.. (2018). Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line. in Phytomedicine, 47, 151-160.
https://doi.org/10.1016/J.PHYMED.2018.03.052

Tovilović-Kovačević G, Krstić Milošević D, Vinterhalter B, Toljić M, Perović V, Trajković V, Harhaji-Trajković L, Zogović N. Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line. in Phytomedicine. 2018;47:151-160.
doi:10.1016/J.PHYMED.2018.03.052 .

Tovilović-Kovačević, Gordana, Krstić Milošević, Dijana, Vinterhalter, Branka, Toljić, Mina, Perović, Vladimir, Trajković, Vladimir, Harhaji-Trajković, Ljubica, Zogović, Nevena, "Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line" in Phytomedicine, 47 (2018):151-160,
https://doi.org/10.1016/J.PHYMED.2018.03.052 . .

TY  - GEN
AU  - Gazdić, Marina
AU  - Simović Marković, Bojana
AU  - Vučićević, Ljubica
AU  - Nikolić, Tamara
AU  - Đonov, Valentin
AU  - Arsenijević, Nebojša
AU  - Trajković, Vladimir
AU  - Lukić, Miodrag L.
AU  - Volarević, Vladislav
PY  - 2018
UR  - http://doi.wiley.com/10.1002/term.2452
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2833
AB  - The effects of mesenchymal stem cells (MSCs) on the phenotype and function of natural killer T (NKT) cells is not understood. We used concanavalin A (Con A) and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate the effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated the influx of inflammatory [T-bet + , tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ)-producing and GATA3 + , interleukin-4 (IL-4)-producing] liver NKT cells and downregulated TNF-α, IFN-γ and IL-4 levels in the sera. The liver NKT cells cultured in vitro with mMSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. mMSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells and suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. mMSCs reduced the cytotoxicity of liver NKT cells against hepatocytes in vitro. The presence of 1-methyl-dl-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), or l-N G -monomethyl arginine citrate, a specific inhibitor of inducible nitric oxide synthase (iNOS), in mMSC-conditioned medium injected into α-GalCer-treated mice, counteracted the hepatoprotective effect of mMSCs in vivo and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. Human MSCs attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells in an iNOS- and IDO-dependent manner and reduced their cytotoxicity against HepG2 cells. In conclusion, MSCs protect from acute liver injury by attenuating the cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in an iNOS- and IDO-dependent manner.
T2  - Journal of Tissue Engineering and Regenerative Medicine
T1  - Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner
IS  - 2
VL  - 12
DO  - 10.1002/term.2452
SP  - e1173
EP  - e1185
ER  - 

@misc{
author = "Gazdić, Marina and Simović Marković, Bojana and Vučićević, Ljubica and Nikolić, Tamara and Đonov, Valentin and Arsenijević, Nebojša and Trajković, Vladimir and Lukić, Miodrag L. and Volarević, Vladislav",
year = "2018",
abstract = "The effects of mesenchymal stem cells (MSCs) on the phenotype and function of natural killer T (NKT) cells is not understood. We used concanavalin A (Con A) and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate the effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated the influx of inflammatory [T-bet + , tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ)-producing and GATA3 + , interleukin-4 (IL-4)-producing] liver NKT cells and downregulated TNF-α, IFN-γ and IL-4 levels in the sera. The liver NKT cells cultured in vitro with mMSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. mMSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells and suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. mMSCs reduced the cytotoxicity of liver NKT cells against hepatocytes in vitro. The presence of 1-methyl-dl-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), or l-N G -monomethyl arginine citrate, a specific inhibitor of inducible nitric oxide synthase (iNOS), in mMSC-conditioned medium injected into α-GalCer-treated mice, counteracted the hepatoprotective effect of mMSCs in vivo and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. Human MSCs attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells in an iNOS- and IDO-dependent manner and reduced their cytotoxicity against HepG2 cells. In conclusion, MSCs protect from acute liver injury by attenuating the cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in an iNOS- and IDO-dependent manner.",
journal = "Journal of Tissue Engineering and Regenerative Medicine",
title = "Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner",
number = "2",
volume = "12",
doi = "10.1002/term.2452",
pages = "e1173-e1185"
}

