TY  - JOUR
AU  - Đurašević, Siniša
AU  - Stojković, Maja
AU  - Sopta, Jelena
AU  - Pavlović, Slađan
AU  - Borković Mitić, Slavica
AU  - Ivanović, Anđelija
AU  - Jasnić, Nebojša
AU  - Tosti, Tomislav
AU  - Đurović, Saša
AU  - Đorđević, Jelena
AU  - Todorović, Zoran
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4090
AB  - Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium
is an anti‑ischemic agent that shifts energy production from fatty acid oxidation to less oxygen‑
consuming glycolysis. Thus, we investigated the effects of a 4‑week meldonium pre‑treatment
(300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that
meldonium ameliorates I/R‑induced liver inflammation and injury, as confirmed by liver histology,
and by attenuation of serum alanine‑ and aspartate aminotransferase activity, serum and liver
high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and
the phosphorylated nuclear factor kappa‑light‑chain‑enhancer of activated B cells. Through the
increased hepatic activation of the nuclear factor erythroid 2‑related factor 2, meldonium improves
the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum
and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione
and free thiol groups content, and hepatic copper‑zinc superoxide dismutase, manganese superoxide
dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results,
it can be concluded that meldonium represent a protective agent against I/R‑induced liver injury, with
a clinical significance in surgical procedures.
PB  - Nature Publishing Group
T2  - Scientific Reports
T1  - The effects of meldonium on the acute ischemia/reperfusion liver injury in rats
IS  - 1
VL  - 11
DO  - 10.1038/s41598-020-80011-y
SP  - 1305
ER  - 

@article{
author = "Đurašević, Siniša and Stojković, Maja and Sopta, Jelena and Pavlović, Slađan and Borković Mitić, Slavica and Ivanović, Anđelija and Jasnić, Nebojša and Tosti, Tomislav and Đurović, Saša and Đorđević, Jelena and Todorović, Zoran",
year = "2021",
abstract = "Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium
is an anti‑ischemic agent that shifts energy production from fatty acid oxidation to less oxygen‑
consuming glycolysis. Thus, we investigated the effects of a 4‑week meldonium pre‑treatment
(300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that
meldonium ameliorates I/R‑induced liver inflammation and injury, as confirmed by liver histology,
and by attenuation of serum alanine‑ and aspartate aminotransferase activity, serum and liver
high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and
the phosphorylated nuclear factor kappa‑light‑chain‑enhancer of activated B cells. Through the
increased hepatic activation of the nuclear factor erythroid 2‑related factor 2, meldonium improves
the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum
and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione
and free thiol groups content, and hepatic copper‑zinc superoxide dismutase, manganese superoxide
dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results,
it can be concluded that meldonium represent a protective agent against I/R‑induced liver injury, with
a clinical significance in surgical procedures.",
publisher = "Nature Publishing Group",
journal = "Scientific Reports",
title = "The effects of meldonium on the acute ischemia/reperfusion liver injury in rats",
number = "1",
volume = "11",
doi = "10.1038/s41598-020-80011-y",
pages = "1305"
}

Đurašević, S., Stojković, M., Sopta, J., Pavlović, S., Borković Mitić, S., Ivanović, A., Jasnić, N., Tosti, T., Đurović, S., Đorđević, J.,& Todorović, Z.. (2021). The effects of meldonium on the acute ischemia/reperfusion liver injury in rats. in Scientific Reports
Nature Publishing Group., 11(1), 1305.
https://doi.org/10.1038/s41598-020-80011-y

Đurašević S, Stojković M, Sopta J, Pavlović S, Borković Mitić S, Ivanović A, Jasnić N, Tosti T, Đurović S, Đorđević J, Todorović Z. The effects of meldonium on the acute ischemia/reperfusion liver injury in rats. in Scientific Reports. 2021;11(1):1305.
doi:10.1038/s41598-020-80011-y .

Đurašević, Siniša, Stojković, Maja, Sopta, Jelena, Pavlović, Slađan, Borković Mitić, Slavica, Ivanović, Anđelija, Jasnić, Nebojša, Tosti, Tomislav, Đurović, Saša, Đorđević, Jelena, Todorović, Zoran, "The effects of meldonium on the acute ischemia/reperfusion liver injury in rats" in Scientific Reports, 11, no. 1 (2021):1305,
https://doi.org/10.1038/s41598-020-80011-y . .

