TY  - JOUR
AU  - Jonić, Natalija
AU  - Koprivica, Ivan
AU  - Chatzigiannis, Christos M.
AU  - Tsiailanis, Antonis D.
AU  - Kyrkou, Stavroula G
AU  - Tzakos, Eleftherios Paraskevas
AU  - Pavić, Aleksandar
AU  - Dimitrijević, Mirjana
AU  - Jovanović, Andjelina
AU  - Jovanović, Milan B.
AU  - Marinho, Sergio
AU  - Castro-Almeida, Ines
AU  - Otašević, Vesna
AU  - Moura-Alves, Pedro
AU  - Tzakos, Andreas G
AU  - Stojanović, Ivana D.
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6870
AB  - Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects.
In this study, we designed, synthesized and evaluated three indole-containing potential AHR
ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to
emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in
silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs
were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their
immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant
anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory
regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5
actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation,
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator
of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also
observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish
embryos and was therefore considered safe for animal studies. Following oral administration to
C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1
cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized
both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the
small intestine). These findings make AGT-5 a promising candidate for further exploration in the
treatment of inflammatory and autoimmune diseases.
PB  - Basel: MDPI
T2  - Molecules
T1  - Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells
IS  - 13
VL  - 29
DO  - 10.3390/molecules29132988
SP  - 2988
ER  - 

@article{
author = "Jonić, Natalija and Koprivica, Ivan and Chatzigiannis, Christos M. and Tsiailanis, Antonis D. and Kyrkou, Stavroula G and Tzakos, Eleftherios Paraskevas and Pavić, Aleksandar and Dimitrijević, Mirjana and Jovanović, Andjelina and Jovanović, Milan B. and Marinho, Sergio and Castro-Almeida, Ines and Otašević, Vesna and Moura-Alves, Pedro and Tzakos, Andreas G and Stojanović, Ivana D.",
year = "2024",
abstract = "Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects.
In this study, we designed, synthesized and evaluated three indole-containing potential AHR
ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to
emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in
silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs
were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their
immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant
anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory
regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5
actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation,
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator
of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also
observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish
embryos and was therefore considered safe for animal studies. Following oral administration to
C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1
cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized
both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the
small intestine). These findings make AGT-5 a promising candidate for further exploration in the
treatment of inflammatory and autoimmune diseases.",
publisher = "Basel: MDPI",
journal = "Molecules",
title = "Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells",
number = "13",
volume = "29",
doi = "10.3390/molecules29132988",
pages = "2988"
}

Jonić, N., Koprivica, I., Chatzigiannis, C. M., Tsiailanis, A. D., Kyrkou, S. G., Tzakos, E. P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Marinho, S., Castro-Almeida, I., Otašević, V., Moura-Alves, P., Tzakos, A. G.,& Stojanović, I. D.. (2024). Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. in Molecules
Basel: MDPI., 29(13), 2988.
https://doi.org/10.3390/molecules29132988

Jonić N, Koprivica I, Chatzigiannis CM, Tsiailanis AD, Kyrkou SG, Tzakos EP, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Marinho S, Castro-Almeida I, Otašević V, Moura-Alves P, Tzakos AG, Stojanović ID. Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. in Molecules. 2024;29(13):2988.
doi:10.3390/molecules29132988 .

Jonić, Natalija, Koprivica, Ivan, Chatzigiannis, Christos M., Tsiailanis, Antonis D., Kyrkou, Stavroula G, Tzakos, Eleftherios Paraskevas, Pavić, Aleksandar, Dimitrijević, Mirjana, Jovanović, Andjelina, Jovanović, Milan B., Marinho, Sergio, Castro-Almeida, Ines, Otašević, Vesna, Moura-Alves, Pedro, Tzakos, Andreas G, Stojanović, Ivana D., "Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells" in Molecules, 29, no. 13 (2024):2988,
https://doi.org/10.3390/molecules29132988 . .

TY  - CONF
AU  - Stančić, Ana
AU  - Markelić, Milica
AU  - Savić, Nevena
AU  - Veličković, Ksenija
AU  - Gudelj, Anđelija
AU  - Martinović, Vesna
AU  - Grigorov, Ilijana
AU  - Otašević, Vesna
PY  - 2024
UR  - https://genapp.ba/editions/index.php/journal/article/view/214/158
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6849
AB  - Sulforaphane (SFN) is a natural sulfur-rich compound found in cruciferous vegetables. SFN has been recognized as a powerful bioactive agent for reducing hyperglycemia and hyperlipidemia, improving insulin resistance, oxidative stress and inflammation in diabetic conditions. We aimed here to examine whether and how SFN affects diabetic-related skeletal muscle disorders associated with cell death signaling pathways. Precisely, the effect of SFN on ferroptosis, iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides, was examined. Male C57BL/6 mice were divided into four groups: control, diabetic (streptozotocin-induced; 40 mg/kg, from days 1 to 5), non- diabetic SFN-treated (SFN) and diabetic treated with SFN (DM + SFN). SFN was administrated i.p. in a dose of 2.5 mg/kg/day for 42 days. The results from histochemical analyses have shown the increased level of ferroptotic markers, seen as an accumulation of iron, as well 4-hydroxynonenal (4-HNE), an abundant end-product of lipid peroxidation, in skeletal muscle of diabetic animals. Along with this, there was decrease in antioxidant capacity, observed as lower immunohistochemical positivity for glutathione peroxidase 4 (GPX4), the main lipid peroxides-scavenging enzyme as well decrease in protein expression of cystine-glutamate antiporter system (xCT), the important determinant of intracellular synthesis of glutathione, GPX cofactor. Treatment of diabetic animals with SFN induced decreased accumulation of iron and 4-HNE and increased GPX4 immunopositivity and xCT protein level in skeletal muscle compared to the untreated diabetic animals. We can conclude that SFN has beneficial effects on the main core of ferroptosis signaling composed of xCT/GPX4/lipid peroxides axis and thus improves ferroptotic phenotype of skeletal muscle in diabetic conditions. This shed light on  the new mechanism of SFN action over diabetes-related skeletal muscle dysfunction based on antiferroptotic action and nominates SFN as a promising phytoparmaceutical in the treatment of diabetes-related metabolic disorders
PB  - Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo
C3  - Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
T1  - Anti-ferroptotic action of sulforaphane in skeletal muscle of diabetic mice
SP  - 69
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6849
ER  - 

@conference{
author = "Stančić, Ana and Markelić, Milica and Savić, Nevena and Veličković, Ksenija and Gudelj, Anđelija and Martinović, Vesna and Grigorov, Ilijana and Otašević, Vesna",
year = "2024",
abstract = "Sulforaphane (SFN) is a natural sulfur-rich compound found in cruciferous vegetables. SFN has been recognized as a powerful bioactive agent for reducing hyperglycemia and hyperlipidemia, improving insulin resistance, oxidative stress and inflammation in diabetic conditions. We aimed here to examine whether and how SFN affects diabetic-related skeletal muscle disorders associated with cell death signaling pathways. Precisely, the effect of SFN on ferroptosis, iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides, was examined. Male C57BL/6 mice were divided into four groups: control, diabetic (streptozotocin-induced; 40 mg/kg, from days 1 to 5), non- diabetic SFN-treated (SFN) and diabetic treated with SFN (DM + SFN). SFN was administrated i.p. in a dose of 2.5 mg/kg/day for 42 days. The results from histochemical analyses have shown the increased level of ferroptotic markers, seen as an accumulation of iron, as well 4-hydroxynonenal (4-HNE), an abundant end-product of lipid peroxidation, in skeletal muscle of diabetic animals. Along with this, there was decrease in antioxidant capacity, observed as lower immunohistochemical positivity for glutathione peroxidase 4 (GPX4), the main lipid peroxides-scavenging enzyme as well decrease in protein expression of cystine-glutamate antiporter system (xCT), the important determinant of intracellular synthesis of glutathione, GPX cofactor. Treatment of diabetic animals with SFN induced decreased accumulation of iron and 4-HNE and increased GPX4 immunopositivity and xCT protein level in skeletal muscle compared to the untreated diabetic animals. We can conclude that SFN has beneficial effects on the main core of ferroptosis signaling composed of xCT/GPX4/lipid peroxides axis and thus improves ferroptotic phenotype of skeletal muscle in diabetic conditions. This shed light on  the new mechanism of SFN action over diabetes-related skeletal muscle dysfunction based on antiferroptotic action and nominates SFN as a promising phytoparmaceutical in the treatment of diabetes-related metabolic disorders",
publisher = "Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo",
journal = "Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina",
title = "Anti-ferroptotic action of sulforaphane in skeletal muscle of diabetic mice",
pages = "69",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6849"
}

Stančić, A., Markelić, M., Savić, N., Veličković, K., Gudelj, A., Martinović, V., Grigorov, I.,& Otašević, V.. (2024). Anti-ferroptotic action of sulforaphane in skeletal muscle of diabetic mice. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo., 69.
https://hdl.handle.net/21.15107/rcub_ibiss_6849

Stančić A, Markelić M, Savić N, Veličković K, Gudelj A, Martinović V, Grigorov I, Otašević V. Anti-ferroptotic action of sulforaphane in skeletal muscle of diabetic mice. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina. 2024;:69.
https://hdl.handle.net/21.15107/rcub_ibiss_6849 .

Stančić, Ana, Markelić, Milica, Savić, Nevena, Veličković, Ksenija, Gudelj, Anđelija, Martinović, Vesna, Grigorov, Ilijana, Otašević, Vesna, "Anti-ferroptotic action of sulforaphane in skeletal muscle of diabetic mice" in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina (2024):69,
https://hdl.handle.net/21.15107/rcub_ibiss_6849 .

TY  - CONF
AU  - Otašević, Vesna
AU  - Stančić, Ana
AU  - Gudelj, Anđelija
AU  - Savić, Nevena
AU  - Markelić, Milica
AU  - Veličković, Ksenija
AU  - Martinović, Vesna
AU  - Grigorov, Ilijana
PY  - 2024
UR  - https://genapp.ba/editions/index.php/journal/article/view/214/158
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6850
AB  - The activation of inflammation is closely associated with ferroptosis and vice versa. Recently, we have demonstrated the involvement of ferroptosis, a newly defined form of iron-dependent cell death, in diabetes-induced liver pathology. We also found that sulforaphane (SFN), a natural isothiocyanate from cruciferous vegetables, prevents diabetes-induced hepatic ferroptosis by activating the Nrf2 signaling axis. Since ferroptosis and inflammation jointly fulfill physiological and pathological functions, in this study we investigated whether the anti-inflammatory effect of SFN is reflected in the modulation of high mobility group box 1 (HMGB1)-related activation of the inflammatory cascade in the liver of diabetic mice and how it is related to the extent of ferroptosis. HMGB1 is a damage-associated molecular pattern molecule that is released by ferroptotic cells, among others. Extracellular HMGB1 is  a potent activator of well-characterized inflammation-related pathways, including JAK-STAT, NF-κB, and mitogen-activated protein kinase (MAPK), whose activities are associated with ferroptosis.For this purpose, male C57BL/6 mice in which diabetes was induced with streptozotocin (40 mg/kg/5 consecutive days) were treated with SFN (2.5 mg/kg/day from day 1 to 42). Blood glucose levels were measured once a week during the trial. On day 43, the liver was isolated and prepared for Western immunoblotting and ELISA tests. SFN was found to improve serum levels of glucose, ALT and triglycerides in diabetic mice and to enhance the diabetes-induced decrease in liver expression of GPX4, a hallmark of ferroptosis events. This improvement was partly due to the SFN-induced decrease in the increased expression of HMGB1 and its downstream pro-inflammatory activities related to the activation of MAPKs, NF-кB p65 and JAK1/STAT3 signaling pathways. SFN prevented diabetes- induced phosphorylation of p38 and extracellular signal-regulated kinases (ERKs), NF-κB 65 and STAT3 phosphorylation, and phosphorylation of protein kinase B (Akt), a key mediator of cell  survival. The results obtained suggest that interfering with HMGB1 signaling pathways through SFN may enable effective intervention in diabetes by exerting therapeutic effects on inflammatory status and cell death such as ferroptosis.
PB  - Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo
C3  - Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
T1  - Sulforaphane attenuates HMGB1-mediated activation of inflammatory pathways in the liver of diabetic mice and suppresses ferroptosis
SP  - 74
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6850
ER  - 

@conference{
author = "Otašević, Vesna and Stančić, Ana and Gudelj, Anđelija and Savić, Nevena and Markelić, Milica and Veličković, Ksenija and Martinović, Vesna and Grigorov, Ilijana",
year = "2024",
abstract = "The activation of inflammation is closely associated with ferroptosis and vice versa. Recently, we have demonstrated the involvement of ferroptosis, a newly defined form of iron-dependent cell death, in diabetes-induced liver pathology. We also found that sulforaphane (SFN), a natural isothiocyanate from cruciferous vegetables, prevents diabetes-induced hepatic ferroptosis by activating the Nrf2 signaling axis. Since ferroptosis and inflammation jointly fulfill physiological and pathological functions, in this study we investigated whether the anti-inflammatory effect of SFN is reflected in the modulation of high mobility group box 1 (HMGB1)-related activation of the inflammatory cascade in the liver of diabetic mice and how it is related to the extent of ferroptosis. HMGB1 is a damage-associated molecular pattern molecule that is released by ferroptotic cells, among others. Extracellular HMGB1 is  a potent activator of well-characterized inflammation-related pathways, including JAK-STAT, NF-κB, and mitogen-activated protein kinase (MAPK), whose activities are associated with ferroptosis.For this purpose, male C57BL/6 mice in which diabetes was induced with streptozotocin (40 mg/kg/5 consecutive days) were treated with SFN (2.5 mg/kg/day from day 1 to 42). Blood glucose levels were measured once a week during the trial. On day 43, the liver was isolated and prepared for Western immunoblotting and ELISA tests. SFN was found to improve serum levels of glucose, ALT and triglycerides in diabetic mice and to enhance the diabetes-induced decrease in liver expression of GPX4, a hallmark of ferroptosis events. This improvement was partly due to the SFN-induced decrease in the increased expression of HMGB1 and its downstream pro-inflammatory activities related to the activation of MAPKs, NF-кB p65 and JAK1/STAT3 signaling pathways. SFN prevented diabetes- induced phosphorylation of p38 and extracellular signal-regulated kinases (ERKs), NF-κB 65 and STAT3 phosphorylation, and phosphorylation of protein kinase B (Akt), a key mediator of cell  survival. The results obtained suggest that interfering with HMGB1 signaling pathways through SFN may enable effective intervention in diabetes by exerting therapeutic effects on inflammatory status and cell death such as ferroptosis.",
publisher = "Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo",
journal = "Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina",
title = "Sulforaphane attenuates HMGB1-mediated activation of inflammatory pathways in the liver of diabetic mice and suppresses ferroptosis",
pages = "74",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6850"
}

Otašević, V., Stančić, A., Gudelj, A., Savić, N., Markelić, M., Veličković, K., Martinović, V.,& Grigorov, I.. (2024). Sulforaphane attenuates HMGB1-mediated activation of inflammatory pathways in the liver of diabetic mice and suppresses ferroptosis. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo., 74.
https://hdl.handle.net/21.15107/rcub_ibiss_6850

Otašević V, Stančić A, Gudelj A, Savić N, Markelić M, Veličković K, Martinović V, Grigorov I. Sulforaphane attenuates HMGB1-mediated activation of inflammatory pathways in the liver of diabetic mice and suppresses ferroptosis. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina. 2024;:74.
https://hdl.handle.net/21.15107/rcub_ibiss_6850 .

