TY  - JOUR
AU  - Stevanović, Darko M
AU  - Starčević, Vesna P.
AU  - Vilimanović, Uros
AU  - Nesić, Dejan M
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Savić, Emina
AU  - Popadić, Dusan M
AU  - Sudar, Emina M
AU  - Micić, Dragan D
AU  - Sumarac-Dumanović, Mirjana S
AU  - Trajković, Vladimir S
PY  - 2012
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1238
AB  - We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1 beta, IFN-gamma) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1 beta, IL-6, IFN-gamma, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-beta remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 mu g/day) for five consecutive days significantly reduced TNF, IL-1 beta and IFN-gamma levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of 1FN-gamma, IL-17,1L-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways. (C) 2011 Elsevier Inc. All rights reserved.
T2  - Brain Behavior and Immunity
T1  - Immunomodulatory actions of central ghrelin in diet-induced energy imbalance
IS  - 1
VL  - 26
EP  - 158
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1238
ER  - 

@article{
author = "Stevanović, Darko M and Starčević, Vesna P. and Vilimanović, Uros and Nesić, Dejan M and Vučićević, Ljubica and Misirkić Marjanović, Maja and Janjetović, Kristina and Savić, Emina and Popadić, Dusan M and Sudar, Emina M and Micić, Dragan D and Sumarac-Dumanović, Mirjana S and Trajković, Vladimir S",
year = "2012",
abstract = "We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1 beta, IFN-gamma) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1 beta, IL-6, IFN-gamma, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-beta remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 mu g/day) for five consecutive days significantly reduced TNF, IL-1 beta and IFN-gamma levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of 1FN-gamma, IL-17,1L-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways. (C) 2011 Elsevier Inc. All rights reserved.",
journal = "Brain Behavior and Immunity",
title = "Immunomodulatory actions of central ghrelin in diet-induced energy imbalance",
number = "1",
volume = "26",
pages = "158",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1238"
}

Stevanović, D. M., Starčević, V. P., Vilimanović, U., Nesić, D. M., Vučićević, L., Misirkić Marjanović, M., Janjetović, K., Savić, E., Popadić, D. M., Sudar, E. M., Micić, D. D., Sumarac-Dumanović, M. S.,& Trajković, V. S.. (2012). Immunomodulatory actions of central ghrelin in diet-induced energy imbalance. in Brain Behavior and Immunity, 26(1).
https://hdl.handle.net/21.15107/rcub_ibiss_1238

Stevanović DM, Starčević VP, Vilimanović U, Nesić DM, Vučićević L, Misirkić Marjanović M, Janjetović K, Savić E, Popadić DM, Sudar EM, Micić DD, Sumarac-Dumanović MS, Trajković VS. Immunomodulatory actions of central ghrelin in diet-induced energy imbalance. in Brain Behavior and Immunity. 2012;26(1):null-158.
https://hdl.handle.net/21.15107/rcub_ibiss_1238 .

Stevanović, Darko M, Starčević, Vesna P., Vilimanović, Uros, Nesić, Dejan M, Vučićević, Ljubica, Misirkić Marjanović, Maja, Janjetović, Kristina, Savić, Emina, Popadić, Dusan M, Sudar, Emina M, Micić, Dragan D, Sumarac-Dumanović, Mirjana S, Trajković, Vladimir S, "Immunomodulatory actions of central ghrelin in diet-induced energy imbalance" in Brain Behavior and Immunity, 26, no. 1 (2012),
https://hdl.handle.net/21.15107/rcub_ibiss_1238 .

TY  - JOUR
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Vilimanović, Uros
AU  - Sudar, Emina M
AU  - Isenović, Esma R
AU  - Prica, Marko
AU  - Harhaji-Trajković, Ljubica
AU  - Kravić-Stevović, Tamara K
AU  - Bumbaširević, Vladimir Z
AU  - Trajković, Vladimir S
PY  - 2011
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1321
AB  - In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AICAR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.
T2  - Autophagy
T1  - Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway
IS  - 1
VL  - 7
DO  - 10.4161/auto.7.1.13883
EP  - 50
ER  - 

@article{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Janjetović, Kristina and Vilimanović, Uros and Sudar, Emina M and Isenović, Esma R and Prica, Marko and Harhaji-Trajković, Ljubica and Kravić-Stevović, Tamara K and Bumbaširević, Vladimir Z and Trajković, Vladimir S",
year = "2011",
abstract = "In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AICAR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.",
journal = "Autophagy",
title = "Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway",
number = "1",
volume = "7",
doi = "10.4161/auto.7.1.13883",
pages = "50"
}