Gazdić, M., Simović Marković, B., Vučićević, L., Nikolić, T., Đonov, V., Arsenijević, N., Trajković, V., Lukić, M. L.,& Volarević, V.. (2018). Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. in Journal of Tissue Engineering and Regenerative Medicine, 12(2), e1173-e1185.
https://doi.org/10.1002/term.2452

Gazdić M, Simović Marković B, Vučićević L, Nikolić T, Đonov V, Arsenijević N, Trajković V, Lukić ML, Volarević V. Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. in Journal of Tissue Engineering and Regenerative Medicine. 2018;12(2):e1173-e1185.
doi:10.1002/term.2452 .

Gazdić, Marina, Simović Marković, Bojana, Vučićević, Ljubica, Nikolić, Tamara, Đonov, Valentin, Arsenijević, Nebojša, Trajković, Vladimir, Lukić, Miodrag L., Volarević, Vladislav, "Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner" in Journal of Tissue Engineering and Regenerative Medicine, 12, no. 2 (2018):e1173-e1185,
https://doi.org/10.1002/term.2452 . .

TY  - JOUR
AU  - Pantović, Aleksandar
AU  - Bošnjak, Mihajlo
AU  - Arsikin, Katarina
AU  - Kosić, Milica
AU  - Mandić, Miloš
AU  - Ristić, Biljana
AU  - Tošić, Jelena
AU  - Grujičić, Danica
AU  - Isaković, Aleksandra
AU  - Micic, Nikola
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2017
UR  - http://linkinghub.elsevier.com/retrieve/pii/S1357272516303946
UR  - https://www.scopus.com/record/display.uri?eid=2-s2.0-85008690027&origin=SingleRecordEmailAlert&dgcid=scalert_sc_search_email&txGid=BCBFF82A73D51FA0ED62BC41FE5E5987.wsnAw8kcdt7IPYLO0V48gA%3A29
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2512
AB  - We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G2M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.
T2  - The International Journal of Biochemistry & Cell Biology
T1  - In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway
VL  - 83
DO  - 10.1016/j.biocel.2016.12.007
SP  - 84
EP  - 96
ER  - 

@article{
author = "Pantović, Aleksandar and Bošnjak, Mihajlo and Arsikin, Katarina and Kosić, Milica and Mandić, Miloš and Ristić, Biljana and Tošić, Jelena and Grujičić, Danica and Isaković, Aleksandra and Micic, Nikola and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2017",
abstract = "We investigated the role of the intracellular energy-sensing AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the in vitro antiglioma effect of the cyclooxygenase (COX) inhibitor indomethacin. Indomethacin was more potent than COX inhibitors diclofenac, naproxen, and ketoprofen in reducing the viability of U251 human glioma cells. Antiglioma effect of the drug was associated with p21 increase and G2M cell cycle arrest, as well as with oxidative stress, mitochondrial depolarization, caspase activation, and the induction of apoptosis. Indomethacin increased the phosphorylation of AMPK and its targets Raptor and acetyl-CoA carboxylase (ACC), and reduced the phosphorylation of mTOR and mTOR complex 1 (mTORC1) substrates p70S6 kinase and PRAS40 (Ser183). AMPK knockdown by RNA interference, as well as the treatment with the mTORC1 activator leucine, prevented indomethacin-mediated mTORC1 inhibition and cytotoxic action, while AMPK activators metformin and AICAR mimicked the effects of the drug. AMPK activation by indomethacin correlated with intracellular ATP depletion and increase in AMP/ATP ratio, and was apparently independent of COX inhibition or the increase in intracellular calcium. Finally, the toxicity of indomethacin towards primary human glioma cells was associated with the activation of AMPK/Raptor/ACC and subsequent suppression of mTORC1/S6K. By demonstrating the involvement of AMPK/mTORC1 pathway in the antiglioma action of indomethacin, our results support its further exploration in glioma therapy.",
journal = "The International Journal of Biochemistry & Cell Biology",
title = "In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway",
volume = "83",
doi = "10.1016/j.biocel.2016.12.007",
pages = "84-96"
}