Otašević, Vesna, Stančić, Ana, Gudelj, Anđelija, Savić, Nevena, Markelić, Milica, Veličković, Ksenija, Martinović, Vesna, Grigorov, Ilijana, "Sulforaphane attenuates HMGB1-mediated activation of inflammatory pathways in the liver of diabetic mice and suppresses ferroptosis" in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina (2024):74,
https://hdl.handle.net/21.15107/rcub_ibiss_6850 .

TY  - CONF
AU  - Markelić, Milica
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Martinović, Vesna
AU  - Gudelj, Anđelija
AU  - Otašević, Vesna
AU  - Grigorov, Ilijana
PY  - 2024
UR  - https://genapp.ba/editions/index.php/journal/article/view/214/158
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6848
AB  - Sulforaphane (SFN) is a natural sulphur-containing compound with various beneficial biological 
effects that is found in cruciferous vegetables. Among others, these effects include the activation 
of Nrf2, a transcription factor that plays an important role in the prevention of ferroptosis, a 
cell death characterized by the accumulation of labile iron, glutathione (GSH) depletion and lipid 
peroxidation. Recently, we have demonstrated the antiferroptotic hepatoprotective effect of SFN in 
diabetic mice. Since ferroptosis has also been confirmed by us and others as one of the causes of 
β-cell destruction in diabetes, we aimed to investigate the potential of SFN treatment in 
preventing/eliminating injury of pancreatic islets during diabetes development in vivo. For this 
purpose, male C57BL/6 mice were divided into four groups (n=8): Control (Crtl), SFN-treated (SFN, 
2.5 mg/kg), diabetic (DM, treated with 40 mg/kg streptozotocin from day 1-5) and diabetic 
SFN-treated (DM+SFN) group. All animals received an intraperitoneal injection of SFN or vehicle for 
42 days and were sacrificed on day 43. Pancreata were isolated and prepared for histologic analysis 
and determination of GSH content. Glycemia was measured once a week during the experiment. 
Consistent with the improved glycemia,  we observed histologic evidence of improvement in the 
endocrine pancreas of the DM+SFN animals: pancreatic GSH content was restored, average islet size 
and insulin immunopositivity returned to control values, and there was less insulitis than in the 
DM group. Lipid peroxidation, which was greatly increased in the DM islets as shown by 4-HNE 
immunopositivity, also decreased in the DM+SFN animals, while Nrf2 increased. As a sign of improved 
islet regeneration, PDX-1 immunoexpression strongly increased in this group. To investigate whether 
SFN as a natural H2S donor affects the endogenous production of this gasotransmitter in islet 
cells, immunoexpression of cystathionine-β- synthase (CBS) and cystathionine gamma-lyase (CSE) was 
also analyzed. The results showed that SFN increased CBS expression in islets under diabetogenic 
insults. In summary, we have shown that SFN prevents diabetogenic islet damage by activating 
antiferroptotic signaling pathways. Moreover, our results indicate the importance of the H2S/CBS 
signaling pathway in protecting islet cells from DM
insult, indicating this pathway as a potential antidiabetic target.
PB  - Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo
C3  - Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
T1  - Protective effects of Sulphorhane against injury of endocrine pancreas in diabetic mice include antiferroptotic action
SP  - 41
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6848
ER  - 

@conference{
author = "Markelić, Milica and Stančić, Ana and Veličković, Ksenija and Martinović, Vesna and Gudelj, Anđelija and Otašević, Vesna and Grigorov, Ilijana",
year = "2024",
abstract = "Sulforaphane (SFN) is a natural sulphur-containing compound with various beneficial biological 
effects that is found in cruciferous vegetables. Among others, these effects include the activation 
of Nrf2, a transcription factor that plays an important role in the prevention of ferroptosis, a 
cell death characterized by the accumulation of labile iron, glutathione (GSH) depletion and lipid 
peroxidation. Recently, we have demonstrated the antiferroptotic hepatoprotective effect of SFN in 
diabetic mice. Since ferroptosis has also been confirmed by us and others as one of the causes of 
β-cell destruction in diabetes, we aimed to investigate the potential of SFN treatment in 
preventing/eliminating injury of pancreatic islets during diabetes development in vivo. For this 
purpose, male C57BL/6 mice were divided into four groups (n=8): Control (Crtl), SFN-treated (SFN, 
2.5 mg/kg), diabetic (DM, treated with 40 mg/kg streptozotocin from day 1-5) and diabetic 
SFN-treated (DM+SFN) group. All animals received an intraperitoneal injection of SFN or vehicle for 
42 days and were sacrificed on day 43. Pancreata were isolated and prepared for histologic analysis 
and determination of GSH content. Glycemia was measured once a week during the experiment. 
Consistent with the improved glycemia,  we observed histologic evidence of improvement in the 
endocrine pancreas of the DM+SFN animals: pancreatic GSH content was restored, average islet size 
and insulin immunopositivity returned to control values, and there was less insulitis than in the 
DM group. Lipid peroxidation, which was greatly increased in the DM islets as shown by 4-HNE 
immunopositivity, also decreased in the DM+SFN animals, while Nrf2 increased. As a sign of improved 
islet regeneration, PDX-1 immunoexpression strongly increased in this group. To investigate whether 
SFN as a natural H2S donor affects the endogenous production of this gasotransmitter in islet 
cells, immunoexpression of cystathionine-β- synthase (CBS) and cystathionine gamma-lyase (CSE) was 
also analyzed. The results showed that SFN increased CBS expression in islets under diabetogenic 
insults. In summary, we have shown that SFN prevents diabetogenic islet damage by activating 
antiferroptotic signaling pathways. Moreover, our results indicate the importance of the H2S/CBS 
signaling pathway in protecting islet cells from DM
insult, indicating this pathway as a potential antidiabetic target.",
publisher = "Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo",
journal = "Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina",
title = "Protective effects of Sulphorhane against injury of endocrine pancreas in diabetic mice include antiferroptotic action",
pages = "41",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6848"
}

Markelić, M., Stančić, A., Veličković, K., Martinović, V., Gudelj, A., Otašević, V.,& Grigorov, I.. (2024). Protective effects of Sulphorhane against injury of endocrine pancreas in diabetic mice include antiferroptotic action. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina
Sarajevo: Institute for Genetic Engineering and Biotechnology, University of Sarajevo., 41.
https://hdl.handle.net/21.15107/rcub_ibiss_6848

Markelić M, Stančić A, Veličković K, Martinović V, Gudelj A, Otašević V, Grigorov I. Protective effects of Sulphorhane against injury of endocrine pancreas in diabetic mice include antiferroptotic action. in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina. 2024;:41.
https://hdl.handle.net/21.15107/rcub_ibiss_6848 .

Markelić, Milica, Stančić, Ana, Veličković, Ksenija, Martinović, Vesna, Gudelj, Anđelija, Otašević, Vesna, Grigorov, Ilijana, "Protective effects of Sulphorhane against injury of endocrine pancreas in diabetic mice include antiferroptotic action" in Book of abstracts: 2nd European Symposium on Phytochemicals in Medicine and Food: 2-EuSPMF; 2024 Jun 3-6; Sarajevo, Bosnia and Herzegovina (2024):41,
https://hdl.handle.net/21.15107/rcub_ibiss_6848 .

TY  - JOUR
AU  - Savić, Nevena
AU  - Markelić, Milica
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Grigorov, Ilijana
AU  - Vučetić, Milica
AU  - Martinović, Vesna
AU  - Gudelj, Anđelija
AU  - Otašević, Vesna
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6627
AB  - Recently, we characterized the ferroptotic phenotype in the liver of diabetic
mice and revealed nuclear factor (erythroid-derived-2)-related factor 2 (Nrf2)
inactivation as an integral part of hepatic injury. Here, we aim to investigate
whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice
were divided into four groups: control (vehicle-treated), diabetic (streptozoto cin-induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane-treated
(2.5 mg/kg from Days 1 to 42) and non-diabetic sulforaphane-treated group
(2.5 mg/kg from Days 1 to 42). Results showed that diabetes-induced inactiva tion of Nrf2 and decreased expression of its downstream antiferroptotic mole cules critical for antioxidative defense (catalase, superoxide dismutases,
thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferro portin 1), glutathione (GSH) synthesis (cystine-glutamate antiporter system,
cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine
ligase modifier subunit, glutathione synthetase), and GSH recycling - glutathi one reductase (GR) were reversed/increased by sulforaphane treatment. In
addition, we found that the ferroptotic phenotype in diabetic liver is associated
with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the
increased level of GSH, decreased accumulation of labile iron and lipid perox ides (4-hydroxy-2-nonenal, lipofuscin), decreased ferritinophagy and liver dam age (decreased fibrosis, alanine aminotransferase, and aspartate
aminotransferase). Finally, diabetes-induced increase in serum glucose and tri glyceride level was significantly reduced by sulforaphane. Regardless of the fact
that this study is limited by the use of one model of experimentally induced
diabetes, the results obtained demonstrate for the first time that sulforaphane
prevents diabetes-induced hepatic ferroptosis in vivo through the activation of
Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related
pathologies.
PB  - Hoboken: Wiley
T2  - BioFactors
T1  - Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis
DO  - 10.1002/biof.2042
ER  - 

@article{
author = "Savić, Nevena and Markelić, Milica and Stančić, Ana and Veličković, Ksenija and Grigorov, Ilijana and Vučetić, Milica and Martinović, Vesna and Gudelj, Anđelija and Otašević, Vesna",
year = "2024",
abstract = "Recently, we characterized the ferroptotic phenotype in the liver of diabetic
mice and revealed nuclear factor (erythroid-derived-2)-related factor 2 (Nrf2)
inactivation as an integral part of hepatic injury. Here, we aim to investigate
whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice
were divided into four groups: control (vehicle-treated), diabetic (streptozoto cin-induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane-treated
(2.5 mg/kg from Days 1 to 42) and non-diabetic sulforaphane-treated group
(2.5 mg/kg from Days 1 to 42). Results showed that diabetes-induced inactiva tion of Nrf2 and decreased expression of its downstream antiferroptotic mole cules critical for antioxidative defense (catalase, superoxide dismutases,
thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferro portin 1), glutathione (GSH) synthesis (cystine-glutamate antiporter system,
cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine
ligase modifier subunit, glutathione synthetase), and GSH recycling - glutathi one reductase (GR) were reversed/increased by sulforaphane treatment. In
addition, we found that the ferroptotic phenotype in diabetic liver is associated
with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the
increased level of GSH, decreased accumulation of labile iron and lipid perox ides (4-hydroxy-2-nonenal, lipofuscin), decreased ferritinophagy and liver dam age (decreased fibrosis, alanine aminotransferase, and aspartate
aminotransferase). Finally, diabetes-induced increase in serum glucose and tri glyceride level was significantly reduced by sulforaphane. Regardless of the fact
that this study is limited by the use of one model of experimentally induced
diabetes, the results obtained demonstrate for the first time that sulforaphane
prevents diabetes-induced hepatic ferroptosis in vivo through the activation of
Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related
pathologies.",
publisher = "Hoboken: Wiley",
journal = "BioFactors",
title = "Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis",
doi = "10.1002/biof.2042"
}

Savić, N., Markelić, M., Stančić, A., Veličković, K., Grigorov, I., Vučetić, M., Martinović, V., Gudelj, A.,& Otašević, V.. (2024). Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis. in BioFactors
Hoboken: Wiley..
https://doi.org/10.1002/biof.2042

Savić N, Markelić M, Stančić A, Veličković K, Grigorov I, Vučetić M, Martinović V, Gudelj A, Otašević V. Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis. in BioFactors. 2024;.
doi:10.1002/biof.2042 .

Savić, Nevena, Markelić, Milica, Stančić, Ana, Veličković, Ksenija, Grigorov, Ilijana, Vučetić, Milica, Martinović, Vesna, Gudelj, Anđelija, Otašević, Vesna, "Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis" in BioFactors (2024),
https://doi.org/10.1002/biof.2042 . .

