TY  - JOUR
AU  - Krunić, Matija
AU  - Ristić, Biljana
AU  - Bošnjak, Mihajlo
AU  - Paunović, Verica
AU  - Tovilović-Kovačević, Gordana
AU  - Zagović, Nevena
AU  - Mirčić, Aleksandar
AU  - Marković, Zoran
AU  - Todorović Marković, Biljana
AU  - Jovanović, Svetlana
AU  - Kleut, Duška
AU  - Mojović, Miloš
AU  - Nakarada, Đura
AU  - Marković, Olivera S.
AU  - Vuković, Irena
AU  - Harhaji-Trajković, Ljubica
AU  - Trajković, Vladimir
PY  - 2021
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5467
AB  - We investigated the ability of graphene quantum dot (GQD) nanoparticles to protect SH-SY5Y human neuro blastoma cells from oxidative/nitrosative stress induced by iron-nitrosyl complex sodium nitroprusside (SNP). 
GQD reduced SNP cytotoxicity by preventing mitochondrial depolarization, caspase-2 activation, and subsequent 
apoptotic death. Although GQD diminished the levels of nitric oxide (NO) in SNP-exposed cells, NO scavengers 
displayed only a slight protective effect, suggesting that NO quenching was not the main protective mechanism of 
GQD. GQD also reduced SNP-triggered increase in the intracellular levels of hydroxyl radical (
•
OH), superoxide 
anion (O2
•− ), and lipid peroxidation. Nonselective antioxidants, •
OH scavenging, and iron chelators, but not 
superoxide dismutase, mimicked GQD cytoprotective activity, indicating that GQD protect cells by neutralizing •
OH generated in the presence of SNP-released iron. Cellular internalization of GQD was required for optimal 
protection, since a removal of extracellular GQD by extensive washing only partly diminished their protective 
effect. Moreover, GQD cooperated with SNP to induce autophagy, as confirmed by the inhibition of autophagy limiting Akt/PRAS40/mTOR signaling and increase in autophagy gene transcription, protein levels of proauto phagic beclin-1 and LC3-II, formation of autophagic vesicles, and degradation of autophagic target p62. The 
antioxidant activity of GQD was not involved in autophagy induction, as antioxidants N-acetylcysteine and 
dimethyl sulfoxide failed to stimulate autophagy in SNP-exposed cells. Pharmacological inhibitors of early 
(wortmannin, 3-methyladenine) or late stages of autophagy (NH4Cl) efficiently reduced the protective effect of 
GQD. Therefore, the ability of GQD to prevent the in vitro neurotoxicity of SNP depends on both •
OH/NO 
scavenging and induction of cytoprotective autophagy.
PB  - Elsevier
T2  - Free Radical Biology and Medicine
T1  - Graphene quantum dot antioxidant and proautophagic actions protect  SH-SY5Y neuroblastoma cells from oxidative stress-mediated  apoptotic death
VL  - 177
SP  - 167
EP  - 180
DO  - 10.1016/j.freeradbiomed.2021.10.025
ER  - 

@article{
author = "Krunić, Matija and Ristić, Biljana and Bošnjak, Mihajlo and Paunović, Verica and Tovilović-Kovačević, Gordana and Zagović, Nevena and Mirčić, Aleksandar and Marković, Zoran and Todorović Marković, Biljana and Jovanović, Svetlana and Kleut, Duška and Mojović, Miloš and Nakarada, Đura and Marković, Olivera S. and Vuković, Irena and Harhaji-Trajković, Ljubica and Trajković, Vladimir",
year = "2021",
abstract = "We investigated the ability of graphene quantum dot (GQD) nanoparticles to protect SH-SY5Y human neuro blastoma cells from oxidative/nitrosative stress induced by iron-nitrosyl complex sodium nitroprusside (SNP). 
GQD reduced SNP cytotoxicity by preventing mitochondrial depolarization, caspase-2 activation, and subsequent 
apoptotic death. Although GQD diminished the levels of nitric oxide (NO) in SNP-exposed cells, NO scavengers 
displayed only a slight protective effect, suggesting that NO quenching was not the main protective mechanism of 
GQD. GQD also reduced SNP-triggered increase in the intracellular levels of hydroxyl radical (
•
OH), superoxide 
anion (O2
•− ), and lipid peroxidation. Nonselective antioxidants, •
OH scavenging, and iron chelators, but not 
superoxide dismutase, mimicked GQD cytoprotective activity, indicating that GQD protect cells by neutralizing •
OH generated in the presence of SNP-released iron. Cellular internalization of GQD was required for optimal 
protection, since a removal of extracellular GQD by extensive washing only partly diminished their protective 
effect. Moreover, GQD cooperated with SNP to induce autophagy, as confirmed by the inhibition of autophagy limiting Akt/PRAS40/mTOR signaling and increase in autophagy gene transcription, protein levels of proauto phagic beclin-1 and LC3-II, formation of autophagic vesicles, and degradation of autophagic target p62. The 
antioxidant activity of GQD was not involved in autophagy induction, as antioxidants N-acetylcysteine and 
dimethyl sulfoxide failed to stimulate autophagy in SNP-exposed cells. Pharmacological inhibitors of early 
(wortmannin, 3-methyladenine) or late stages of autophagy (NH4Cl) efficiently reduced the protective effect of 
GQD. Therefore, the ability of GQD to prevent the in vitro neurotoxicity of SNP depends on both •
OH/NO 
scavenging and induction of cytoprotective autophagy.",
publisher = "Elsevier",
journal = "Free Radical Biology and Medicine",
title = "Graphene quantum dot antioxidant and proautophagic actions protect  SH-SY5Y neuroblastoma cells from oxidative stress-mediated  apoptotic death",
volume = "177",
pages = "167-180",
doi = "10.1016/j.freeradbiomed.2021.10.025"
}