Pantović, A., Bošnjak, M., Arsikin, K., Kosić, M., Mandić, M., Ristić, B., Tošić, J., Grujičić, D., Isaković, A., Micic, N., Trajković, V.,& Harhaji-Trajković, L.. (2017). In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway. in The International Journal of Biochemistry & Cell Biology, 83, 84-96.
https://doi.org/10.1016/j.biocel.2016.12.007

Pantović A, Bošnjak M, Arsikin K, Kosić M, Mandić M, Ristić B, Tošić J, Grujičić D, Isaković A, Micic N, Trajković V, Harhaji-Trajković L. In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway. in The International Journal of Biochemistry & Cell Biology. 2017;83:84-96.
doi:10.1016/j.biocel.2016.12.007 .

Pantović, Aleksandar, Bošnjak, Mihajlo, Arsikin, Katarina, Kosić, Milica, Mandić, Miloš, Ristić, Biljana, Tošić, Jelena, Grujičić, Danica, Isaković, Aleksandra, Micic, Nikola, Trajković, Vladimir, Harhaji-Trajković, Ljubica, "In vitro antiglioma action of indomethacin is mediated via AMP-activated protein kinase/mTOR complex 1 signalling pathway" in The International Journal of Biochemistry & Cell Biology, 83 (2017):84-96,
https://doi.org/10.1016/j.biocel.2016.12.007 . .

TY  - CONF
AU  - Kosić, Milica
AU  - Arsikin-Csordas, Katarina
AU  - Paunović, Verica
AU  - Firestone, Raymond A
AU  - Ristić, Biljana
AU  - Mirčić, Aleksandar
AU  - Petričević, Saša
AU  - Bošnjak, Mihajlo
AU  - Zogović, Nevena
AU  - Bumbaširević, Vladimir
AU  - Trajković, Vladimir
AU  - Harhaji-Trajković, Ljubica
PY  - 2015
UR  - http://ssmfrp.edu.rs/article-12
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6356
AB  - We investigated the in vitro anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-D-glucose (2DG). Cell viability was measured by MTT and LDH tests. Oxidative stress, lysosomal permeabilization, mitochondrial depolarization and apoptosis/necrosis were analyzed by flow cytometry. Cell morphology was examined by electron microscopy. Intracellular ATP content was measured by bioluminescence assay. NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial
damage, and reactive oxygen species (ROS) production, eventually leading to necrotic death
of U251 glioma cells, but not primary astrocytes. NDI/2DG-induced death of glioma cells was
partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, indicating the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agents chloroquine and NH4Cl also displayed synergistic anticancer effect with 2DG, while glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus confirming that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block, respectively. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive
feedback cycle of mitochondrial dysfunction, ATP loss, and ROS production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy.
PB  - Belgrade : Serbian Society for Mitochondrial and Free-Radical Physiology
C3  - Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia
T1  - Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition
SP  - 71
EP  - 71
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6356
ER  - 

@conference{
author = "Kosić, Milica and Arsikin-Csordas, Katarina and Paunović, Verica and Firestone, Raymond A and Ristić, Biljana and Mirčić, Aleksandar and Petričević, Saša and Bošnjak, Mihajlo and Zogović, Nevena and Bumbaširević, Vladimir and Trajković, Vladimir and Harhaji-Trajković, Ljubica",
year = "2015",
abstract = "We investigated the in vitro anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-D-glucose (2DG). Cell viability was measured by MTT and LDH tests. Oxidative stress, lysosomal permeabilization, mitochondrial depolarization and apoptosis/necrosis were analyzed by flow cytometry. Cell morphology was examined by electron microscopy. Intracellular ATP content was measured by bioluminescence assay. NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial
damage, and reactive oxygen species (ROS) production, eventually leading to necrotic death
of U251 glioma cells, but not primary astrocytes. NDI/2DG-induced death of glioma cells was
partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, indicating the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agents chloroquine and NH4Cl also displayed synergistic anticancer effect with 2DG, while glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus confirming that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block, respectively. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive
feedback cycle of mitochondrial dysfunction, ATP loss, and ROS production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy.",
publisher = "Belgrade : Serbian Society for Mitochondrial and Free-Radical Physiology",
journal = "Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia",
title = "Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition",
pages = "71-71",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6356"
}