TY  - JOUR
AU  - Markelić, Milica
AU  - Stančić, Ana
AU  - Saksida, Tamara
AU  - Grigorov, Ilijana
AU  - Mićanović, Dragica
AU  - Veličković, Ksenija
AU  - Martinović, Vesna
AU  - Savić, Nevena
AU  - Gudelj, Anđelija
AU  - Otašević, Vesna
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6071
AB  - Introduction: Recently, the involvement of ferroptotic cell death in the reduction of β-cell mass in diabetes has been demonstrated. To elucidate the mechanisms of β-cell ferroptosis and potential antidiabetic effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in vivo, a mouse model of type 1 diabetes (T1D) was used.

Methods: Animals were divided into three groups: control (vehicle-treated), diabetic (streptozotocin-treated, 40 mg/kg, from days 1-5), and diabetic treated with Fer-1 (1 mg/kg, from days 1-21). On day 22, glycemia and insulinemia were measured and pancreases were isolated for microscopic analyses.

Results: Diabetes disturbed general parameters of β-cell mass (islet size, β-cell abundance and distribution) and health (insulin and PDX-1 expression), increased lipid peroxidation in islet cells, and phagocytic removal of iron-containing material. It also downregulated the main players of the antiferroptotic pathway - Nrf2, GPX4, and xCT. In contrast, Fer-1 ameliorated the signs of deterioration of β-cell/islets, decreased lipid peroxidation, and reduced phagocytic activity, while upregulated expression of Nrf2 (and its nuclear translocation), GPX4, and xCT in β-cell/islets.

Discussion: Overall, our study confirms ferroptosis as an important mode of β-cell death in T1D and suggests antiferroptotic agents as a promising strategy for the prevention and treatment of diabetes
PB  - Lausanne: Frontiers Media SA
T2  - Frontiers in Endocrinology
T1  - Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy
VL  - 14
DO  - 10.3389/fendo.2023.1227498
SP  - 1227498
ER  - 

@article{
author = "Markelić, Milica and Stančić, Ana and Saksida, Tamara and Grigorov, Ilijana and Mićanović, Dragica and Veličković, Ksenija and Martinović, Vesna and Savić, Nevena and Gudelj, Anđelija and Otašević, Vesna",
year = "2023",
abstract = "Introduction: Recently, the involvement of ferroptotic cell death in the reduction of β-cell mass in diabetes has been demonstrated. To elucidate the mechanisms of β-cell ferroptosis and potential antidiabetic effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in vivo, a mouse model of type 1 diabetes (T1D) was used.

Methods: Animals were divided into three groups: control (vehicle-treated), diabetic (streptozotocin-treated, 40 mg/kg, from days 1-5), and diabetic treated with Fer-1 (1 mg/kg, from days 1-21). On day 22, glycemia and insulinemia were measured and pancreases were isolated for microscopic analyses.

Results: Diabetes disturbed general parameters of β-cell mass (islet size, β-cell abundance and distribution) and health (insulin and PDX-1 expression), increased lipid peroxidation in islet cells, and phagocytic removal of iron-containing material. It also downregulated the main players of the antiferroptotic pathway - Nrf2, GPX4, and xCT. In contrast, Fer-1 ameliorated the signs of deterioration of β-cell/islets, decreased lipid peroxidation, and reduced phagocytic activity, while upregulated expression of Nrf2 (and its nuclear translocation), GPX4, and xCT in β-cell/islets.

Discussion: Overall, our study confirms ferroptosis as an important mode of β-cell death in T1D and suggests antiferroptotic agents as a promising strategy for the prevention and treatment of diabetes",
publisher = "Lausanne: Frontiers Media SA",
journal = "Frontiers in Endocrinology",
title = "Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy",
volume = "14",
doi = "10.3389/fendo.2023.1227498",
pages = "1227498"
}

Markelić, M., Stančić, A., Saksida, T., Grigorov, I., Mićanović, D., Veličković, K., Martinović, V., Savić, N., Gudelj, A.,& Otašević, V.. (2023). Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy. in Frontiers in Endocrinology
Lausanne: Frontiers Media SA., 14, 1227498.
https://doi.org/10.3389/fendo.2023.1227498

Markelić M, Stančić A, Saksida T, Grigorov I, Mićanović D, Veličković K, Martinović V, Savić N, Gudelj A, Otašević V. Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy. in Frontiers in Endocrinology. 2023;14:1227498.
doi:10.3389/fendo.2023.1227498 .

Markelić, Milica, Stančić, Ana, Saksida, Tamara, Grigorov, Ilijana, Mićanović, Dragica, Veličković, Ksenija, Martinović, Vesna, Savić, Nevena, Gudelj, Anđelija, Otašević, Vesna, "Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy" in Frontiers in Endocrinology, 14 (2023):1227498,
https://doi.org/10.3389/fendo.2023.1227498 . .

TY  - CONF
AU  - Jonić, Natalija
AU  - Chatzigiannis, Christos M.
AU  - Koprivica, Ivan
AU  - Marinho, Sergio
AU  - Moura-Alves, Pedro
AU  - Pavić, Aleksandar
AU  - Otašević, Vesna
AU  - Pejnović, Nada
AU  - Tzakos, Andreas
AU  - Stojanović, Ivana D.
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6295
AB  - Introduction: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which is highly expressed in mucosal tissues - by epithelial cells and immune cells such as Th17 CD4+ and T regulatory cells (Treg). Besides its function of clearing environmental pollutants from the body, it was also revealed that AhR has immunoregulatory effects, thus becoming a potential therapeutic target for modulating the immune response. For that purpose we tested a novel synthetic AhR modulator under the code name C43.
Methods: CYP1A1 (downstream effector of AhR) activation was tested by the EROD assay. Sort-purified CD4+ cells from mesenteric lymph nodes (MLN) were treated with C43 for 24 h. Zebrafish embryos were used to test the toxicity of C43. Male C57BL/6 mice orally received C43 (10 mg/kg) for 5 consecutive days, after which MLN were harvested. Phenotype and function of the cells were analyzed by flow cytometry.
Results: C43 showed mild AhR agonistic activity. After treating the sort-purified CD4+ cells with C43, there was a shift in the Th17/Treg ratio in favour of the latter. C43 showed no signs of toxicity when tested on zebrafish embryos. MLN cells from mice that received C43 revealed a shift in the Th1/Treg ratio in favour of Tregs, with a documented rise of the portion of Tregs that expressed CYP1A1 in comparison with the control group of mice. 
Conclusion: C43 can modulate the immune response through the intestine by promoting the immunosuppressive Treg population.
PB  - Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
C3  - Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia
T1  - Novel aryl hydrocarbon receptor modulator promotes immunosupressive immune response by stimulating T regulatory cells in the gut
SP  - 38
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6295
ER  - 

@conference{
author = "Jonić, Natalija and Chatzigiannis, Christos M. and Koprivica, Ivan and Marinho, Sergio and Moura-Alves, Pedro and Pavić, Aleksandar and Otašević, Vesna and Pejnović, Nada and Tzakos, Andreas and Stojanović, Ivana D.",
year = "2023",
abstract = "Introduction: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which is highly expressed in mucosal tissues - by epithelial cells and immune cells such as Th17 CD4+ and T regulatory cells (Treg). Besides its function of clearing environmental pollutants from the body, it was also revealed that AhR has immunoregulatory effects, thus becoming a potential therapeutic target for modulating the immune response. For that purpose we tested a novel synthetic AhR modulator under the code name C43.
Methods: CYP1A1 (downstream effector of AhR) activation was tested by the EROD assay. Sort-purified CD4+ cells from mesenteric lymph nodes (MLN) were treated with C43 for 24 h. Zebrafish embryos were used to test the toxicity of C43. Male C57BL/6 mice orally received C43 (10 mg/kg) for 5 consecutive days, after which MLN were harvested. Phenotype and function of the cells were analyzed by flow cytometry.
Results: C43 showed mild AhR agonistic activity. After treating the sort-purified CD4+ cells with C43, there was a shift in the Th17/Treg ratio in favour of the latter. C43 showed no signs of toxicity when tested on zebrafish embryos. MLN cells from mice that received C43 revealed a shift in the Th1/Treg ratio in favour of Tregs, with a documented rise of the portion of Tregs that expressed CYP1A1 in comparison with the control group of mice. 
Conclusion: C43 can modulate the immune response through the intestine by promoting the immunosuppressive Treg population.",
publisher = "Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade",
journal = "Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia",
title = "Novel aryl hydrocarbon receptor modulator promotes immunosupressive immune response by stimulating T regulatory cells in the gut",
pages = "38",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6295"
}

Jonić, N., Chatzigiannis, C. M., Koprivica, I., Marinho, S., Moura-Alves, P., Pavić, A., Otašević, V., Pejnović, N., Tzakos, A.,& Stojanović, I. D.. (2023). Novel aryl hydrocarbon receptor modulator promotes immunosupressive immune response by stimulating T regulatory cells in the gut. in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia
Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade., 38.
https://hdl.handle.net/21.15107/rcub_ibiss_6295

Jonić N, Chatzigiannis CM, Koprivica I, Marinho S, Moura-Alves P, Pavić A, Otašević V, Pejnović N, Tzakos A, Stojanović ID. Novel aryl hydrocarbon receptor modulator promotes immunosupressive immune response by stimulating T regulatory cells in the gut. in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia. 2023;:38.
https://hdl.handle.net/21.15107/rcub_ibiss_6295 .

Jonić, Natalija, Chatzigiannis, Christos M., Koprivica, Ivan, Marinho, Sergio, Moura-Alves, Pedro, Pavić, Aleksandar, Otašević, Vesna, Pejnović, Nada, Tzakos, Andreas, Stojanović, Ivana D., "Novel aryl hydrocarbon receptor modulator promotes immunosupressive immune response by stimulating T regulatory cells in the gut" in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia (2023):38,
https://hdl.handle.net/21.15107/rcub_ibiss_6295 .

TY  - CONF
AU  - Markelić, Milica
AU  - Otašević, Vesna
AU  - Gudelj, Anđelija
AU  - Saksida, Tamara
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Krstić, Jelena
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6404
AB  - Recently, it has been suggested that nutrient deprivation (ND) may be effective as an adjuvant 
therapy to hepatocellular carcinoma (HCC) cell treatment with sorafenib (Sfb)1. These results 
suggest that ND-mediated priming of HCC cells to Sfb is positively correlated with the p53 status, 
suggesting the essential role of p53 in priming of HCC cells for regulated cell death (RCD). 
Preliminary data indicated morphological signs of ferroptotic RCD, so we aimed to determine whether 
ferroptosis plays a role in the removal of HCC cells in vitro with respect to their p53 status. To 
this end, p53 wild-type (p53WT) and p53 knockout (p53KO) HepG2 cells were grown in growth medium or 
in starvation medium and treated with Sfb or with ferroptosis inducer, Rsl- 3, for 6 h. 
Morphological signs of RCD and nuclear translocation (i.e. activation) of Nrf2, (master regulator 
of ferroptosis-related signalling pathways), as well as protein levels of antioxidative defence 
(AD) enzymes (CAT, CuZnSOD, MnSOD) and ferroptosis-related proteins (GPX4, xCT) were analysed. The 
AD response to Rsl-3 treatment in p53WT cells was similar regardless of nutritional status, as the 
level of all analysed enzymes increased. The response to Sfb was enhanced by ND as CAT and CuZnSOD 
were elevated. p53KO cells responded quite differently, even when treated with Rsl-3, increasing 
only MnSOD. Starved Sfb-treated p53KO cells even decreased expression of AD enzymes. All signs of a 
proferroptotic response examined were present in starved p53WT cells (regardless of treatment): 
decreased nuclear translocation of Nrf2, GPX4, and xCT expression. Nrf2 activation and GPX4 
expression were also decreased in starved p53KO cells (especially upon treatment with Sfb or 
Rsl-3), but accompanied by compensatory overexpressed xCT. These results may be indicative of 
enhanced AD in p53KO cells and may therefore explain, at least in part, their resistance to 
treatment with Sfb+ND which, as presented here, induces ferroptosis in p53WT HepG2 cells.
PB  - Belgrade: Faculty of Chemistry
C3  - Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
T1  - Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status
SP  - 86
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6404
ER  - 

@conference{
author = "Markelić, Milica and Otašević, Vesna and Gudelj, Anđelija and Saksida, Tamara and Stančić, Ana and Veličković, Ksenija and Krstić, Jelena",
year = "2023",
abstract = "Recently, it has been suggested that nutrient deprivation (ND) may be effective as an adjuvant 
therapy to hepatocellular carcinoma (HCC) cell treatment with sorafenib (Sfb)1. These results 
suggest that ND-mediated priming of HCC cells to Sfb is positively correlated with the p53 status, 
suggesting the essential role of p53 in priming of HCC cells for regulated cell death (RCD). 
Preliminary data indicated morphological signs of ferroptotic RCD, so we aimed to determine whether 
ferroptosis plays a role in the removal of HCC cells in vitro with respect to their p53 status. To 
this end, p53 wild-type (p53WT) and p53 knockout (p53KO) HepG2 cells were grown in growth medium or 
in starvation medium and treated with Sfb or with ferroptosis inducer, Rsl- 3, for 6 h. 
Morphological signs of RCD and nuclear translocation (i.e. activation) of Nrf2, (master regulator 
of ferroptosis-related signalling pathways), as well as protein levels of antioxidative defence 
(AD) enzymes (CAT, CuZnSOD, MnSOD) and ferroptosis-related proteins (GPX4, xCT) were analysed. The 
AD response to Rsl-3 treatment in p53WT cells was similar regardless of nutritional status, as the 
level of all analysed enzymes increased. The response to Sfb was enhanced by ND as CAT and CuZnSOD 
were elevated. p53KO cells responded quite differently, even when treated with Rsl-3, increasing 
only MnSOD. Starved Sfb-treated p53KO cells even decreased expression of AD enzymes. All signs of a 
proferroptotic response examined were present in starved p53WT cells (regardless of treatment): 
decreased nuclear translocation of Nrf2, GPX4, and xCT expression. Nrf2 activation and GPX4 
expression were also decreased in starved p53KO cells (especially upon treatment with Sfb or 
Rsl-3), but accompanied by compensatory overexpressed xCT. These results may be indicative of 
enhanced AD in p53KO cells and may therefore explain, at least in part, their resistance to 
treatment with Sfb+ND which, as presented here, induces ferroptosis in p53WT HepG2 cells.",
publisher = "Belgrade: Faculty of Chemistry",
journal = "Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia",
title = "Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status",
pages = "86",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6404"
}

Markelić, M., Otašević, V., Gudelj, A., Saksida, T., Stančić, A., Veličković, K.,& Krstić, J.. (2023). Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
Belgrade: Faculty of Chemistry., 86.
https://hdl.handle.net/21.15107/rcub_ibiss_6404

Markelić M, Otašević V, Gudelj A, Saksida T, Stančić A, Veličković K, Krstić J. Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia. 2023;:86.
https://hdl.handle.net/21.15107/rcub_ibiss_6404 .