Krunić, M., Ristić, B., Bošnjak, M., Paunović, V., Tovilović-Kovačević, G., Zagović, N., Mirčić, A., Marković, Z., Todorović Marković, B., Jovanović, S., Kleut, D., Mojović, M., Nakarada, Đ., Marković, O. S., Vuković, I., Harhaji-Trajković, L.,& Trajković, V.. (2021). Graphene quantum dot antioxidant and proautophagic actions protect  SH-SY5Y neuroblastoma cells from oxidative stress-mediated  apoptotic death. in Free Radical Biology and Medicine
Elsevier., 177, 167-180.
https://doi.org/10.1016/j.freeradbiomed.2021.10.025

Krunić M, Ristić B, Bošnjak M, Paunović V, Tovilović-Kovačević G, Zagović N, Mirčić A, Marković Z, Todorović Marković B, Jovanović S, Kleut D, Mojović M, Nakarada Đ, Marković OS, Vuković I, Harhaji-Trajković L, Trajković V. Graphene quantum dot antioxidant and proautophagic actions protect  SH-SY5Y neuroblastoma cells from oxidative stress-mediated  apoptotic death. in Free Radical Biology and Medicine. 2021;177:167-180.
doi:10.1016/j.freeradbiomed.2021.10.025 .

Krunić, Matija, Ristić, Biljana, Bošnjak, Mihajlo, Paunović, Verica, Tovilović-Kovačević, Gordana, Zagović, Nevena, Mirčić, Aleksandar, Marković, Zoran, Todorović Marković, Biljana, Jovanović, Svetlana, Kleut, Duška, Mojović, Miloš, Nakarada, Đura, Marković, Olivera S., Vuković, Irena, Harhaji-Trajković, Ljubica, Trajković, Vladimir, "Graphene quantum dot antioxidant and proautophagic actions protect  SH-SY5Y neuroblastoma cells from oxidative stress-mediated  apoptotic death" in Free Radical Biology and Medicine, 177 (2021):167-180,
https://doi.org/10.1016/j.freeradbiomed.2021.10.025 . .

TY  - JOUR
AU  - Paunović, Verica
AU  - Kosic, Milica
AU  - Đorđević, S.
AU  - Žugić, Ana
AU  - Đalinac, Nataša
AU  - Gašić, Uroš M.
AU  - Trajković, Vladimir S.
AU  - Harhaji-Trajkovic, Ljubica
PY  - 2016
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2434
AB  - Marrubium vulgare is a European medicinal plant with numerous beneficial effects on human health. The aim of the study was to isolate the plant ethanolic extract (MVE) and to investigate its anti-melanoma and anti-glioma effects. MVE was prepared by the modified pharmacopoeial percolation method and characterized by UHPLC-LTQ OrbiTrap MS. MVE dose-dependently reduced viability of melanoma (B16) and glioma (U251) cells, but not peripheral blood mononuclear cells. It arrested cell cycle in S+G2/M phase, which was associated with the activation of MAP kinase p38 and up-regulation of antiproliferative genes p53, p21 and p27. MVE induced oxidative stress, while antioxidants abrogated its antitumor effect. Furthermore, MVE induced mitochondrial depolarization, activation of caspase-9 and -3, Parp cleavage, phosphatidylserine exposure and DNA fragmentation. The mitochondrial apoptotic pathway was associated with the up-regulation of proapoptotic genes Pten, Bak1, Apaf1, and Puma and down-regulation of antiapoptotic genes survivin and Xiap. MVE also stimulated the expression of autophagy-related genes Atg5, Atg7, Atg12, Beclin-1, Gabarab and Sqstm1, as well as LC3-I conversion to the autophagosome associated LC3-II, while autophagy inhibitors exacerbated its cytotoxicity. Finally, the most abundant phenolic components of MVE, ferulic, p-hydroxybenzoic, caffeic and chlorogenic acids, did not exert a profound effect on viability of tumor cells, suggesting that other components individually or in concert are the mediators of the extracts' cytotoxicity. By demonstrating the ability of MVE to inhibit proliferation, induce apoptosis and cytoprotective autophagy, our results suggest that MVE, alone or combined with autophagy inhibitors, could be a good candidate for anti-melanoma and anti-glioma therapy.
PB  - C M B  Assoc, Poitiers
T2  - Cellular and Molecular Biology
T1  - Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro
VL  - 62
IS  - 11
SP  - 108
EP  - 114
DO  - 10.14715/cmb/2016.62.11.18
ER  - 