Kosić, M., Arsikin-Csordas, K., Paunović, V., Firestone, R. A., Ristić, B., Mirčić, A., Petričević, S., Bošnjak, M., Zogović, N., Bumbaširević, V., Trajković, V.,& Harhaji-Trajković, L.. (2015). Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition. in Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia
Belgrade : Serbian Society for Mitochondrial and Free-Radical Physiology., 71-71.
https://hdl.handle.net/21.15107/rcub_ibiss_6356

Kosić M, Arsikin-Csordas K, Paunović V, Firestone RA, Ristić B, Mirčić A, Petričević S, Bošnjak M, Zogović N, Bumbaširević V, Trajković V, Harhaji-Trajković L. Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition. in Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia. 2015;:71-71.
https://hdl.handle.net/21.15107/rcub_ibiss_6356 .

Kosić, Milica, Arsikin-Csordas, Katarina, Paunović, Verica, Firestone, Raymond A, Ristić, Biljana, Mirčić, Aleksandar, Petričević, Saša, Bošnjak, Mihajlo, Zogović, Nevena, Bumbaširević, Vladimir, Trajković, Vladimir, Harhaji-Trajković, Ljubica, "Synergistic anticancer action of lysosomal membrane permeabilization and glycolysis inhibition" in Book of Abstracts: Third Congress Redox Medicine: Reactive Species Signaling, Analytical Methods, Phytopharmacy, Molecular Mechanisms of Disease - SSMFRP-2015; 2015 Sep 25-26; Belgrade, Serbia (2015):71-71,
https://hdl.handle.net/21.15107/rcub_ibiss_6356 .

TY  - JOUR
AU  - Tovilović-Kovačević, Gordana
AU  - Ristić, Biljana
AU  - Milenković, Marina
AU  - Stanojević, Maja
AU  - Trajković, Vladimir
PY  - 2014
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6346
AB  - Macroautophagy (hereafter referred to as autophagy) is an evolutionary conserved catabolic process in which the cytoplasmic content is sequestered and degraded by the lysosomal machinery in order to maintain cellular homeostasis or provide energy during metabolic and hypoxic stress. It also represents an important component of the host response against infectious agents, performing surveillance and effector functions involved in detection and clearance of pathogens, including viruses. Moreover, it appears that autophagy plays a major role in determining the fate of both virally infected and uninfected cells by blocking or promoting their death in a virus- and cell-type-dependent manner. We here review the current knowledge on the complex involvement of autophagy in survival and death of the host cells during viral infection, focusing on the molecular mechanisms underlying viral modulation of autophagic response and its interference with the cell death pathways. We also discuss a possible significance of the autophagy-dependent modulation of cell death for the outcome and therapy of viral infections, emphasizing the need for a time- and cell-type-dependent fine-tuning of the autophagic response in achieving an optimal balance between beneficial and adverse effects.
PB  - John Wiley & Sons, Inc.
T2  - Medicinal Research Reviews
T1  - The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death
IS  - 4
VL  - 34
DO  - 10.1002/med.21303
SP  - 744
EP  - 767
ER  - 

@article{
author = "Tovilović-Kovačević, Gordana and Ristić, Biljana and Milenković, Marina and Stanojević, Maja and Trajković, Vladimir",
year = "2014",
abstract = "Macroautophagy (hereafter referred to as autophagy) is an evolutionary conserved catabolic process in which the cytoplasmic content is sequestered and degraded by the lysosomal machinery in order to maintain cellular homeostasis or provide energy during metabolic and hypoxic stress. It also represents an important component of the host response against infectious agents, performing surveillance and effector functions involved in detection and clearance of pathogens, including viruses. Moreover, it appears that autophagy plays a major role in determining the fate of both virally infected and uninfected cells by blocking or promoting their death in a virus- and cell-type-dependent manner. We here review the current knowledge on the complex involvement of autophagy in survival and death of the host cells during viral infection, focusing on the molecular mechanisms underlying viral modulation of autophagic response and its interference with the cell death pathways. We also discuss a possible significance of the autophagy-dependent modulation of cell death for the outcome and therapy of viral infections, emphasizing the need for a time- and cell-type-dependent fine-tuning of the autophagic response in achieving an optimal balance between beneficial and adverse effects.",
publisher = "John Wiley & Sons, Inc.",
journal = "Medicinal Research Reviews",
title = "The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death",
number = "4",
volume = "34",
doi = "10.1002/med.21303",
pages = "744-767"
}