Markelić, Milica, Otašević, Vesna, Gudelj, Anđelija, Saksida, Tamara, Stančić, Ana, Veličković, Ksenija, Krstić, Jelena, "Proferroptotic response to nutrient deprivation in hepatocellular carcinoma cells is related to p53 status" in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia (2023):86,
https://hdl.handle.net/21.15107/rcub_ibiss_6404 .

TY  - CONF
AU  - Veličković, Ksenija
AU  - Markelić, Milica
AU  - Stančić, Ana
AU  - Otašević, Vesna
AU  - Gudelj, Anđelija
AU  - Savić, Nevena
AU  - Martinović, Vesna
AU  - Grigorov, Ilijana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6403
AB  - A high-sugar diet is associated with an increased risk of chronic intestinal disease1, but the capacity of the gut to adapt to dietary changes in young and adult rats is unknown. Therefore, the effects of an 8-week dextrose-enriched diet (20% or 60%) on intestinal histology, antioxidative defence status, and the expression pattern of high mobility group box-1 (HMGB1), a mediator of the inflammatory response2, were investigated. Numerous signs of tissue damage were associated with decreases in villus height (Vh), crypt depth (Cd), villus surface area (VSA), and muscle thickness (Mt) in adult rats fed with 60% dextrose. While the decrease in Vh and Cd was affected by age, the decrease in VSA and Mt was interactively affected by age and treatment. Structural changes were associated with decreased activity of antioxidative defence enzymes, particularly catalase, which is affected by treatment, and CuZnSOD, which is interactively modulated by age and treatment. Moreover, massive translocation of HMGB1 from the nucleus to the cytoplasm was detected in epithelial cells in the same group (interactive effect of age and treatment). We concluded that supraphysiological dextrose concentrations induce changes in the oxidative state, possibly leading to redox modification of HMGB1 and consequent tissue damage. The intestine undergoes dynamic functional and morphological changes with age that are more pronounced under high dextrose concentrations.
PB  - Belgrade: Faculty of Chemistry
C3  - Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
T1  - Diet- and age-dependent changes of intestinal injury in rats
SP  - 80
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6403
ER  - 

@conference{
author = "Veličković, Ksenija and Markelić, Milica and Stančić, Ana and Otašević, Vesna and Gudelj, Anđelija and Savić, Nevena and Martinović, Vesna and Grigorov, Ilijana",
year = "2023",
abstract = "A high-sugar diet is associated with an increased risk of chronic intestinal disease1, but the capacity of the gut to adapt to dietary changes in young and adult rats is unknown. Therefore, the effects of an 8-week dextrose-enriched diet (20% or 60%) on intestinal histology, antioxidative defence status, and the expression pattern of high mobility group box-1 (HMGB1), a mediator of the inflammatory response2, were investigated. Numerous signs of tissue damage were associated with decreases in villus height (Vh), crypt depth (Cd), villus surface area (VSA), and muscle thickness (Mt) in adult rats fed with 60% dextrose. While the decrease in Vh and Cd was affected by age, the decrease in VSA and Mt was interactively affected by age and treatment. Structural changes were associated with decreased activity of antioxidative defence enzymes, particularly catalase, which is affected by treatment, and CuZnSOD, which is interactively modulated by age and treatment. Moreover, massive translocation of HMGB1 from the nucleus to the cytoplasm was detected in epithelial cells in the same group (interactive effect of age and treatment). We concluded that supraphysiological dextrose concentrations induce changes in the oxidative state, possibly leading to redox modification of HMGB1 and consequent tissue damage. The intestine undergoes dynamic functional and morphological changes with age that are more pronounced under high dextrose concentrations.",
publisher = "Belgrade: Faculty of Chemistry",
journal = "Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia",
title = "Diet- and age-dependent changes of intestinal injury in rats",
pages = "80",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6403"
}

Veličković, K., Markelić, M., Stančić, A., Otašević, V., Gudelj, A., Savić, N., Martinović, V.,& Grigorov, I.. (2023). Diet- and age-dependent changes of intestinal injury in rats. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia
Belgrade: Faculty of Chemistry., 80.
https://hdl.handle.net/21.15107/rcub_ibiss_6403

Veličković K, Markelić M, Stančić A, Otašević V, Gudelj A, Savić N, Martinović V, Grigorov I. Diet- and age-dependent changes of intestinal injury in rats. in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia. 2023;:80.
https://hdl.handle.net/21.15107/rcub_ibiss_6403 .

Veličković, Ksenija, Markelić, Milica, Stančić, Ana, Otašević, Vesna, Gudelj, Anđelija, Savić, Nevena, Martinović, Vesna, Grigorov, Ilijana, "Diet- and age-dependent changes of intestinal injury in rats" in Biochemistry in Biotechnology: Serbian Biochemical Society, Twelfth Conference, International scientific meeting; 2023 Sep 21-23; Belgrade, Serbia (2023):80,
https://hdl.handle.net/21.15107/rcub_ibiss_6403 .

TY  - CONF
AU  - Jonić, Natalija
AU  - Chatzigiannis, Christos M.
AU  - Koprivica, Ivan
AU  - Marinho, Sergio
AU  - Moura-Alves, Pedro
AU  - Pavić, Aleksandar
AU  - Otašević, Vesna
AU  - Pejnović, Nada
AU  - Tzakos, Andreas
AU  - Stojanović, Ivana D.
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6296
AB  - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has an important role in regulating the immune system, with high expression in Th17 CD4+ T cells and T regulatory cells (Treg). The expression of AhR is especially important at mucosal surfaces where it is involved in balancing the immune response towards external factors. The aim of our research was to evaluate the effect on the gut immune system of a novel fluorescent indole-containing compound that was designed as a putative AhR ligand (encoded C43). By using the EROD assay, we determined that C43 has mild AhR agonistic activity. Sort-purified mesenteric lymph node (MLN) CD4+ cells were treated with C43 for 24 h and flow cytometry analysis (FCM) showed that the Treg/Th17 ratio shifted in favour of Tregs. Zebrafish embryos were used for the evaluation of potential C43 toxicity. No nephrotoxicity, hepatotoxicity or cardiotoxicity was detected, even at the highest concentrations. Next, C43 was orally administered to healthy male C57BL/6 mice for 5 consecutive days, and later its effects on the gut immune system were recorded by analyzing the MLNs. FCM unveiled a higher proportion of Treg cells that expressed CYP1A1 (downstream effector of AhR) and the ratio of Treg/Th1 shifted towards Tregs. The presence of C43 was also visualized by confocal microscopy in the small intestine lamina propria of treated animals. With such results obtained from healthy animals, C43 presents a promising compound for the treatment of inflammatory diseases that generally involve activation of the gut immune system.
PB  - European Federation of Immunological Societies (EFIS)
C3  - Program and Abstracts: 12th EFIS-EJI South Eastern European Immunology School (SEEIS2023); 2023 Oct 20-23; Trogir, Croatia
T1  - Development of a novel compound that upregulates Treg in the gut by modulating aryl hydrocarbon receptor's activity
SP  - 17
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6296
ER  - 

@conference{
author = "Jonić, Natalija and Chatzigiannis, Christos M. and Koprivica, Ivan and Marinho, Sergio and Moura-Alves, Pedro and Pavić, Aleksandar and Otašević, Vesna and Pejnović, Nada and Tzakos, Andreas and Stojanović, Ivana D.",
year = "2023",
abstract = "The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has an important role in regulating the immune system, with high expression in Th17 CD4+ T cells and T regulatory cells (Treg). The expression of AhR is especially important at mucosal surfaces where it is involved in balancing the immune response towards external factors. The aim of our research was to evaluate the effect on the gut immune system of a novel fluorescent indole-containing compound that was designed as a putative AhR ligand (encoded C43). By using the EROD assay, we determined that C43 has mild AhR agonistic activity. Sort-purified mesenteric lymph node (MLN) CD4+ cells were treated with C43 for 24 h and flow cytometry analysis (FCM) showed that the Treg/Th17 ratio shifted in favour of Tregs. Zebrafish embryos were used for the evaluation of potential C43 toxicity. No nephrotoxicity, hepatotoxicity or cardiotoxicity was detected, even at the highest concentrations. Next, C43 was orally administered to healthy male C57BL/6 mice for 5 consecutive days, and later its effects on the gut immune system were recorded by analyzing the MLNs. FCM unveiled a higher proportion of Treg cells that expressed CYP1A1 (downstream effector of AhR) and the ratio of Treg/Th1 shifted towards Tregs. The presence of C43 was also visualized by confocal microscopy in the small intestine lamina propria of treated animals. With such results obtained from healthy animals, C43 presents a promising compound for the treatment of inflammatory diseases that generally involve activation of the gut immune system.",
publisher = "European Federation of Immunological Societies (EFIS)",
journal = "Program and Abstracts: 12th EFIS-EJI South Eastern European Immunology School (SEEIS2023); 2023 Oct 20-23; Trogir, Croatia",
title = "Development of a novel compound that upregulates Treg in the gut by modulating aryl hydrocarbon receptor's activity",
pages = "17",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6296"
}

Jonić, N., Chatzigiannis, C. M., Koprivica, I., Marinho, S., Moura-Alves, P., Pavić, A., Otašević, V., Pejnović, N., Tzakos, A.,& Stojanović, I. D.. (2023). Development of a novel compound that upregulates Treg in the gut by modulating aryl hydrocarbon receptor's activity. in Program and Abstracts: 12th EFIS-EJI South Eastern European Immunology School (SEEIS2023); 2023 Oct 20-23; Trogir, Croatia
European Federation of Immunological Societies (EFIS)., 17.
https://hdl.handle.net/21.15107/rcub_ibiss_6296

Jonić N, Chatzigiannis CM, Koprivica I, Marinho S, Moura-Alves P, Pavić A, Otašević V, Pejnović N, Tzakos A, Stojanović ID. Development of a novel compound that upregulates Treg in the gut by modulating aryl hydrocarbon receptor's activity. in Program and Abstracts: 12th EFIS-EJI South Eastern European Immunology School (SEEIS2023); 2023 Oct 20-23; Trogir, Croatia. 2023;:17.
https://hdl.handle.net/21.15107/rcub_ibiss_6296 .

Jonić, Natalija, Chatzigiannis, Christos M., Koprivica, Ivan, Marinho, Sergio, Moura-Alves, Pedro, Pavić, Aleksandar, Otašević, Vesna, Pejnović, Nada, Tzakos, Andreas, Stojanović, Ivana D., "Development of a novel compound that upregulates Treg in the gut by modulating aryl hydrocarbon receptor's activity" in Program and Abstracts: 12th EFIS-EJI South Eastern European Immunology School (SEEIS2023); 2023 Oct 20-23; Trogir, Croatia (2023):17,
https://hdl.handle.net/21.15107/rcub_ibiss_6296 .

TY  - CONF
AU  - Stančić, Ana
AU  - Otašević, Vesna
AU  - Markelić, Milica
AU  - Veličković, Ksenija
AU  - Gudelj, Anđelija
AU  - Savić, Nevena
AU  - Martinović, Vesna
AU  - Grigorov, Ilijana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6068
AB  - We showed recently that ferroptosis contributes to liver pathological changes in diabetes. So, targeting of ferroptosis-related pathways could be novel approach for treatment of diabetes- related liver diseases. Ethyl pyruvate (EP) showed antidiabetic action due to anti-oxidative, - inflammatory and -apoptotic properties. We aimed to examine its potential antiferroptotic action  in diabetes-related liver pathology.
Male Wistar rats were divided into four groups: control; diabetic (STZ, 65 mg/kg); diabetic pre- treated with EP (80 mg/kg/day, starting one week before STZ and continuing following 4  weeks) and diabetic treated with EP, starting with STZ and lasted 4   weeks.
Both modes of EP treatment induced attenuation of ferroptotic events in the liver of diabetic  rats: accumulation of lipid peroxides (4-HNE), disturbances in iron metabolism (decreased   FTH and increased TFR expression), decrease in expression level/activity of ferroptosis-  related antioxidative-defense molecules (GPX4, GCL, GSS, Nrf2, HO-1), and activation of ferroptosis-related pro-inflammatory events (HMGB1 nucleus-to-cytosol and NF-kB cytosol-to- nucleus translocation). Those changes reflected on the improvement of diabetes-related morphological alterations such as liver fibrosis and  binucleation.
Overall, EP interferes with ferroptosis signaling pathways and exerts antiferroptotic activity in the liver in diabetic state. This highlighting the significance of ferroptosis targeting in diabetes- related liver diseases and novel mechanisms/targets of EP beneficial   actions.
PB  - EMBO
C3  - EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany
T1  - Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate
SP  - 92
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6068
ER  - 