Vučićević, L., Misirkić Marjanović, M., Janjetović, K., Vilimanović, U., Sudar, E. M., Isenović, E. R., Prica, M., Harhaji-Trajković, L., Kravić-Stevović, T. K., Bumbaširević, V. Z.,& Trajković, V. S.. (2011). Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy, 7(1).
https://doi.org/10.4161/auto.7.1.13883

Vučićević L, Misirkić Marjanović M, Janjetović K, Vilimanović U, Sudar EM, Isenović ER, Prica M, Harhaji-Trajković L, Kravić-Stevović TK, Bumbaširević VZ, Trajković VS. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy. 2011;7(1):null-50.
doi:10.4161/auto.7.1.13883 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Janjetović, Kristina, Vilimanović, Uros, Sudar, Emina M, Isenović, Esma R, Prica, Marko, Harhaji-Trajković, Ljubica, Kravić-Stevović, Tamara K, Bumbaširević, Vladimir Z, Trajković, Vladimir S, "Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway" in Autophagy, 7, no. 1 (2011),
https://doi.org/10.4161/auto.7.1.13883 . .

TY  - JOUR
AU  - Sudar, Emina M
AU  - Dobutović, Branislava D
AU  - Soskić, Sanja S
AU  - Mandušić, Vesna
AU  - Zakula, Zorica
AU  - Misirkić Marjanović, Maja
AU  - Vučićević, Ljubica
AU  - Janjetović, Kristina
AU  - Trajković, Vladimir S
AU  - Mikhailidis, Dimitri P
AU  - Isenović, Esma R
PY  - 2011
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1121
AB  - The purpose of this study was to examine the effects of ghrelin on protein kinase B (Akt) and mitogen-activated protein kinase p42/44 (ERK1/2) activation as well as ghrelin effects on inducible nitric oxide (NO) synthase (iNOS; for gene Nos2) activity/expression in rat hearts. Male Wistar rats were treated with ghrelin (0.3 nmol/5 mu l) or an equal volume of phosphate-buffered saline, injected every 24 h into the lateral cerebral ventricle for 5 days and 2 h after the last treatment the animals were sacrificed. Serum NO, l-arginine (l-Arg), and arginase activity were measured spectrophotometrically. For phosphorylation of Akt, ERK1/2, and iNOS protein expression, Western blot method was used. The expression of Nos2 mRNA was measured by the quantitative real-time polymerase chain reaction (qRT-PCR). Treatment with ghrelin significantly increased NO production in serum by 1.4-fold compared with control. The concentration of l-Arg was significantly higher in ghrelin-treated rats than in control while arginase activity was significantly lower in ghrelin-treated than in control hearts. Ghrelin treatment increased phosphorylation of Akt by 1.9-fold and ERK1/2 by 1.6-fold and increased iNOS expression by 2.5-fold compared with control. In addition, ghrelin treatment increased Nos2 gene expression by 2.2-fold as determined by qRT-PCR. These results indicate that ghrelin regulation of iNOS expression/activity is mediated via Akt/ERK1/2 signaling pathway. These results may be relevant to understanding molecular mechanisms underlying direct cardiovascular actions of ghrelin.
T2  - Journal of Physiology and Biochemistry
T1  - Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats
IS  - 2
VL  - 67
SP  - 483
EP  - 204
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1121
ER  - 

@article{
author = "Sudar, Emina M and Dobutović, Branislava D and Soskić, Sanja S and Mandušić, Vesna and Zakula, Zorica and Misirkić Marjanović, Maja and Vučićević, Ljubica and Janjetović, Kristina and Trajković, Vladimir S and Mikhailidis, Dimitri P and Isenović, Esma R",
year = "2011",
abstract = "The purpose of this study was to examine the effects of ghrelin on protein kinase B (Akt) and mitogen-activated protein kinase p42/44 (ERK1/2) activation as well as ghrelin effects on inducible nitric oxide (NO) synthase (iNOS; for gene Nos2) activity/expression in rat hearts. Male Wistar rats were treated with ghrelin (0.3 nmol/5 mu l) or an equal volume of phosphate-buffered saline, injected every 24 h into the lateral cerebral ventricle for 5 days and 2 h after the last treatment the animals were sacrificed. Serum NO, l-arginine (l-Arg), and arginase activity were measured spectrophotometrically. For phosphorylation of Akt, ERK1/2, and iNOS protein expression, Western blot method was used. The expression of Nos2 mRNA was measured by the quantitative real-time polymerase chain reaction (qRT-PCR). Treatment with ghrelin significantly increased NO production in serum by 1.4-fold compared with control. The concentration of l-Arg was significantly higher in ghrelin-treated rats than in control while arginase activity was significantly lower in ghrelin-treated than in control hearts. Ghrelin treatment increased phosphorylation of Akt by 1.9-fold and ERK1/2 by 1.6-fold and increased iNOS expression by 2.5-fold compared with control. In addition, ghrelin treatment increased Nos2 gene expression by 2.2-fold as determined by qRT-PCR. These results indicate that ghrelin regulation of iNOS expression/activity is mediated via Akt/ERK1/2 signaling pathway. These results may be relevant to understanding molecular mechanisms underlying direct cardiovascular actions of ghrelin.",
journal = "Journal of Physiology and Biochemistry",
title = "Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats",
number = "2",
volume = "67",
pages = "483-204",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1121"
}