Tovilović-Kovačević, G., Ristić, B., Milenković, M., Stanojević, M.,& Trajković, V.. (2014). The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death. in Medicinal Research Reviews
John Wiley & Sons, Inc.., 34(4), 744-767.
https://doi.org/10.1002/med.21303

Tovilović-Kovačević G, Ristić B, Milenković M, Stanojević M, Trajković V. The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death. in Medicinal Research Reviews. 2014;34(4):744-767.
doi:10.1002/med.21303 .

Tovilović-Kovačević, Gordana, Ristić, Biljana, Milenković, Marina, Stanojević, Maja, Trajković, Vladimir, "The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death" in Medicinal Research Reviews, 34, no. 4 (2014):744-767,
https://doi.org/10.1002/med.21303 . .

TY  - JOUR
AU  - Tovilović-Kovačević, Gordana
AU  - Zogović, Nevena
AU  - Harhaji-Trajković, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Vučićević, Ljubica
AU  - Kostić-Rajačić, Slađana
AU  - Schrattenholz, Andre
AU  - Isaković, Aleksandra
AU  - Šoškić, Vukić
AU  - Trajković, Vladimir
PY  - 2012
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6367
AB  - The protective ability of novel arylpiperazine-based dopaminergic ligands against nitric oxide (NO)-mediated neurotoxicity is investigated. The most potent neuroprotective arylpiperazine identified during the study was N-{4-[2-(4-phenyl-piperazin-1-yl)ethyl]-phenyl}picolinamide, which protected SH-SY5Y human neuron-like cells from the proapoptotic effect of NO donor sodium nitroprusside (SNP) by decreasing oxidative stress, mitochondrial membrane depolarization, caspase activation and subsequent phosphatydilserine externalization/DNA fragmentation. The protective effect was associated with the inhibition of proapoptotic (JNK, ERK, AMPK) and activation of antiapoptotic (Akt) signaling pathways, in the absence of interference with intracellular NO accumulation. The neuroprotective action of arylpiperazines was shown to be independent of dopamine receptor binding, as it was not affected by the high-affinity D₁/D₂ receptor blocker butaclamol. These results reported support the further study of arylpiperazines as potential neuroprotective agents.
PB  - John Wiley and Sons
T2  - ChemMedChem
T1  - Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis
IS  - 3
VL  - 7
DO  - 10.1002/cmdc.201100537
SP  - 495
EP  - 508
ER  - 

@article{
author = "Tovilović-Kovačević, Gordana and Zogović, Nevena and Harhaji-Trajković, Ljubica and Misirkić Marjanović, Maja and Janjetović, Kristina and Vučićević, Ljubica and Kostić-Rajačić, Slađana and Schrattenholz, Andre and Isaković, Aleksandra and Šoškić, Vukić and Trajković, Vladimir",
year = "2012",
abstract = "The protective ability of novel arylpiperazine-based dopaminergic ligands against nitric oxide (NO)-mediated neurotoxicity is investigated. The most potent neuroprotective arylpiperazine identified during the study was N-{4-[2-(4-phenyl-piperazin-1-yl)ethyl]-phenyl}picolinamide, which protected SH-SY5Y human neuron-like cells from the proapoptotic effect of NO donor sodium nitroprusside (SNP) by decreasing oxidative stress, mitochondrial membrane depolarization, caspase activation and subsequent phosphatydilserine externalization/DNA fragmentation. The protective effect was associated with the inhibition of proapoptotic (JNK, ERK, AMPK) and activation of antiapoptotic (Akt) signaling pathways, in the absence of interference with intracellular NO accumulation. The neuroprotective action of arylpiperazines was shown to be independent of dopamine receptor binding, as it was not affected by the high-affinity D₁/D₂ receptor blocker butaclamol. These results reported support the further study of arylpiperazines as potential neuroprotective agents.",
publisher = "John Wiley and Sons",
journal = "ChemMedChem",
title = "Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis",
number = "3",
volume = "7",
doi = "10.1002/cmdc.201100537",
pages = "495-508"
}

