TY  - JOUR
AU  - Stevanović, Darko
AU  - Starčević, Vesna
AU  - Vilimanovich, Urosh
AU  - Nešić, Dejan
AU  - Vucicevic, Ljubica
AU  - Misirkić, Maja
AU  - Janjetović, Kristina D.
AU  - Savić, Emina
AU  - Popadic, Dusan
AU  - Sudar, Emina
AU  - Micic, Dragan
AU  - Šumarac-Dumanović, Mirjana
AU  - Trajković, Vladimir S.
PY  - 2012
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/4590
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
VL  - 26
IS  - 1
SP  - 150
EP  - 158
DO  - 10.1016/j.bbi.2011.08.009
ER  - 

@article{
author = "Stevanović, Darko and Starčević, Vesna and Vilimanovich, Urosh and Nešić, Dejan and Vucicevic, Ljubica and Misirkić, Maja and Janjetović, Kristina D. and Savić, Emina and Popadic, Dusan and Sudar, Emina and Micic, Dragan and Šumarac-Dumanović, Mirjana 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",
volume = "26",
number = "1",
pages = "150-158",
doi = "10.1016/j.bbi.2011.08.009"
}

Stevanović, D., Starčević, V., Vilimanovich, U., Nešić, D., Vucicevic, L., Misirkić, M., Janjetović, K. D., Savić, E., Popadic, D., Sudar, E., Micic, D., Šumarac-Dumanović, M.,& Trajković, V. S.. (2012). Immunomodulatory actions of central ghrelin in diet-induced energy imbalance. in Brain Behavior and Immunity, 26(1), 150-158.
https://doi.org/10.1016/j.bbi.2011.08.009

Stevanović D, Starčević V, Vilimanovich U, Nešić D, Vucicevic L, Misirkić M, Janjetović KD, Savić E, Popadic D, Sudar E, Micic D, Šumarac-Dumanović M, Trajković VS. Immunomodulatory actions of central ghrelin in diet-induced energy imbalance. in Brain Behavior and Immunity. 2012;26(1):150-158.
doi:10.1016/j.bbi.2011.08.009 .

Stevanović, Darko, Starčević, Vesna, Vilimanovich, Urosh, Nešić, Dejan, Vucicevic, Ljubica, Misirkić, Maja, Janjetović, Kristina D., Savić, Emina, Popadic, Dusan, Sudar, Emina, Micic, Dragan, Šumarac-Dumanović, Mirjana, Trajković, Vladimir S., "Immunomodulatory actions of central ghrelin in diet-induced energy imbalance" in Brain Behavior and Immunity, 26, no. 1 (2012):150-158,
https://doi.org/10.1016/j.bbi.2011.08.009 . .

TY  - JOUR
AU  - Janjetović, Kristina D.
AU  - Vucicevic, Ljubica
AU  - Misirkić, Maja
AU  - Vilimanovich, Urosh
AU  - Tovilovic, Gordana
AU  - Zogovic, Nevena
AU  - Nikolić, Zoran M.
AU  - Jovanović, Svetlana P.
AU  - Bumbaširević, Vladimir Ž.
AU  - Trajković, Vladimir S.
AU  - Harhaji-Trajković, Ljubica M.
PY  - 2011
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/4205
AB  - Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens. (c) 2010 Published by Elsevier B.V.
T2  - European Journal of Pharmacology
T1  - Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt
VL  - 651
IS  - 1-3
SP  - 41
EP  - 50
DO  - 10.1016/j.ejphar.2010.11.005
ER  - 

@article{
author = "Janjetović, Kristina D. and Vucicevic, Ljubica and Misirkić, Maja and Vilimanovich, Urosh and Tovilovic, Gordana and Zogovic, Nevena and Nikolić, Zoran M. and Jovanović, Svetlana P. and Bumbaširević, Vladimir Ž. and Trajković, Vladimir S. and Harhaji-Trajković, Ljubica M.",
year = "2011",
abstract = "Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens. (c) 2010 Published by Elsevier B.V.",
journal = "European Journal of Pharmacology",
title = "Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt",
volume = "651",
number = "1-3",
pages = "41-50",
doi = "10.1016/j.ejphar.2010.11.005"
}