@conference{
author = "Stančić, Ana and Otašević, Vesna and Markelić, Milica and Veličković, Ksenija and Gudelj, Anđelija and Savić, Nevena and Martinović, Vesna and Grigorov, Ilijana",
year = "2023",
abstract = "We showed recently that ferroptosis contributes to liver pathological changes in diabetes. So, targeting of ferroptosis-related pathways could be novel approach for treatment of diabetes- related liver diseases. Ethyl pyruvate (EP) showed antidiabetic action due to anti-oxidative, - inflammatory and -apoptotic properties. We aimed to examine its potential antiferroptotic action  in diabetes-related liver pathology.
Male Wistar rats were divided into four groups: control; diabetic (STZ, 65 mg/kg); diabetic pre- treated with EP (80 mg/kg/day, starting one week before STZ and continuing following 4  weeks) and diabetic treated with EP, starting with STZ and lasted 4   weeks.
Both modes of EP treatment induced attenuation of ferroptotic events in the liver of diabetic  rats: accumulation of lipid peroxides (4-HNE), disturbances in iron metabolism (decreased   FTH and increased TFR expression), decrease in expression level/activity of ferroptosis-  related antioxidative-defense molecules (GPX4, GCL, GSS, Nrf2, HO-1), and activation of ferroptosis-related pro-inflammatory events (HMGB1 nucleus-to-cytosol and NF-kB cytosol-to- nucleus translocation). Those changes reflected on the improvement of diabetes-related morphological alterations such as liver fibrosis and  binucleation.
Overall, EP interferes with ferroptosis signaling pathways and exerts antiferroptotic activity in the liver in diabetic state. This highlighting the significance of ferroptosis targeting in diabetes- related liver diseases and novel mechanisms/targets of EP beneficial   actions.",
publisher = "EMBO",
journal = "EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany",
title = "Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate",
pages = "92",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6068"
}

Stančić, A., Otašević, V., Markelić, M., Veličković, K., Gudelj, A., Savić, N., Martinović, V.,& Grigorov, I.. (2023). Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate. in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany
EMBO., 92.
https://hdl.handle.net/21.15107/rcub_ibiss_6068

Stančić A, Otašević V, Markelić M, Veličković K, Gudelj A, Savić N, Martinović V, Grigorov I. Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate. in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany. 2023;:92.
https://hdl.handle.net/21.15107/rcub_ibiss_6068 .

Stančić, Ana, Otašević, Vesna, Markelić, Milica, Veličković, Ksenija, Gudelj, Anđelija, Savić, Nevena, Martinović, Vesna, Grigorov, Ilijana, "Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate" in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany (2023):92,
https://hdl.handle.net/21.15107/rcub_ibiss_6068 .

TY  - CONF
AU  - Otašević, Vesna
AU  - Grigorov, Ilijana
AU  - Savić, Nevena
AU  - Markelić, Milica
AU  - Veličković, Ksenija
AU  - Gudelj, Anđelija
AU  - Martinović, Vesna
AU  - Stančić, Ana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6067
AB  - Recently, we characterized the ferroptotic phenotype of the liver of diabetic mice and revealed the inactivation of Nrf2 as an integral part of diabetes-induced liver ferroptosis. We aim here to examine does sulforaphane, an Nrf2 activator and antioxidant, prevent diabetes-induced liver ferroptosis and the mechanisms  involved.
For that purpose, male C57BL/6 mice were divided into three groups: control, diabetic (streptozotocin-treated, 40 mg/kg/5 consecutive days), diabetic+sulforaphane treated (2.5 mg/kg, from day 1-42).
Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic parameters crucial for antioxidative defense (HO-1, catalase, SOD), iron metabolism (ferroportin, ferritin), glutathione synthesis (xCT, GCLC, CTH, CBS) and recycling (GR) were reversed/increased by sulforaphane treatment. Antiferroptotic effect of sulforaphane in the diabetic liver was further evidenced through the increased level of glutathione, decreased accumulation of liable iron and lipid peroxides (4-HNE) and decreased tissue damage (fibrosis and infiltration). Finally, diabetes-induced increase in serum glucose, ALT, AST and triglyceride level was significantly reduced by   sulforaphane.
These findings revealed for the first time that sulforaphane prevents in vivo diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis. This suggests sulforaphane as a promising therapeutic tool for preventing ferroptosis at least in diabetes and diabetes-related pathologies.
PB  - EMBO
C3  - EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany
T1  - Sulforaphane prevents diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis
SP  - 91
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6067
ER  - 

@conference{
author = "Otašević, Vesna and Grigorov, Ilijana and Savić, Nevena and Markelić, Milica and Veličković, Ksenija and Gudelj, Anđelija and Martinović, Vesna and Stančić, Ana",
year = "2023",
abstract = "Recently, we characterized the ferroptotic phenotype of the liver of diabetic mice and revealed the inactivation of Nrf2 as an integral part of diabetes-induced liver ferroptosis. We aim here to examine does sulforaphane, an Nrf2 activator and antioxidant, prevent diabetes-induced liver ferroptosis and the mechanisms  involved.
For that purpose, male C57BL/6 mice were divided into three groups: control, diabetic (streptozotocin-treated, 40 mg/kg/5 consecutive days), diabetic+sulforaphane treated (2.5 mg/kg, from day 1-42).
Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic parameters crucial for antioxidative defense (HO-1, catalase, SOD), iron metabolism (ferroportin, ferritin), glutathione synthesis (xCT, GCLC, CTH, CBS) and recycling (GR) were reversed/increased by sulforaphane treatment. Antiferroptotic effect of sulforaphane in the diabetic liver was further evidenced through the increased level of glutathione, decreased accumulation of liable iron and lipid peroxides (4-HNE) and decreased tissue damage (fibrosis and infiltration). Finally, diabetes-induced increase in serum glucose, ALT, AST and triglyceride level was significantly reduced by   sulforaphane.
These findings revealed for the first time that sulforaphane prevents in vivo diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis. This suggests sulforaphane as a promising therapeutic tool for preventing ferroptosis at least in diabetes and diabetes-related pathologies.",
publisher = "EMBO",
journal = "EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany",
title = "Sulforaphane prevents diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis",
pages = "91",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6067"
}

Otašević, V., Grigorov, I., Savić, N., Markelić, M., Veličković, K., Gudelj, A., Martinović, V.,& Stančić, A.. (2023). Sulforaphane prevents diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis. in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany
EMBO., 91.
https://hdl.handle.net/21.15107/rcub_ibiss_6067

Otašević V, Grigorov I, Savić N, Markelić M, Veličković K, Gudelj A, Martinović V, Stančić A. Sulforaphane prevents diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis. in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany. 2023;:91.
https://hdl.handle.net/21.15107/rcub_ibiss_6067 .

Otašević, Vesna, Grigorov, Ilijana, Savić, Nevena, Markelić, Milica, Veličković, Ksenija, Gudelj, Anđelija, Martinović, Vesna, Stančić, Ana, "Sulforaphane prevents diabetes-induced liver ferroptosis through activation of Nrf2 signaling axis" in EMBO Workshop: Ferroptosis: When metabolism meets cell death; 2023 Apr 23-27; Seeon, Germany (2023):91,
https://hdl.handle.net/21.15107/rcub_ibiss_6067 .

TY  - CONF
AU  - Jonić, Natalija
AU  - Chatzigiannis, Christos M
AU  - Koprivica, Ivan
AU  - Marinho, Sérgio
AU  - Moura-Alves, Pedro
AU  - Pavić, Aleksandar
AU  - Dimitrijević, Mirjana
AU  - Jovanović, Anđelina
AU  - Jovanović, Milan B
AU  - Otašević, Vesna
AU  - Pejnović, Nada
AU  - Tzakos, Andreas
AU  - Stojanović, Ivana D.
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5731
AB  - Aril ugljovodonični receptor (AhR) je transkripcioni faktor aktiviran ligandom i prevashodno je eksprimiran u imunskom tkivu creva. Kako istraživanja ukazuju na povezanost mukoznog imuniteta i različitih inflamatornih i autoimunskih oboljenja, ispitivali smo modulaciju imunskih ćelija creva pomoću novosintetisanog liganda AhR (šifra C43). Primenjen u kulturi mišjih CD4+ ćelija izolovanih iz mezenteričnih limfnih čvorova (MLČ), kao i na humanim ćelijama izolovanih iz tonzila, C43 je značajno uvećao udeo Treg nakon 24h. Nakon što je pokazano da C43 ne ostvaruje toksičnost (ni pri najvećim koncentracijama) pri razviću embriona zebrica (lat. Danio rerio), gavažom je 5 dana davan zdravim C57BL/6 mužjacima. U odnosu zastupljenosti Th1/Treg u MLČ, uočeno je pomeranje balansa ka Treg, kao i povećanje udela Treg koje eksprimiraju Cyp1a1 (nishodni signalni molekul od AhR) kod tretiranih miševa. Kada je C43 gavažom davan C57BL/6 mužjacima kojima je dijabetes tipa 1 (DT1) indukovan streptozotocinom, glikemijski indeksi su bili niži, a histološka analiza pankreasa je pokazala bolje očuvanje β ćelija i pankreasnih ostrvaca. Analiza lamine proprije tankog creva je pokazala povećanje udela tolerogenih dendritskih ćelija (tolDC), dok je udeo CD11b+MHCII+ ćelija bio snižen. Udeo Treg je takođe bio veći, kao i Cyp1a1+ Treg i IL-10+ Treg. Analizom pankreasnog limfnog čvora uočeno je sniženje udela Th1 i CD8+ ćelija, uz povećanje udela tolDC koje eksprimiraju indolamin 2,3-dioksigenazu, što je zabeleženo i u inflitratima pankreasa. Na osnovu dobijenih rezultata može se zaključiti da C43 ostvaruje antiinflamatorni efekat u DT1 i da pristup stimulacije AhR u mukozi creva može imati povoljan efekat u modulaciji autoimunosti i/ili inflamatornih oboljenja.
PB  - Belgrade: Serbian Academy of Sciences and Arts
C3  - Naučni skup Svetski dan imunologije 2023; 2023 Apr 27; Belgrade, Serbia
T1  - Novosintetisani fluorescentni AhR ligand podstiče povećanje udela T regulatornih ćelija i ublažava kliničku sliku dijabetesa tipa 1 kod C57BL/6 miševa
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5731
ER  - 

@conference{
author = "Jonić, Natalija and Chatzigiannis, Christos M and Koprivica, Ivan and Marinho, Sérgio and Moura-Alves, Pedro and Pavić, Aleksandar and Dimitrijević, Mirjana and Jovanović, Anđelina and Jovanović, Milan B and Otašević, Vesna and Pejnović, Nada and Tzakos, Andreas and Stojanović, Ivana D.",
year = "2023",
abstract = "Aril ugljovodonični receptor (AhR) je transkripcioni faktor aktiviran ligandom i prevashodno je eksprimiran u imunskom tkivu creva. Kako istraživanja ukazuju na povezanost mukoznog imuniteta i različitih inflamatornih i autoimunskih oboljenja, ispitivali smo modulaciju imunskih ćelija creva pomoću novosintetisanog liganda AhR (šifra C43). Primenjen u kulturi mišjih CD4+ ćelija izolovanih iz mezenteričnih limfnih čvorova (MLČ), kao i na humanim ćelijama izolovanih iz tonzila, C43 je značajno uvećao udeo Treg nakon 24h. Nakon što je pokazano da C43 ne ostvaruje toksičnost (ni pri najvećim koncentracijama) pri razviću embriona zebrica (lat. Danio rerio), gavažom je 5 dana davan zdravim C57BL/6 mužjacima. U odnosu zastupljenosti Th1/Treg u MLČ, uočeno je pomeranje balansa ka Treg, kao i povećanje udela Treg koje eksprimiraju Cyp1a1 (nishodni signalni molekul od AhR) kod tretiranih miševa. Kada je C43 gavažom davan C57BL/6 mužjacima kojima je dijabetes tipa 1 (DT1) indukovan streptozotocinom, glikemijski indeksi su bili niži, a histološka analiza pankreasa je pokazala bolje očuvanje β ćelija i pankreasnih ostrvaca. Analiza lamine proprije tankog creva je pokazala povećanje udela tolerogenih dendritskih ćelija (tolDC), dok je udeo CD11b+MHCII+ ćelija bio snižen. Udeo Treg je takođe bio veći, kao i Cyp1a1+ Treg i IL-10+ Treg. Analizom pankreasnog limfnog čvora uočeno je sniženje udela Th1 i CD8+ ćelija, uz povećanje udela tolDC koje eksprimiraju indolamin 2,3-dioksigenazu, što je zabeleženo i u inflitratima pankreasa. Na osnovu dobijenih rezultata može se zaključiti da C43 ostvaruje antiinflamatorni efekat u DT1 i da pristup stimulacije AhR u mukozi creva može imati povoljan efekat u modulaciji autoimunosti i/ili inflamatornih oboljenja.",
publisher = "Belgrade: Serbian Academy of Sciences and Arts",
journal = "Naučni skup Svetski dan imunologije 2023; 2023 Apr 27; Belgrade, Serbia",
title = "Novosintetisani fluorescentni AhR ligand podstiče povećanje udela T regulatornih ćelija i ublažava kliničku sliku dijabetesa tipa 1 kod C57BL/6 miševa",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5731"
}

Jonić, N., Chatzigiannis, C. M., Koprivica, I., Marinho, S., Moura-Alves, P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Otašević, V., Pejnović, N., Tzakos, A.,& Stojanović, I. D.. (2023). Novosintetisani fluorescentni AhR ligand podstiče povećanje udela T regulatornih ćelija i ublažava kliničku sliku dijabetesa tipa 1 kod C57BL/6 miševa. in Naučni skup Svetski dan imunologije 2023; 2023 Apr 27; Belgrade, Serbia
Belgrade: Serbian Academy of Sciences and Arts..
https://hdl.handle.net/21.15107/rcub_ibiss_5731

Jonić N, Chatzigiannis CM, Koprivica I, Marinho S, Moura-Alves P, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Otašević V, Pejnović N, Tzakos A, Stojanović ID. Novosintetisani fluorescentni AhR ligand podstiče povećanje udela T regulatornih ćelija i ublažava kliničku sliku dijabetesa tipa 1 kod C57BL/6 miševa. in Naučni skup Svetski dan imunologije 2023; 2023 Apr 27; Belgrade, Serbia. 2023;.
https://hdl.handle.net/21.15107/rcub_ibiss_5731 .