Tovilović-Kovačević, G., Zogović, N., Harhaji-Trajković, L., Misirkić Marjanović, M., Janjetović, K., Vučićević, L., Kostić-Rajačić, S., Schrattenholz, A., Isaković, A., Šoškić, V.,& Trajković, V.. (2012). Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis. in ChemMedChem
John Wiley and Sons., 7(3), 495-508.
https://doi.org/10.1002/cmdc.201100537

Tovilović-Kovačević G, Zogović N, Harhaji-Trajković L, Misirkić Marjanović M, Janjetović K, Vučićević L, Kostić-Rajačić S, Schrattenholz A, Isaković A, Šoškić V, Trajković V. Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis. in ChemMedChem. 2012;7(3):495-508.
doi:10.1002/cmdc.201100537 .

Tovilović-Kovačević, Gordana, Zogović, Nevena, Harhaji-Trajković, Ljubica, Misirkić Marjanović, Maja, Janjetović, Kristina, Vučićević, Ljubica, Kostić-Rajačić, Slađana, Schrattenholz, Andre, Isaković, Aleksandra, Šoškić, Vukić, Trajković, Vladimir, "Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis" in ChemMedChem, 7, no. 3 (2012):495-508,
https://doi.org/10.1002/cmdc.201100537 . .

TY  - JOUR
AU  - Isaković, Aleksandra
AU  - Marković, Zoran
AU  - Todorović-Marković, Biljana
AU  - Nikolić, Nadežda
AU  - Vranješ-Đurić, Sanja
AU  - Mirković, Marija
AU  - Dramićanin, Miroslav
AU  - Harhaji-Trajković, Ljubica
AU  - Zogović, Nevena
AU  - Nikolić, Zoran
AU  - Trajković, Vladimir
PY  - 2006
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3589
AB  - The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C 60 ) and water-soluble polyhydroxylated fullerene [C 60 (OH) n ] were investigated. Crystal violet assay for cell viability demonstrated that nano-C 60 was at least three orders of magnitude more toxic than C 60 (OH) n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C 60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C 60 (OH) n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C 60 toxicity, but not C 60 (OH) n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C 60 (OH) n -induced apoptosis, but not nano-C 60 -mediated necrosis. Finally, C 60 (OH) n antagomozed, while nano-C 60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C 60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C 60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.
PB  - Oxford University Press (OUP)
T2  - Toxicological Sciences
T1  - Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene
IS  - 1
VL  - 91
DO  - 10.1093/toxsci/kfj127
SP  - 173
EP  - 183
ER  - 

@article{
author = "Isaković, Aleksandra and Marković, Zoran and Todorović-Marković, Biljana and Nikolić, Nadežda and Vranješ-Đurić, Sanja and Mirković, Marija and Dramićanin, Miroslav and Harhaji-Trajković, Ljubica and Zogović, Nevena and Nikolić, Zoran and Trajković, Vladimir",
year = "2006",
abstract = "The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C 60 ) and water-soluble polyhydroxylated fullerene [C 60 (OH) n ] were investigated. Crystal violet assay for cell viability demonstrated that nano-C 60 was at least three orders of magnitude more toxic than C 60 (OH) n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C 60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C 60 (OH) n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C 60 toxicity, but not C 60 (OH) n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C 60 (OH) n -induced apoptosis, but not nano-C 60 -mediated necrosis. Finally, C 60 (OH) n antagomozed, while nano-C 60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C 60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C 60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.",
publisher = "Oxford University Press (OUP)",
journal = "Toxicological Sciences",
title = "Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene",
number = "1",
volume = "91",
doi = "10.1093/toxsci/kfj127",
pages = "173-183"
}

Isaković, A., Marković, Z., Todorović-Marković, B., Nikolić, N., Vranješ-Đurić, S., Mirković, M., Dramićanin, M., Harhaji-Trajković, L., Zogović, N., Nikolić, Z.,& Trajković, V.. (2006). Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene. in Toxicological Sciences
Oxford University Press (OUP)., 91(1), 173-183.
https://doi.org/10.1093/toxsci/kfj127

Isaković A, Marković Z, Todorović-Marković B, Nikolić N, Vranješ-Đurić S, Mirković M, Dramićanin M, Harhaji-Trajković L, Zogović N, Nikolić Z, Trajković V. Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene. in Toxicological Sciences. 2006;91(1):173-183.
doi:10.1093/toxsci/kfj127 .