TY  - JOUR
AU  - Todorović, Zoran
AU  - Đurašević, Siniša
AU  - Stojković, Maja
AU  - Grigorov, Ilijana
AU  - Pavlović, Slađan
AU  - Jasnić, Nebojša
AU  - Tosti, Tomislav
AU  - Bjekić Macut, Jelica
AU  - Thiemermann, Christoph
AU  - Đorđević, Jelena
PY  - 2021
UR  - https://www.mdpi.com/1422-0067/22/6/2798
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4162
AB  - Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.
PB  - Multidisciplinary Digital Publishing Institute
T2  - International Journal of Molecular Sciences
T1  - Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury
IS  - 6
VL  - 22
DO  - 10.3390/ijms22062798
SP  - 2798
ER  - 

@article{
author = "Todorović, Zoran and Đurašević, Siniša and Stojković, Maja and Grigorov, Ilijana and Pavlović, Slađan and Jasnić, Nebojša and Tosti, Tomislav and Bjekić Macut, Jelica and Thiemermann, Christoph and Đorđević, Jelena",
year = "2021",
abstract = "Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.",
publisher = "Multidisciplinary Digital Publishing Institute",
journal = "International Journal of Molecular Sciences",
title = "Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury",
number = "6",
volume = "22",
doi = "10.3390/ijms22062798",
pages = "2798"
}

Todorović, Z., Đurašević, S., Stojković, M., Grigorov, I., Pavlović, S., Jasnić, N., Tosti, T., Bjekić Macut, J., Thiemermann, C.,& Đorđević, J.. (2021). Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury. in International Journal of Molecular Sciences
Multidisciplinary Digital Publishing Institute., 22(6), 2798.
https://doi.org/10.3390/ijms22062798

Todorović Z, Đurašević S, Stojković M, Grigorov I, Pavlović S, Jasnić N, Tosti T, Bjekić Macut J, Thiemermann C, Đorđević J. Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury. in International Journal of Molecular Sciences. 2021;22(6):2798.
doi:10.3390/ijms22062798 .

Todorović, Zoran, Đurašević, Siniša, Stojković, Maja, Grigorov, Ilijana, Pavlović, Slađan, Jasnić, Nebojša, Tosti, Tomislav, Bjekić Macut, Jelica, Thiemermann, Christoph, Đorđević, Jelena, "Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia—Reperfusion Injury" in International Journal of Molecular Sciences, 22, no. 6 (2021):2798,
https://doi.org/10.3390/ijms22062798 . .

TY  - CONF
AU  - Đurašević, Siniša
AU  - Stojković, Maja
AU  - Bogdanović, Ljiljana
AU  - Grigorov, Ilijana
AU  - Bogojević, Desanka
AU  - Jasnić, Nebojša
AU  - Vujović, Predrag
AU  - Dakić, Tamara
AU  - Todorović, Zoran
AU  - Đorđević, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6333
AB  - Acute renal ischemia/reperfusion (I/R) is a temporary restriction of kidney blood supply, followed by blood flow restoration and re-oxygenation. During I/R, decreased oxygen supply disturbs ion transport, intracellular ATP, calcium and pH levels, and numerous signalling pathways. Upon reperfusion, a restoration of oxygen level rises a reactive oxygen species generation, cytokines and chemokines release from activated tissue-resident macrophages, and infiltration of pro-inflammatory neutrophils into ischemic tissues. All these changes result in cell swelling and rupturing, and consequent necrotic or apoptotic cell death. Meldonium is an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, which acts by shifting energy production from fatty acid oxidation to glycolysis. We investigated the effects of a 4-week meldonium pre-treatment with 300 mg/kg b.m./day of rats subjected to a well-established experimental model of renal I/R, with ischemia lasting for 45 minutes, followed by 4 hours of reperfusion. The degree of apoptosis and necrosis was evaluated by measuring renal pro-apoptotic Bax and anti-apoptotic Bcl-2 ratio, serum and kidney levels of necrotic marker - high mobility group box 1 protein (HMGB1), together with the kidney histology analysis. Our results showed that apoptotic and necrotic cell death occur simultaneously under I/R conditions, judging by the renal Bax/Bcl2 ratio rise (2.7-fold), increase in serum (22%) and renal (30%) levels of HMGB1, as well as severe tubular necrosis with dilatation of the tubular structure, cast formation, tubular lumina dilatation, brush border reduction, and loss in some renal areas cells. Meldonium pretreatment reduced the elevated Bax/Bcl2 ratio by 35%, as well as the serum and renal HMGB1 levels by 20% and notably diminished histological evidence of renal I/R necrotic injury, especially regarding tubular structures. These findings proved that meldonium protects renal cells against I/R-induced necrosis and apoptosis.
PB  - Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade
C3  - Immunology at the Confluence of Multidisciplinary Approaches
T1  - Meldonium prevents acute ishemia/reperfusion inducend-renal cells death in rats
SP  - 86
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6333
ER  - 