Janjetović, K. D., Vucicevic, L., Misirkić, M., Vilimanovich, U., Tovilovic, G., Zogovic, N., Nikolić, Z. M., Jovanović, S. P., Bumbaširević, V. Ž., Trajković, V. S.,& Harhaji-Trajković, L. M.. (2011). Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. in European Journal of Pharmacology, 651(1-3), 41-50.
https://doi.org/10.1016/j.ejphar.2010.11.005

Janjetović KD, Vucicevic L, Misirkić M, Vilimanovich U, Tovilovic G, Zogovic N, Nikolić ZM, Jovanović SP, Bumbaširević VŽ, Trajković VS, Harhaji-Trajković LM. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. in European Journal of Pharmacology. 2011;651(1-3):41-50.
doi:10.1016/j.ejphar.2010.11.005 .

Janjetović, Kristina D., Vucicevic, Ljubica, Misirkić, Maja, Vilimanovich, Urosh, Tovilovic, Gordana, Zogovic, Nevena, Nikolić, Zoran M., Jovanović, Svetlana P., Bumbaširević, Vladimir Ž., Trajković, Vladimir S., Harhaji-Trajković, Ljubica M., "Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt" in European Journal of Pharmacology, 651, no. 1-3 (2011):41-50,
https://doi.org/10.1016/j.ejphar.2010.11.005 . .

TY  - JOUR
AU  - Vucicevic, Ljubica
AU  - Misirkić, Maja
AU  - Janjetović, Kristina D.
AU  - Vilimanovich, Urosh
AU  - Sudar, Emina
AU  - Isenović, Esma R.
AU  - Prica, Marko
AU  - Harhaji-Trajković, Ljubica M.
AU  - Kravić-Stevović, Tamara K.
AU  - Bumbaširević, Vladimir Ž.
AU  - Trajković, Vladimir S.
PY  - 2011
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/4180
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
VL  - 7
IS  - 1
SP  - 40
EP  - 50
DO  - 10.4161/auto.7.1.13883
ER  - 

@article{
author = "Vucicevic, Ljubica and Misirkić, Maja and Janjetović, Kristina D. and Vilimanovich, Urosh and Sudar, Emina and Isenović, Esma R. and Prica, Marko and Harhaji-Trajković, Ljubica M. and Kravić-Stevović, Tamara K. and Bumbaširević, Vladimir Ž. 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",
volume = "7",
number = "1",
pages = "40-50",
doi = "10.4161/auto.7.1.13883"
}

Vucicevic, L., Misirkić, M., Janjetović, K. D., Vilimanovich, U., Sudar, E., Isenović, E. R., Prica, M., Harhaji-Trajković, L. M., Kravić-Stevović, T. K., Bumbaširević, V. Ž.,& 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), 40-50.
https://doi.org/10.4161/auto.7.1.13883

Vucicevic L, Misirkić M, Janjetović KD, Vilimanovich U, Sudar E, Isenović ER, Prica M, Harhaji-Trajković LM, Kravić-Stevović TK, Bumbaširević VŽ, Trajković VS. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. in Autophagy. 2011;7(1):40-50.
doi:10.4161/auto.7.1.13883 .

Vucicevic, Ljubica, Misirkić, Maja, Janjetović, Kristina D., Vilimanovich, Urosh, Sudar, Emina, Isenović, Esma R., Prica, Marko, Harhaji-Trajković, Ljubica M., Kravić-Stevović, Tamara K., Bumbaširević, Vladimir Ž., 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):40-50,
https://doi.org/10.4161/auto.7.1.13883 . .