Isaković, Aleksandra, Marković, Zoran, Todorović-Marković, Biljana, Nikolić, Nadežda, Vranješ-Đurić, Sanja, Mirković, Marija, Dramićanin, Miroslav, Harhaji-Trajković, Ljubica, Zogović, Nevena, Nikolić, Zoran, Trajković, Vladimir, "Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene" in Toxicological Sciences, 91, no. 1 (2006):173-183,
https://doi.org/10.1093/toxsci/kfj127 . .

TY  - JOUR
AU  - Harhaji-Trajković, Ljubica
AU  - Vučković, Olivera
AU  - Miljković, Đorđe
AU  - Stošić-Grujičić, Stanislava
AU  - Trajković, Vladimir
PY  - 2004
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6011
AB  - Although the inhibitory effect of iron on macrophage production of tumoricidal free radical nitric oxide (NO) has been reported, its possible influence on macrophage anti-tumour activity has not been established. In the present study, FeSO4 markedly reduced IFN-gamma + LPS-induced NO synthesis in mouse and rat macrophages. The effect of iron coincided with the loss of macrophage cytotoxic activity against NO-sensitive C6 rat astrocytoma and L929 mouse fibrosarcoma cell lines, as measured by MTT assay for cellular respiration and the crystal violet test for cell viability. Tumour cell survival did not improve further in the presence of FeSO4 if macrophage NO release and cytotoxicity were already blocked by aminoguanidine. In accordance with the results obtained with exogenous iron, cell membrane permeable iron chelator o-phenanthroline enhanced both macrophage NO release and anti-tumour activity. Iron also down-regulated NO production and increased the viability of L929 fibrosarcoma cells stimulated with IFN-gamma + LPS in the absence of macrophages. However, neither NO release nor cell viability was affected by iron addition to cultures of the C6 astrocytoma cell line. Iron was unable to prevent L929 and C6 cell death induced by the NO releasing chemicals SNP and SIN-1, indicating that iron-mediated inhibition of NO synthesis, rather than interference with its cytotoxic action, was responsible for the protection of tumour cells. Collectively, these results indicate that iron might protect tumour cells by reducing both macrophage and tumour cell-derived NO release.
PB  - Blackwell Publishing Ltd
T2  - Clinical Experimental Immunology
T1  - Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production
IS  - 1
VL  - 137
DO  - 10.1111/j.1365-2249.2004.02515.x
SP  - 109
EP  - 116
ER  - 

@article{
author = "Harhaji-Trajković, Ljubica and Vučković, Olivera and Miljković, Đorđe and Stošić-Grujičić, Stanislava and Trajković, Vladimir",
year = "2004",
abstract = "Although the inhibitory effect of iron on macrophage production of tumoricidal free radical nitric oxide (NO) has been reported, its possible influence on macrophage anti-tumour activity has not been established. In the present study, FeSO4 markedly reduced IFN-gamma + LPS-induced NO synthesis in mouse and rat macrophages. The effect of iron coincided with the loss of macrophage cytotoxic activity against NO-sensitive C6 rat astrocytoma and L929 mouse fibrosarcoma cell lines, as measured by MTT assay for cellular respiration and the crystal violet test for cell viability. Tumour cell survival did not improve further in the presence of FeSO4 if macrophage NO release and cytotoxicity were already blocked by aminoguanidine. In accordance with the results obtained with exogenous iron, cell membrane permeable iron chelator o-phenanthroline enhanced both macrophage NO release and anti-tumour activity. Iron also down-regulated NO production and increased the viability of L929 fibrosarcoma cells stimulated with IFN-gamma + LPS in the absence of macrophages. However, neither NO release nor cell viability was affected by iron addition to cultures of the C6 astrocytoma cell line. Iron was unable to prevent L929 and C6 cell death induced by the NO releasing chemicals SNP and SIN-1, indicating that iron-mediated inhibition of NO synthesis, rather than interference with its cytotoxic action, was responsible for the protection of tumour cells. Collectively, these results indicate that iron might protect tumour cells by reducing both macrophage and tumour cell-derived NO release.",
publisher = "Blackwell Publishing Ltd",
journal = "Clinical Experimental Immunology",
title = "Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production",
number = "1",
volume = "137",
doi = "10.1111/j.1365-2249.2004.02515.x",
pages = "109-116"
}