@conference{
author = "Đurašević, Siniša and Stojković, Maja and Bogdanović, Ljiljana and Grigorov, Ilijana and Bogojević, Desanka and Jasnić, Nebojša and Vujović, Predrag and Dakić, Tamara and Todorović, Zoran and Đorđević, Jelena",
year = "2019",
abstract = "Acute renal ischemia/reperfusion (I/R) is a temporary restriction of kidney blood supply, followed by blood flow restoration and re-oxygenation. During I/R, decreased oxygen supply disturbs ion transport, intracellular ATP, calcium and pH levels, and numerous signalling pathways. Upon reperfusion, a restoration of oxygen level rises a reactive oxygen species generation, cytokines and chemokines release from activated tissue-resident macrophages, and infiltration of pro-inflammatory neutrophils into ischemic tissues. All these changes result in cell swelling and rupturing, and consequent necrotic or apoptotic cell death. Meldonium is an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, which acts by shifting energy production from fatty acid oxidation to glycolysis. We investigated the effects of a 4-week meldonium pre-treatment with 300 mg/kg b.m./day of rats subjected to a well-established experimental model of renal I/R, with ischemia lasting for 45 minutes, followed by 4 hours of reperfusion. The degree of apoptosis and necrosis was evaluated by measuring renal pro-apoptotic Bax and anti-apoptotic Bcl-2 ratio, serum and kidney levels of necrotic marker - high mobility group box 1 protein (HMGB1), together with the kidney histology analysis. Our results showed that apoptotic and necrotic cell death occur simultaneously under I/R conditions, judging by the renal Bax/Bcl2 ratio rise (2.7-fold), increase in serum (22%) and renal (30%) levels of HMGB1, as well as severe tubular necrosis with dilatation of the tubular structure, cast formation, tubular lumina dilatation, brush border reduction, and loss in some renal areas cells. Meldonium pretreatment reduced the elevated Bax/Bcl2 ratio by 35%, as well as the serum and renal HMGB1 levels by 20% and notably diminished histological evidence of renal I/R necrotic injury, especially regarding tubular structures. These findings proved that meldonium protects renal cells against I/R-induced necrosis and apoptosis.",
publisher = "Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade",
journal = "Immunology at the Confluence of Multidisciplinary Approaches",
title = "Meldonium prevents acute ishemia/reperfusion inducend-renal cells death in rats",
pages = "86",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6333"
}

Đurašević, S., Stojković, M., Bogdanović, L., Grigorov, I., Bogojević, D., Jasnić, N., Vujović, P., Dakić, T., Todorović, Z.,& Đorđević, J.. (2019). Meldonium prevents acute ishemia/reperfusion inducend-renal cells death in rats. in Immunology at the Confluence of Multidisciplinary Approaches
Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade., 86.
https://hdl.handle.net/21.15107/rcub_ibiss_6333

Đurašević S, Stojković M, Bogdanović L, Grigorov I, Bogojević D, Jasnić N, Vujović P, Dakić T, Todorović Z, Đorđević J. Meldonium prevents acute ishemia/reperfusion inducend-renal cells death in rats. in Immunology at the Confluence of Multidisciplinary Approaches. 2019;:86.
https://hdl.handle.net/21.15107/rcub_ibiss_6333 .