@article{
author = "Paunović, Verica and Kosic, Milica and Đorđević, S. and Žugić, Ana and Đalinac, Nataša and Gašić, Uroš M. and Trajković, Vladimir S. and Harhaji-Trajkovic, Ljubica",
year = "2016",
abstract = "Marrubium vulgare is a European medicinal plant with numerous beneficial effects on human health. The aim of the study was to isolate the plant ethanolic extract (MVE) and to investigate its anti-melanoma and anti-glioma effects. MVE was prepared by the modified pharmacopoeial percolation method and characterized by UHPLC-LTQ OrbiTrap MS. MVE dose-dependently reduced viability of melanoma (B16) and glioma (U251) cells, but not peripheral blood mononuclear cells. It arrested cell cycle in S+G2/M phase, which was associated with the activation of MAP kinase p38 and up-regulation of antiproliferative genes p53, p21 and p27. MVE induced oxidative stress, while antioxidants abrogated its antitumor effect. Furthermore, MVE induced mitochondrial depolarization, activation of caspase-9 and -3, Parp cleavage, phosphatidylserine exposure and DNA fragmentation. The mitochondrial apoptotic pathway was associated with the up-regulation of proapoptotic genes Pten, Bak1, Apaf1, and Puma and down-regulation of antiapoptotic genes survivin and Xiap. MVE also stimulated the expression of autophagy-related genes Atg5, Atg7, Atg12, Beclin-1, Gabarab and Sqstm1, as well as LC3-I conversion to the autophagosome associated LC3-II, while autophagy inhibitors exacerbated its cytotoxicity. Finally, the most abundant phenolic components of MVE, ferulic, p-hydroxybenzoic, caffeic and chlorogenic acids, did not exert a profound effect on viability of tumor cells, suggesting that other components individually or in concert are the mediators of the extracts' cytotoxicity. By demonstrating the ability of MVE to inhibit proliferation, induce apoptosis and cytoprotective autophagy, our results suggest that MVE, alone or combined with autophagy inhibitors, could be a good candidate for anti-melanoma and anti-glioma therapy.",
publisher = "C M B  Assoc, Poitiers",
journal = "Cellular and Molecular Biology",
title = "Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro",
volume = "62",
number = "11",
pages = "108-114",
doi = "10.14715/cmb/2016.62.11.18"
}

Paunović, V., Kosic, M., Đorđević, S., Žugić, A., Đalinac, N., Gašić, U. M., Trajković, V. S.,& Harhaji-Trajkovic, L.. (2016). Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro. in Cellular and Molecular Biology
C M B  Assoc, Poitiers., 62(11), 108-114.
https://doi.org/10.14715/cmb/2016.62.11.18

Paunović V, Kosic M, Đorđević S, Žugić A, Đalinac N, Gašić UM, Trajković VS, Harhaji-Trajkovic L. Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro. in Cellular and Molecular Biology. 2016;62(11):108-114.
doi:10.14715/cmb/2016.62.11.18 .

Paunović, Verica, Kosic, Milica, Đorđević, S., Žugić, Ana, Đalinac, Nataša, Gašić, Uroš M., Trajković, Vladimir S., Harhaji-Trajkovic, Ljubica, "Marrubium vulgare ethanolic extract induces proliferation block, apoptosis, and cytoprotective autophagy in cancer cells in vitro" in Cellular and Molecular Biology, 62, no. 11 (2016):108-114,
https://doi.org/10.14715/cmb/2016.62.11.18 . .