Harhaji-Trajković, L., Vučković, O., Miljković, Đ., Stošić-Grujičić, S.,& Trajković, V.. (2004). Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production. in Clinical Experimental Immunology
Blackwell Publishing Ltd., 137(1), 109-116.
https://doi.org/10.1111/j.1365-2249.2004.02515.x

Harhaji-Trajković L, Vučković O, Miljković Đ, Stošić-Grujičić S, Trajković V. Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production. in Clinical Experimental Immunology. 2004;137(1):109-116.
doi:10.1111/j.1365-2249.2004.02515.x .

Harhaji-Trajković, Ljubica, Vučković, Olivera, Miljković, Đorđe, Stošić-Grujičić, Stanislava, Trajković, Vladimir, "Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide production" in Clinical Experimental Immunology, 137, no. 1 (2004):109-116,
https://doi.org/10.1111/j.1365-2249.2004.02515.x . .

TY  - JOUR
AU  - Trajković, Vladimir
AU  - Stošić-Grujičić, Stanislava
AU  - Samardzić, Tatjana
AU  - Marković, Miloš
AU  - Miljković, Đorđe
AU  - Ramić, Zorica
AU  - Mostarica Stojković, Marija
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5997
AB  - The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-gamma-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-gamma-pretreated astrocytes was abolished by antagonists of nuclear factor-kappaB (NF-kappaB) activation--a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1beta and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1beta and TNF-alpha for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS.
PB  - Amsterdam: Elsevier
T2  - Journal of Neuroimmunology
T1  - Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes
IS  - 2
VL  - 119
DO  - 10.1016/s0165-5728(01)00391-5
SP  - 183
EP  - 191
ER  - 

@article{
author = "Trajković, Vladimir and Stošić-Grujičić, Stanislava and Samardzić, Tatjana and Marković, Miloš and Miljković, Đorđe and Ramić, Zorica and Mostarica Stojković, Marija",
year = "2001",
abstract = "The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-gamma-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-gamma-pretreated astrocytes was abolished by antagonists of nuclear factor-kappaB (NF-kappaB) activation--a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1beta and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1beta and TNF-alpha for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS.",
publisher = "Amsterdam: Elsevier",
journal = "Journal of Neuroimmunology",
title = "Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes",
number = "2",
volume = "119",
doi = "10.1016/s0165-5728(01)00391-5",
pages = "183-191"
}

Trajković, V., Stošić-Grujičić, S., Samardzić, T., Marković, M., Miljković, Đ., Ramić, Z.,& Mostarica Stojković, M.. (2001). Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. in Journal of Neuroimmunology
Amsterdam: Elsevier., 119(2), 183-191.
https://doi.org/10.1016/s0165-5728(01)00391-5

Trajković V, Stošić-Grujičić S, Samardzić T, Marković M, Miljković Đ, Ramić Z, Mostarica Stojković M. Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. in Journal of Neuroimmunology. 2001;119(2):183-191.
doi:10.1016/s0165-5728(01)00391-5 .

Trajković, Vladimir, Stošić-Grujičić, Stanislava, Samardzić, Tatjana, Marković, Miloš, Miljković, Đorđe, Ramić, Zorica, Mostarica Stojković, Marija, "Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes" in Journal of Neuroimmunology, 119, no. 2 (2001):183-191,
https://doi.org/10.1016/s0165-5728(01)00391-5 . .