Jonić, Natalija, Chatzigiannis, Christos M, Koprivica, Ivan, Marinho, Sérgio, Moura-Alves, Pedro, Pavić, Aleksandar, Dimitrijević, Mirjana, Jovanović, Anđelina, Jovanović, Milan B, Otašević, Vesna, Pejnović, Nada, Tzakos, Andreas, Stojanović, Ivana D., "Novosintetisani fluorescentni AhR ligand podstiče povećanje udela T regulatornih ćelija i ublažava kliničku sliku dijabetesa tipa 1 kod C57BL/6 miševa" in Naučni skup Svetski dan imunologije 2023; 2023 Apr 27; Belgrade, Serbia (2023),
https://hdl.handle.net/21.15107/rcub_ibiss_5731 .

TY  - CONF
AU  - Savić, Nevena
AU  - Otašević, Vesna
AU  - Saksida, Tamara
AU  - Markelić, Milica
AU  - Grigorov, Ilijana
AU  - Veličković, Ksenija
AU  - Martinović, Vesna
AU  - Mićanović, Dragica
AU  - Ivanović, Anđelija
AU  - Stančić, Ana
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5195
AB  - Један од узрока патолошких промена јетре током Diabetes mellitus-a (ДМ) јесте повећање ћелијске смрти. До данас је описана апоптоза, некроза и аутофагија хепатоцита.1 Циљ ове студије био је испитивање укључености фероптозе, ћелијске смрти која настаје услед интезивираног процеса липидне пероксидације зависне од гвожђа, на развој патолошких промена јетре у ДМ, коришћењем фероптотског инхибитора феростатина-1 (Фер-1). Мужјаци C57BL/6 мишева подељени су у три групе: 1. контрола (К); 2. дијабетeс (индукован стрептозотоцином, Д) и 3. дијабетес + Фер-1 (ДФ). У групи Д забележена је смањена експресија цитопротективног транскрипционог фактора Nrf2 (енгл. nuclear factor (erythroid-derived-2)-related factor2), што је случај и са његовим таргетним протеинима битним за регулисање процеса фероптозе, као што су кључни ензим за уклањање липидних пероксида, GPx4 (глутатион пероксидаза 4), цистеин-глутаматни трансмембрански антипортер (xCT) укључен у регулацију метаболизма глутатиона и хем оксигеназа 1 (HO-1) која регулише метаболизам гвожђа. У групи ДФ забележено је значајно повећање експресије Nrf2, GPx4, xCT и HO-1. Маркер липидне пероксидације 4-HNE повећан је у хепатоцитима Д групе, а смањен у ДФ групи. Наши резултати показују да хепатоцити у ДМ подлежу фероптози, с обзиром на чињеницу да Фер-1 делује цитопротективно, активирајући Nrf2-зависну сигналну каскаду. Ово нас упућује на фероптозу као нову терапеутску мету у лечењу патолошких промена јетре у ДМ и то стимулисаном активацијом Nrf2.
AB  - Jedan od uzroka patoloških promena jetre tokom Diabetes mellitus-a (DM) jeste povećanje ćelijske smrti. Do danas je opisana apoptoza, nekroza i autofagija hepatocita.1 Cilj ove studije bio je ispitivanje uključenosti feroptoze, ćelijske smrti koja nastaje usled inteziviranog procesa lipidne peroksidacije zavisne od gvožđa, na razvoj patoloških promena jetre u DM, korišćenjem feroptotskog inhibitora ferostatina-1 (Fer-1). Mužjaci C57BL/6 miševa podeljeni su u tri grupe: 1. kontrola (K); 2. dijabetes (indukovan streptozotocinom, D) i 3. dijabetes + Fer-1 (DF). U grupi D zabeležena je smanjena ekspresija citoprotektivnog transkripcionog faktora Nrf2 (engl. nuclear factor (erythroid-derived-2)-related factor2), što je slučaj i sa njegovim targetnim proteinima bitnim za regulisanje procesa feroptoze, kao što su ključni enzim za uklanjanje lipidnih peroksida, GPx4 (glutation peroksidaza 4), cistein-glutamatni transmembranski antiporter (xCT) uključen u regulaciju metabolizma glutationa i hem oksigenaza 1 (HO-1) koja reguliše metabolizam gvožđa. U grupi DF zabeleženo je značajno povećanje ekspresije Nrf2, GPx4, xCT i HO-1. Marker lipidne peroksidacije 4-HNE povećan je u hepatocitima D grupe, a smanjen u DF grupi. Naši rezultati pokazuju da hepatociti u DM podležu feroptozi, s obzirom na činjenicu da Fer-1 deluje citoprotektivno, aktivirajući Nrf2-zavisnu signalnu kaskadu. Ovo nas upućuje na feroptozu kao novu terapeutsku metu u lečenju patoloških promena jetre u DM i to stimulisanom aktivacijom Nrf2.
PB  - Belgrade: Serbian Biological Society
C3  - Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
T1  - Допринос фероптозе патолошким променама јетре дијабетичних мишева
T1  - Doprinos feroptoze patološkim promenama jetre dijabetičnih miševa
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5195
ER  - 

@conference{
author = "Savić, Nevena and Otašević, Vesna and Saksida, Tamara and Markelić, Milica and Grigorov, Ilijana and Veličković, Ksenija and Martinović, Vesna and Mićanović, Dragica and Ivanović, Anđelija and Stančić, Ana",
year = "2022",
abstract = "Један од узрока патолошких промена јетре током Diabetes mellitus-a (ДМ) јесте повећање ћелијске смрти. До данас је описана апоптоза, некроза и аутофагија хепатоцита.1 Циљ ове студије био је испитивање укључености фероптозе, ћелијске смрти која настаје услед интезивираног процеса липидне пероксидације зависне од гвожђа, на развој патолошких промена јетре у ДМ, коришћењем фероптотског инхибитора феростатина-1 (Фер-1). Мужјаци C57BL/6 мишева подељени су у три групе: 1. контрола (К); 2. дијабетeс (индукован стрептозотоцином, Д) и 3. дијабетес + Фер-1 (ДФ). У групи Д забележена је смањена експресија цитопротективног транскрипционог фактора Nrf2 (енгл. nuclear factor (erythroid-derived-2)-related factor2), што је случај и са његовим таргетним протеинима битним за регулисање процеса фероптозе, као што су кључни ензим за уклањање липидних пероксида, GPx4 (глутатион пероксидаза 4), цистеин-глутаматни трансмембрански антипортер (xCT) укључен у регулацију метаболизма глутатиона и хем оксигеназа 1 (HO-1) која регулише метаболизам гвожђа. У групи ДФ забележено је значајно повећање експресије Nrf2, GPx4, xCT и HO-1. Маркер липидне пероксидације 4-HNE повећан је у хепатоцитима Д групе, а смањен у ДФ групи. Наши резултати показују да хепатоцити у ДМ подлежу фероптози, с обзиром на чињеницу да Фер-1 делује цитопротективно, активирајући Nrf2-зависну сигналну каскаду. Ово нас упућује на фероптозу као нову терапеутску мету у лечењу патолошких промена јетре у ДМ и то стимулисаном активацијом Nrf2., Jedan od uzroka patoloških promena jetre tokom Diabetes mellitus-a (DM) jeste povećanje ćelijske smrti. Do danas je opisana apoptoza, nekroza i autofagija hepatocita.1 Cilj ove studije bio je ispitivanje uključenosti feroptoze, ćelijske smrti koja nastaje usled inteziviranog procesa lipidne peroksidacije zavisne od gvožđa, na razvoj patoloških promena jetre u DM, korišćenjem feroptotskog inhibitora ferostatina-1 (Fer-1). Mužjaci C57BL/6 miševa podeljeni su u tri grupe: 1. kontrola (K); 2. dijabetes (indukovan streptozotocinom, D) i 3. dijabetes + Fer-1 (DF). U grupi D zabeležena je smanjena ekspresija citoprotektivnog transkripcionog faktora Nrf2 (engl. nuclear factor (erythroid-derived-2)-related factor2), što je slučaj i sa njegovim targetnim proteinima bitnim za regulisanje procesa feroptoze, kao što su ključni enzim za uklanjanje lipidnih peroksida, GPx4 (glutation peroksidaza 4), cistein-glutamatni transmembranski antiporter (xCT) uključen u regulaciju metabolizma glutationa i hem oksigenaza 1 (HO-1) koja reguliše metabolizam gvožđa. U grupi DF zabeleženo je značajno povećanje ekspresije Nrf2, GPx4, xCT i HO-1. Marker lipidne peroksidacije 4-HNE povećan je u hepatocitima D grupe, a smanjen u DF grupi. Naši rezultati pokazuju da hepatociti u DM podležu feroptozi, s obzirom na činjenicu da Fer-1 deluje citoprotektivno, aktivirajući Nrf2-zavisnu signalnu kaskadu. Ovo nas upućuje na feroptozu kao novu terapeutsku metu u lečenju patoloških promena jetre u DM i to stimulisanom aktivacijom Nrf2.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia",
title = "Допринос фероптозе патолошким променама јетре дијабетичних мишева, Doprinos feroptoze patološkim promenama jetre dijabetičnih miševa",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5195"
}

Savić, N., Otašević, V., Saksida, T., Markelić, M., Grigorov, I., Veličković, K., Martinović, V., Mićanović, D., Ivanović, A.,& Stančić, A.. (2022). Допринос фероптозе патолошким променама јетре дијабетичних мишева. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society..
https://hdl.handle.net/21.15107/rcub_ibiss_5195

Savić N, Otašević V, Saksida T, Markelić M, Grigorov I, Veličković K, Martinović V, Mićanović D, Ivanović A, Stančić A. Допринос фероптозе патолошким променама јетре дијабетичних мишева. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;.
https://hdl.handle.net/21.15107/rcub_ibiss_5195 .

Savić, Nevena, Otašević, Vesna, Saksida, Tamara, Markelić, Milica, Grigorov, Ilijana, Veličković, Ksenija, Martinović, Vesna, Mićanović, Dragica, Ivanović, Anđelija, Stančić, Ana, "Допринос фероптозе патолошким променама јетре дијабетичних мишева" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia (2022),
https://hdl.handle.net/21.15107/rcub_ibiss_5195 .

TY  - CONF
AU  - Otašević, Vesna
AU  - Saksida, Tamara
AU  - Markelić, Milica
AU  - Grigorov, Ilijana
AU  - Vučetić, Milica
AU  - Veličković, Ksenija
AU  - Martinović, Vesna
AU  - Mićanović, Dragica
AU  - Ivanović, Anđelija
AU  - Savić, Nevena
AU  - Stančić, Ana
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5197
AB  - Кључни патолошки догађај у настанку дијабетеса је губитак функционалних β-ћелија. Улога фероптозе, новоописаног типа регулисане ћелијске смрти зависне од гвожђа, у смањењу популације β-ћелија код дијабетеса није довољно испитана. Стога је у овом раду испитиван допринос фероптозе умирању β-ћелија у дијабетичним условима in vivo и in vitro. Код мишева са дијабетесом индукованим стрептозотоцином, СТЗ забележено је значајно повећање инфилтрације макрофага и акумулације липидних пероксида у острвцима панкреаса, праћено смањењем популације инсулин позитивних ћелија, експресије глутатион пероксидазе 4, GPX4, цистеин/глутамат транспортера xCT и хем оксигеназе 1. Резултати добијени in vitro на Rin-5f β-ћелијама су показали да дијабетични услови (висока концентрација глукозе, СТЗ, цитокини и водоник пероксид снижавају експресију транскрипционог фактора Nrf2, GPX4 и митохондријални мембрански потенцијал, а повећавају продукцију реактивних врста кисеоника, акумулацију слободног гвожђа, липидних пероксида и смртност β-ћелија. Примена инхибитора фероптозе, феростатина-1 у потпуности је поништила наведене промене, тј. остварила позитивне ефекте на β-ћелије/панкреас дијабетичних животиња, осим у случају in vitro третмана цитокинима, указујући на разлике између дијабетогених стимулуса у одређивању судбине β-ћелија. Наведени резултати показују да модулирање тј. инхибиција фероптозе у дијабетесу може бити нови обећавајући приступ за очување популације β-ћелија и третман дијабетеса.
AB  - Ključni patološki događaj u nastanku dijabetesa je gubitak funkcionalnih β-ćelija. Uloga feroptoze, novoopisanog tipa regulisane ćelijske smrti zavisne od gvožđa, u smanjenju populacije β-ćelija kod dijabetesa nije dovoljno ispitana. Stoga je u ovom radu ispitivan doprinos feroptoze umiranju β-ćelija u dijabetičnim uslovima in vivo i in vitro. Kod miševa sa dijabetesom indukovanim streptozotocinom, STZ zabeleženo je značajno povećanje infiltracije makrofaga i akumulacije lipidnih peroksida u ostrvcima pankreasa, praćeno smanjenjem populacije insulin pozitivnih ćelija, ekspresije glutation peroksidaze 4, GPX4, cistein/glutamat transportera xCT i hem oksigenaze 1. Rezultati dobijeni in vitro na Rin-5f β-ćelijama su pokazali da dijabetični uslovi (visoka koncentracija glukoze, STZ, citokini i vodonik peroksid snižavaju ekspresiju transkripcionog faktora Nrf2, GPX4 i mitohondrijalni membranski potencijal, a povećavaju produkciju reaktivnih vrsta kiseonika, akumulaciju slobodnog gvožđa, lipidnih peroksida i smrtnost β-ćelija. Primena inhibitora feroptoze, ferostatina-1 u potpunosti je poništila navedene promene, tj. ostvarila pozitivne efekte na β-ćelije/pankreas dijabetičnih životinja, osim u slučaju in vitro tretmana citokinima, ukazujući na razlike između dijabetogenih stimulusa u određivanju sudbine β-ćelija. Navedeni rezultati pokazuju da moduliranje tj. inhibicija feroptoze u dijabetesu može biti novi obećavajući pristup za očuvanje populacije β-ćelija i tretman dijabetesa.
PB  - Belgrade: Serbian Biological Society
C3  - Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
T1  - Фероптоза у дијабетесу и дијабетичним компликацијама
T1  - Feroptoza u dijabetesu i dijabetičnim komplikacijama
SP  - 279
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5197
ER  - 