Sudar, E. M., Dobutović, B. D., Soskić, S. S., Mandušić, V., Zakula, Z., Misirkić Marjanović, M., Vučićević, L., Janjetović, K., Trajković, V. S., Mikhailidis, D. P.,& Isenović, E. R.. (2011). Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. in Journal of Physiology and Biochemistry, 67(2), 483-204.
https://hdl.handle.net/21.15107/rcub_ibiss_1121

Sudar EM, Dobutović BD, Soskić SS, Mandušić V, Zakula Z, Misirkić Marjanović M, Vučićević L, Janjetović K, Trajković VS, Mikhailidis DP, Isenović ER. Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. in Journal of Physiology and Biochemistry. 2011;67(2):483-204.
https://hdl.handle.net/21.15107/rcub_ibiss_1121 .

Sudar, Emina M, Dobutović, Branislava D, Soskić, Sanja S, Mandušić, Vesna, Zakula, Zorica, Misirkić Marjanović, Maja, Vučićević, Ljubica, Janjetović, Kristina, Trajković, Vladimir S, Mikhailidis, Dimitri P, Isenović, Esma R, "Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats" in Journal of Physiology and Biochemistry, 67, no. 2 (2011):483-204,
https://hdl.handle.net/21.15107/rcub_ibiss_1121 .

TY  - JOUR
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Harhaji-Trajković, Ljubica
AU  - Prica, Marko
AU  - Stevanović, Darko M
AU  - Isenović, Esma R
AU  - Sudar, Emina M
AU  - Sumarac-Dumanović, Mirjana S
AU  - Micić, Dragan D
AU  - Trajković, Vladimir S
PY  - 2009
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1446
AB  - We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells. (c) 2009 Elsevier Inc. All rights reserved.
T2  - Biochemical Pharmacology
T1  - AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C
IS  - 11
VL  - 77
EP  - 1693
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1446
ER  - 

@article{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Janjetović, Kristina and Harhaji-Trajković, Ljubica and Prica, Marko and Stevanović, Darko M and Isenović, Esma R and Sudar, Emina M and Sumarac-Dumanović, Mirjana S and Micić, Dragan D and Trajković, Vladimir S",
year = "2009",
abstract = "We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells. (c) 2009 Elsevier Inc. All rights reserved.",
journal = "Biochemical Pharmacology",
title = "AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C",
number = "11",
volume = "77",
pages = "1693",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1446"
}

Vučićević, L., Misirkić Marjanović, M., Janjetović, K., Harhaji-Trajković, L., Prica, M., Stevanović, D. M., Isenović, E. R., Sudar, E. M., Sumarac-Dumanović, M. S., Micić, D. D.,& Trajković, V. S.. (2009). AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. in Biochemical Pharmacology, 77(11).
https://hdl.handle.net/21.15107/rcub_ibiss_1446

Vučićević L, Misirkić Marjanović M, Janjetović K, Harhaji-Trajković L, Prica M, Stevanović DM, Isenović ER, Sudar EM, Sumarac-Dumanović MS, Micić DD, Trajković VS. AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. in Biochemical Pharmacology. 2009;77(11):null-1693.
https://hdl.handle.net/21.15107/rcub_ibiss_1446 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Janjetović, Kristina, Harhaji-Trajković, Ljubica, Prica, Marko, Stevanović, Darko M, Isenović, Esma R, Sudar, Emina M, Sumarac-Dumanović, Mirjana S, Micić, Dragan D, Trajković, Vladimir S, "AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C" in Biochemical Pharmacology, 77, no. 11 (2009),
https://hdl.handle.net/21.15107/rcub_ibiss_1446 .