Đurašević, Siniša, Stojković, Maja, Bogdanović, Ljiljana, Grigorov, Ilijana, Bogojević, Desanka, Jasnić, Nebojša, Vujović, Predrag, Dakić, Tamara, Todorović, Zoran, Đorđević, Jelena, "Meldonium prevents acute ishemia/reperfusion inducend-renal cells death in rats" in Immunology at the Confluence of Multidisciplinary Approaches (2019):86,
https://hdl.handle.net/21.15107/rcub_ibiss_6333 .

TY  - JOUR
AU  - Đurašević, Siniša
AU  - Stojković, Maja
AU  - Bogdanović, Ljiljana
AU  - Pavlović, Slađan
AU  - Borković Mitić, Slavica
AU  - Grigorov, Ilijana
AU  - Bogojević, Desanka
AU  - Jasnić, Nebojša
AU  - Tosti, Tomislav
AU  - Đurović, Saša
AU  - Đorđević, Jelena
AU  - Todorović, Zoran
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3519
AB  - Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to
treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation
to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week
meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our
results showed that meldonium decreased animal body mass gain, food and water intake, and
carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium
increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and
increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1,
causing manganese superoxide dismutase expression and activity to increase, as well as lipid
peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase
activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum
high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in
I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and
serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex
changes in renal lipidomics. Taken together, our results have confirmed that meldonium pretreatment protects against I/R-induced oxidative stress and apoptosis/necrosis.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - The effects of meldonium on the renal acute ischemia/reperfusion injury in rats
IS  - 22
VL  - 20
DO  - 10.3390/ijms20225747
SP  - 5747
ER  - 

@article{
author = "Đurašević, Siniša and Stojković, Maja and Bogdanović, Ljiljana and Pavlović, Slađan and Borković Mitić, Slavica and Grigorov, Ilijana and Bogojević, Desanka and Jasnić, Nebojša and Tosti, Tomislav and Đurović, Saša and Đorđević, Jelena and Todorović, Zoran",
year = "2019",
abstract = "Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to
treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation
to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week
meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our
results showed that meldonium decreased animal body mass gain, food and water intake, and
carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium
increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and
increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1,
causing manganese superoxide dismutase expression and activity to increase, as well as lipid
peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase
activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum
high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in
I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and
serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex
changes in renal lipidomics. Taken together, our results have confirmed that meldonium pretreatment protects against I/R-induced oxidative stress and apoptosis/necrosis.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "The effects of meldonium on the renal acute ischemia/reperfusion injury in rats",
number = "22",
volume = "20",
doi = "10.3390/ijms20225747",
pages = "5747"
}

Đurašević, S., Stojković, M., Bogdanović, L., Pavlović, S., Borković Mitić, S., Grigorov, I., Bogojević, D., Jasnić, N., Tosti, T., Đurović, S., Đorđević, J.,& Todorović, Z.. (2019). The effects of meldonium on the renal acute ischemia/reperfusion injury in rats. in International Journal of Molecular Sciences
MDPI., 20(22), 5747.
https://doi.org/10.3390/ijms20225747

Đurašević S, Stojković M, Bogdanović L, Pavlović S, Borković Mitić S, Grigorov I, Bogojević D, Jasnić N, Tosti T, Đurović S, Đorđević J, Todorović Z. The effects of meldonium on the renal acute ischemia/reperfusion injury in rats. in International Journal of Molecular Sciences. 2019;20(22):5747.
doi:10.3390/ijms20225747 .

Đurašević, Siniša, Stojković, Maja, Bogdanović, Ljiljana, Pavlović, Slađan, Borković Mitić, Slavica, Grigorov, Ilijana, Bogojević, Desanka, Jasnić, Nebojša, Tosti, Tomislav, Đurović, Saša, Đorđević, Jelena, Todorović, Zoran, "The effects of meldonium on the renal acute ischemia/reperfusion injury in rats" in International Journal of Molecular Sciences, 20, no. 22 (2019):5747,
https://doi.org/10.3390/ijms20225747 . .