@conference{
author = "Otašević, Vesna and Saksida, Tamara and Markelić, Milica and Grigorov, Ilijana and Vučetić, Milica and Veličković, Ksenija and Martinović, Vesna and Mićanović, Dragica and Ivanović, Anđelija and Savić, Nevena and Stančić, Ana",
year = "2022",
abstract = "Кључни патолошки догађај у настанку дијабетеса је губитак функционалних β-ћелија. Улога фероптозе, новоописаног типа регулисане ћелијске смрти зависне од гвожђа, у смањењу популације β-ћелија код дијабетеса није довољно испитана. Стога је у овом раду испитиван допринос фероптозе умирању β-ћелија у дијабетичним условима in vivo и in vitro. Код мишева са дијабетесом индукованим стрептозотоцином, СТЗ забележено је значајно повећање инфилтрације макрофага и акумулације липидних пероксида у острвцима панкреаса, праћено смањењем популације инсулин позитивних ћелија, експресије глутатион пероксидазе 4, GPX4, цистеин/глутамат транспортера xCT и хем оксигеназе 1. Резултати добијени in vitro на Rin-5f β-ћелијама су показали да дијабетични услови (висока концентрација глукозе, СТЗ, цитокини и водоник пероксид снижавају експресију транскрипционог фактора Nrf2, GPX4 и митохондријални мембрански потенцијал, а повећавају продукцију реактивних врста кисеоника, акумулацију слободног гвожђа, липидних пероксида и смртност β-ћелија. Примена инхибитора фероптозе, феростатина-1 у потпуности је поништила наведене промене, тј. остварила позитивне ефекте на β-ћелије/панкреас дијабетичних животиња, осим у случају in vitro третмана цитокинима, указујући на разлике између дијабетогених стимулуса у одређивању судбине β-ћелија. Наведени резултати показују да модулирање тј. инхибиција фероптозе у дијабетесу може бити нови обећавајући приступ за очување популације β-ћелија и третман дијабетеса., Ključni patološki događaj u nastanku dijabetesa je gubitak funkcionalnih β-ćelija. Uloga feroptoze, novoopisanog tipa regulisane ćelijske smrti zavisne od gvožđa, u smanjenju populacije β-ćelija kod dijabetesa nije dovoljno ispitana. Stoga je u ovom radu ispitivan doprinos feroptoze umiranju β-ćelija u dijabetičnim uslovima in vivo i in vitro. Kod miševa sa dijabetesom indukovanim streptozotocinom, STZ zabeleženo je značajno povećanje infiltracije makrofaga i akumulacije lipidnih peroksida u ostrvcima pankreasa, praćeno smanjenjem populacije insulin pozitivnih ćelija, ekspresije glutation peroksidaze 4, GPX4, cistein/glutamat transportera xCT i hem oksigenaze 1. Rezultati dobijeni in vitro na Rin-5f β-ćelijama su pokazali da dijabetični uslovi (visoka koncentracija glukoze, STZ, citokini i vodonik peroksid snižavaju ekspresiju transkripcionog faktora Nrf2, GPX4 i mitohondrijalni membranski potencijal, a povećavaju produkciju reaktivnih vrsta kiseonika, akumulaciju slobodnog gvožđa, lipidnih peroksida i smrtnost β-ćelija. Primena inhibitora feroptoze, ferostatina-1 u potpunosti je poništila navedene promene, tj. ostvarila pozitivne efekte na β-ćelije/pankreas dijabetičnih životinja, osim u slučaju in vitro tretmana citokinima, ukazujući na razlike između dijabetogenih stimulusa u određivanju sudbine β-ćelija. Navedeni rezultati pokazuju da moduliranje tj. inhibicija feroptoze u dijabetesu može biti novi obećavajući pristup za očuvanje populacije β-ćelija i tretman dijabetesa.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia",
title = "Фероптоза у дијабетесу и дијабетичним компликацијама, Feroptoza u dijabetesu i dijabetičnim komplikacijama",
pages = "279",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5197"
}

Otašević, V., Saksida, T., Markelić, M., Grigorov, I., Vučetić, M., Veličković, K., Martinović, V., Mićanović, D., Ivanović, A., Savić, N.,& Stančić, A.. (2022). Фероптоза у дијабетесу и дијабетичним компликацијама. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society., 279.
https://hdl.handle.net/21.15107/rcub_ibiss_5197

Otašević V, Saksida T, Markelić M, Grigorov I, Vučetić M, Veličković K, Martinović V, Mićanović D, Ivanović A, Savić N, Stančić A. Фероптоза у дијабетесу и дијабетичним компликацијама. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;:279.
https://hdl.handle.net/21.15107/rcub_ibiss_5197 .

Otašević, Vesna, Saksida, Tamara, Markelić, Milica, Grigorov, Ilijana, Vučetić, Milica, Veličković, Ksenija, Martinović, Vesna, Mićanović, Dragica, Ivanović, Anđelija, Savić, Nevena, Stančić, Ana, "Фероптоза у дијабетесу и дијабетичним компликацијама" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia (2022):279,
https://hdl.handle.net/21.15107/rcub_ibiss_5197 .

TY  - JOUR
AU  - Stančić, Ana
AU  - Saksida, Tamara
AU  - Markelić, Milica
AU  - Vučetić, Milica
AU  - Grigorov, Ilijana
AU  - Martinović, Vesna
AU  - Mićanović, Dragica
AU  - Ivanović, Anđelija
AU  - Veličković, Ksenija
AU  - Savić, Nevena
AU  - Otašević, Vesna
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4910
AB  - The main pathological hallmark of diabetes is the loss of functional β-cells. Among several types of β-cell death in diabetes, the
involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes-mimicking factors: high glucose
(HG), proinflammatory cytokines, hydrogen peroxide (H2O2), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis
of β-cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ-induced
in vivo diabetic model. All in vitro treatments increased loss of Rin-5F cells along with the accumulation of reactive oxygen
species, lipid peroxides and iron, inactivation of NF-E2-related factor 2 (Nrf2), and decrease in glutathione peroxidase 4
expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer-1), ferroptosis inhibitor, diminished the abovestated effects and rescued cells from death in case of HG, STZ, and H2O2 treatments, while failed to increase MMP and to
attenuate cell death after the cytokines’ treatment. Moreover, Fer-1 protected pancreatic islets from STZ-induced injury in
diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the
population of insulin-positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of
β-cells, emerging HG, H2O2, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an
antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for
preservation of the β-cell population. Our results obtained from in vivo study strongly justify this approach.
PB  - London:Hindawi
T2  - Oxidative Medicine and Cellular Longevity
T1  - Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions
VL  - 2022
DO  - 10.1155/2022/3873420
SP  - 3873420
ER  - 

@article{
author = "Stančić, Ana and Saksida, Tamara and Markelić, Milica and Vučetić, Milica and Grigorov, Ilijana and Martinović, Vesna and Mićanović, Dragica and Ivanović, Anđelija and Veličković, Ksenija and Savić, Nevena and Otašević, Vesna",
year = "2022",
abstract = "The main pathological hallmark of diabetes is the loss of functional β-cells. Among several types of β-cell death in diabetes, the
involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes-mimicking factors: high glucose
(HG), proinflammatory cytokines, hydrogen peroxide (H2O2), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis
of β-cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ-induced
in vivo diabetic model. All in vitro treatments increased loss of Rin-5F cells along with the accumulation of reactive oxygen
species, lipid peroxides and iron, inactivation of NF-E2-related factor 2 (Nrf2), and decrease in glutathione peroxidase 4
expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer-1), ferroptosis inhibitor, diminished the abovestated effects and rescued cells from death in case of HG, STZ, and H2O2 treatments, while failed to increase MMP and to
attenuate cell death after the cytokines’ treatment. Moreover, Fer-1 protected pancreatic islets from STZ-induced injury in
diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the
population of insulin-positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of
β-cells, emerging HG, H2O2, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an
antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for
preservation of the β-cell population. Our results obtained from in vivo study strongly justify this approach.",
publisher = "London:Hindawi",
journal = "Oxidative Medicine and Cellular Longevity",
title = "Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions",
volume = "2022",
doi = "10.1155/2022/3873420",
pages = "3873420"
}

Stančić, A., Saksida, T., Markelić, M., Vučetić, M., Grigorov, I., Martinović, V., Mićanović, D., Ivanović, A., Veličković, K., Savić, N.,& Otašević, V.. (2022). Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions. in Oxidative Medicine and Cellular Longevity
London:Hindawi., 2022, 3873420.
https://doi.org/10.1155/2022/3873420

Stančić A, Saksida T, Markelić M, Vučetić M, Grigorov I, Martinović V, Mićanović D, Ivanović A, Veličković K, Savić N, Otašević V. Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions. in Oxidative Medicine and Cellular Longevity. 2022;2022:3873420.
doi:10.1155/2022/3873420 .

Stančić, Ana, Saksida, Tamara, Markelić, Milica, Vučetić, Milica, Grigorov, Ilijana, Martinović, Vesna, Mićanović, Dragica, Ivanović, Anđelija, Veličković, Ksenija, Savić, Nevena, Otašević, Vesna, "Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions" in Oxidative Medicine and Cellular Longevity, 2022 (2022):3873420,
https://doi.org/10.1155/2022/3873420 . .

TY  - JOUR
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Markelić, Milica
AU  - Grigorov, Ilijana
AU  - Saksida, Tamara
AU  - Savić, Nevena
AU  - Vučetić, Milica
AU  - Martinović, Vesna
AU  - Ivanović, Anđelija
AU  - Otašević, Vesna
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5160
AB  - Cell death plays an important role in diabetes-induced liver dysfunction. Ferroptosis is a
newly defined regulated cell death caused by iron-dependent lipid peroxidation. Our previous studies
have shown that high glucose and streptozotocin (STZ) cause  -cell death through ferroptosis and
that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, improves  -cell viability, islet morphology, and
function. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related
pathological changes in the liver. For this purpose, male C57BL/6 mice, in which diabetes was induced
with STZ (40 mg/kg/5 consecutive days), were treated with Fer-1 (1 mg/kg, from day 1–21 day). It
was found that in diabetic mice Fer-1 improved serum levels of ALT and triglycerides and decreased
liver fibrosis, hepatocytes size, and binucleation. This improvement was due to the Fer-1-induced
attenuation of ferroptotic events in the liver of diabetic mice, such as accumulation of pro-oxidative
parameters (iron, lipofuscin, 4-HNE), decrease in expression level/activity of antioxidative defenserelated
molecules (GPX4, Nrf2, xCT, GSH, GCL, HO-1, SOD), and HMGB1 translocation from nucleus
into cytosol. We concluded that ferroptosis contributes to diabetes-related pathological changes in
the liver and that the targeting of ferroptosis represents a promising approach in the management of
diabetes-induced liver injury.
PB  - Basel: MDPI
T2  - International Journal of Molecular Sciences
T1  - Involvement of Ferroptosis in Diabetes-Induced Liver Pathology
IS  - 16
VL  - 23
DO  - 10.3390/ijms23169309
SP  - 9309
ER  - 

@article{
author = "Stančić, Ana and Veličković, Ksenija and Markelić, Milica and Grigorov, Ilijana and Saksida, Tamara and Savić, Nevena and Vučetić, Milica and Martinović, Vesna and Ivanović, Anđelija and Otašević, Vesna",
year = "2022",
abstract = "Cell death plays an important role in diabetes-induced liver dysfunction. Ferroptosis is a
newly defined regulated cell death caused by iron-dependent lipid peroxidation. Our previous studies
have shown that high glucose and streptozotocin (STZ) cause  -cell death through ferroptosis and
that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, improves  -cell viability, islet morphology, and
function. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related
pathological changes in the liver. For this purpose, male C57BL/6 mice, in which diabetes was induced
with STZ (40 mg/kg/5 consecutive days), were treated with Fer-1 (1 mg/kg, from day 1–21 day). It
was found that in diabetic mice Fer-1 improved serum levels of ALT and triglycerides and decreased
liver fibrosis, hepatocytes size, and binucleation. This improvement was due to the Fer-1-induced
attenuation of ferroptotic events in the liver of diabetic mice, such as accumulation of pro-oxidative
parameters (iron, lipofuscin, 4-HNE), decrease in expression level/activity of antioxidative defenserelated
molecules (GPX4, Nrf2, xCT, GSH, GCL, HO-1, SOD), and HMGB1 translocation from nucleus
into cytosol. We concluded that ferroptosis contributes to diabetes-related pathological changes in
the liver and that the targeting of ferroptosis represents a promising approach in the management of
diabetes-induced liver injury.",
publisher = "Basel: MDPI",
journal = "International Journal of Molecular Sciences",
title = "Involvement of Ferroptosis in Diabetes-Induced Liver Pathology",
number = "16",
volume = "23",
doi = "10.3390/ijms23169309",
pages = "9309"
}

Stančić, A., Veličković, K., Markelić, M., Grigorov, I., Saksida, T., Savić, N., Vučetić, M., Martinović, V., Ivanović, A.,& Otašević, V.. (2022). Involvement of Ferroptosis in Diabetes-Induced Liver Pathology. in International Journal of Molecular Sciences
Basel: MDPI., 23(16), 9309.
https://doi.org/10.3390/ijms23169309

Stančić A, Veličković K, Markelić M, Grigorov I, Saksida T, Savić N, Vučetić M, Martinović V, Ivanović A, Otašević V. Involvement of Ferroptosis in Diabetes-Induced Liver Pathology. in International Journal of Molecular Sciences. 2022;23(16):9309.
doi:10.3390/ijms23169309 .

Stančić, Ana, Veličković, Ksenija, Markelić, Milica, Grigorov, Ilijana, Saksida, Tamara, Savić, Nevena, Vučetić, Milica, Martinović, Vesna, Ivanović, Anđelija, Otašević, Vesna, "Involvement of Ferroptosis in Diabetes-Induced Liver Pathology" in International Journal of Molecular Sciences, 23, no. 16 (2022):9309,
https://doi.org/10.3390/ijms23169309 . .

TY  - CONF
AU  - Stančić, Ana
AU  - Veličković, Ksenija
AU  - Markelić, Milica
AU  - Grigorov, Ilijana
AU  - Martinović, Vesna
AU  - Otašević, Vesna
PY  - 2022
UR  - https://meetings.embo.org/event/22-thiol-oxidation
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5264
AB  - Diabetes is considered as an important cause of wide spectrum of liver disorders with the significant implication of oxidative stress. Cell death assumes a central role in the etiology of most of the liver pathologies. We aim to describe here the ferroptotic phenotype in diabetic liver. For that purpose, male C57BL/6 mice were divided into three groups: diabetic (streptozotocin-treated, 40 mg/kg in 5 consecutive days), diabetic treated with ferrostatin-1 (Fer-1, 1 mg/kg, from day 1-21) and vehicle-treated (control) animals. Diabetes induced biochemical/morphological alterations in the liver, including increases in ALT and TGC levels as well as fibrosis, hepatocytes volume and number of binuclear cells. These were accompanied by following changes at the molecular level: i) increase in accumulation of prooxidative (such as iron, lipofuscin and 4-HNE) and proinflammatory (HMGB1) parameters and ii) decrease in antioxidative-related (Nrf2, xCT, GPX4, GCL, HO-1) parameters. All of these ferroptosis-related events in the liver of diabetic animals were diminished with Fer-1 treatment. Our study reveals ferroptotic phenotype as an important part of the diabetes-related pathological changes in the liver. Also, the results suggest that targeting of ferroptosis represents promising approach in the prevention and treatment of liver diseases accompanying diabetes.
PB  - Heidelberg: European Molecular Biology Organization (EMBO)
C3  - EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13; Sant Feliu de Guixols, Spain
T1  - Characterization of ferroptosis in diabetic liver
SP  - 51
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5264
ER  - 

@conference{
author = "Stančić, Ana and Veličković, Ksenija and Markelić, Milica and Grigorov, Ilijana and Martinović, Vesna and Otašević, Vesna",
year = "2022",
abstract = "Diabetes is considered as an important cause of wide spectrum of liver disorders with the significant implication of oxidative stress. Cell death assumes a central role in the etiology of most of the liver pathologies. We aim to describe here the ferroptotic phenotype in diabetic liver. For that purpose, male C57BL/6 mice were divided into three groups: diabetic (streptozotocin-treated, 40 mg/kg in 5 consecutive days), diabetic treated with ferrostatin-1 (Fer-1, 1 mg/kg, from day 1-21) and vehicle-treated (control) animals. Diabetes induced biochemical/morphological alterations in the liver, including increases in ALT and TGC levels as well as fibrosis, hepatocytes volume and number of binuclear cells. These were accompanied by following changes at the molecular level: i) increase in accumulation of prooxidative (such as iron, lipofuscin and 4-HNE) and proinflammatory (HMGB1) parameters and ii) decrease in antioxidative-related (Nrf2, xCT, GPX4, GCL, HO-1) parameters. All of these ferroptosis-related events in the liver of diabetic animals were diminished with Fer-1 treatment. Our study reveals ferroptotic phenotype as an important part of the diabetes-related pathological changes in the liver. Also, the results suggest that targeting of ferroptosis represents promising approach in the prevention and treatment of liver diseases accompanying diabetes.",
publisher = "Heidelberg: European Molecular Biology Organization (EMBO)",
journal = "EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13; Sant Feliu de Guixols, Spain",
title = "Characterization of ferroptosis in diabetic liver",
pages = "51",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5264"
}

Stančić, A., Veličković, K., Markelić, M., Grigorov, I., Martinović, V.,& Otašević, V.. (2022). Characterization of ferroptosis in diabetic liver. in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13; Sant Feliu de Guixols, Spain
Heidelberg: European Molecular Biology Organization (EMBO)., 51.
https://hdl.handle.net/21.15107/rcub_ibiss_5264

Stančić A, Veličković K, Markelić M, Grigorov I, Martinović V, Otašević V. Characterization of ferroptosis in diabetic liver. in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13; Sant Feliu de Guixols, Spain. 2022;:51.
https://hdl.handle.net/21.15107/rcub_ibiss_5264 .

Stančić, Ana, Veličković, Ksenija, Markelić, Milica, Grigorov, Ilijana, Martinović, Vesna, Otašević, Vesna, "Characterization of ferroptosis in diabetic liver" in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13; Sant Feliu de Guixols, Spain (2022):51,
https://hdl.handle.net/21.15107/rcub_ibiss_5264 .

TY  - CONF
AU  - Otašević, Vesna
AU  - Saksida, Tamara
AU  - Markelić, Milica
AU  - Veličković, Ksenija
AU  - Grigorov, Ilijana
AU  - Stančić, Ana
PY  - 2022
UR  - uri:https://meetings.embo.org/event/22-thiol-oxidation
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5265
AB  - The key pathological event in the development of diabetes is the loss of functional β-cells. We examined here so far unknown the contribution of ferroptosis to β-cell death in diabetic conditions in vivo and in vitro. Thus, male C57BL/6 mice were divided into three groups: diabetic, (strepozotocin-treated 40 mg/kg/5 days), diabetic+ferrostatin-1-treated (Fer-1, 1 mg/kg from day 1-21) and control, while Rin-5F were treated with diabetes-mimicking factors: high glucose (25mM), hydrogen peroxide (75 μM), or streptozotocin (10mM) for 12h. In diabetic mice a significant increase in macrophage infiltration and lipid peroxide accumulation in pancreatic islets, followed by a decrease in an insulin-positive cell population, expression of GPX4, cysteine/glutamate transporter xCT and heme oxygenase 1 were observed. Applied diabetes-mimicking conditions increased death of Rin-5f β-cells, accumulation of reactive oxygen species, lipid peroxides and iron along with a decrease in the activation of transcription factor Nrf2, expression of GPX4 and mitochondrial membrane potential. The use of ferroptosis inhibitor, Fer-1, completely reversed examined ferroptosis-related changes, i.e. had positive effects on both pancreatic islets of diabetic animals and in vitro β-cells. These results show that modulation, i.e. inhibition of ferroptosis in diabetes may be a promising new approach to conserving β-cell populations and treating diabetes.
PB  - Heidelberg: European Molecular Biology Organization (EMBO)
C3  - EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13
T1  - Inhibition of ferroptosis increases the survival of β-cells
SP  - 52
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5265
ER  - 

@conference{
author = "Otašević, Vesna and Saksida, Tamara and Markelić, Milica and Veličković, Ksenija and Grigorov, Ilijana and Stančić, Ana",
year = "2022",
abstract = "The key pathological event in the development of diabetes is the loss of functional β-cells. We examined here so far unknown the contribution of ferroptosis to β-cell death in diabetic conditions in vivo and in vitro. Thus, male C57BL/6 mice were divided into three groups: diabetic, (strepozotocin-treated 40 mg/kg/5 days), diabetic+ferrostatin-1-treated (Fer-1, 1 mg/kg from day 1-21) and control, while Rin-5F were treated with diabetes-mimicking factors: high glucose (25mM), hydrogen peroxide (75 μM), or streptozotocin (10mM) for 12h. In diabetic mice a significant increase in macrophage infiltration and lipid peroxide accumulation in pancreatic islets, followed by a decrease in an insulin-positive cell population, expression of GPX4, cysteine/glutamate transporter xCT and heme oxygenase 1 were observed. Applied diabetes-mimicking conditions increased death of Rin-5f β-cells, accumulation of reactive oxygen species, lipid peroxides and iron along with a decrease in the activation of transcription factor Nrf2, expression of GPX4 and mitochondrial membrane potential. The use of ferroptosis inhibitor, Fer-1, completely reversed examined ferroptosis-related changes, i.e. had positive effects on both pancreatic islets of diabetic animals and in vitro β-cells. These results show that modulation, i.e. inhibition of ferroptosis in diabetes may be a promising new approach to conserving β-cell populations and treating diabetes.",
publisher = "Heidelberg: European Molecular Biology Organization (EMBO)",
journal = "EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13",
title = "Inhibition of ferroptosis increases the survival of β-cells",
pages = "52",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5265"
}

Otašević, V., Saksida, T., Markelić, M., Veličković, K., Grigorov, I.,& Stančić, A.. (2022). Inhibition of ferroptosis increases the survival of β-cells. in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13
Heidelberg: European Molecular Biology Organization (EMBO)., 52.
https://hdl.handle.net/21.15107/rcub_ibiss_5265

Otašević V, Saksida T, Markelić M, Veličković K, Grigorov I, Stančić A. Inhibition of ferroptosis increases the survival of β-cells. in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13. 2022;:52.
https://hdl.handle.net/21.15107/rcub_ibiss_5265 .

Otašević, Vesna, Saksida, Tamara, Markelić, Milica, Veličković, Ksenija, Grigorov, Ilijana, Stančić, Ana, "Inhibition of ferroptosis increases the survival of β-cells" in EMBO workshop: Thiol oxidation in biology: Biochemical mechanisms to physiological outcome; 2022 Oct 8-13 (2022):52,
https://hdl.handle.net/21.15107/rcub_ibiss_5265 .

TY  - CONF
AU  - Ivanović, Anđelija
AU  - Martinović, Vesna
AU  - Stančić, Ana
AU  - Otašević, Vesna
AU  - Savić, Nevena
AU  - Đurašević, Siniša
AU  - Grigorov, Ilijana
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5194
AB  - Повећан унос хранљивих материја са високим садржајем енергије сматра се новим еволутивним изазовом. Иако се ћелијски и молекуларни ефекти хранљивих материја интензивно испитују, недовољно је сазнања која се тичу утицаја прекомерно унетих шећера на активност молекула укључених у регулаторне процесе.1,2 Међу недовољно испитаним деловањем је молекуларни аспект укључивања глукозе у одржавање редокс равнотеже у ћелијама, са аспекта деловања редокс осетљивих регулаторних протеина активираних посредством АТP-а. Стога је циљ ове студије био да се у јетри пацова старости 3(3М), 8(8М) и 16(16М) месеци испитају старосно-зависни ефекти осмонедељне исхране са 20% и 60% раствором декстрозе на експресију и активност редокс-сензитивног фактора транскрипције Nrf2 одговорног за иницирање антиоксидативног одговора (АОО) преко модулације експресије/активности антиоксидативних ензима глутатион пероксидазе (GPx), хем-оксигеназе (HO1), каталазе (CAT) и глутатион С-трансферазе (GST). Повећање количине унете глукозе довело је до повећања нивоа ATP-a у јетри 3М и 8М пацова и смањења увећаног ATP нивоа код 16М. Сразмерно унетој количини глукозе, нивоу ATP-a, eкспресији GLUT2 и ATP-зависног P2X7 рецептора, сваку старосну групу карактерише селективна модулација активности GPx, CAT и GST, активација Nrf2 и експресија HO-1 и CAT. Резултати указују на специфичности коришћеног Wistar Hannover соја у старосно-зависном АОО и на активну улогу Nrf2 у адаптацији на глукозом измењен оксидативни статус у јетри.
AB  - Povećan unos hranljivih materija sa visokim sadržajem energije smatra se novim evolutivnim izazovom. Iako se ćelijski i molekularni efekti hranljivih materija intenzivno ispituju, nedovoljno je saznanja koja se tiču uticaja prekomerno unetih šećera na aktivnost molekula uključenih u regulatorne procese.1,2 Među nedovoljno ispitanim delovanjem je molekularni aspekt uključivanja glukoze u održavanje redoks ravnoteže u ćelijama, sa aspekta delovanja redoks osetljivih regulatornih proteina aktiviranih posredstvom ATP-a. Stoga je cilj ove studije bio da se u jetri pacova starosti 3(3M), 8(8M) i 16(16M) meseci ispitaju starosno-zavisni efekti osmonedeljne ishrane sa 20% i 60% rastvorom dekstroze na ekspresiju i aktivnost redoks-senzitivnog faktora transkripcije Nrf2 odgovornog za iniciranje antioksidativnog odgovora (AOO) preko modulacije ekspresije/aktivnosti antioksidativnih enzima glutation peroksidaze (GPx), hem-oksigenaze (HO1), katalaze (CAT) i glutation S-transferaze (GST). Povećanje količine unete glukoze dovelo je do povećanja nivoa ATP-a u jetri 3M i 8M pacova i smanjenja uvećanog ATP nivoa kod 16M. Srazmerno unetoj količini glukoze, nivou ATP-a, ekspresiji GLUT2 i ATP-zavisnog P2X7 receptora, svaku starosnu grupu karakteriše selektivna modulacija aktivnosti GPx, CAT i GST, aktivacija Nrf2 i ekspresija HO-1 i CAT. Rezultati ukazuju na specifičnosti korišćenog Wistar Hannover soja u starosno-zavisnom AOO i na aktivnu ulogu Nrf2 u adaptaciji na glukozom izmenjen oksidativni status u jetri.
PB  - Belgrade: Serbian Biological Society
C3  - Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
T1  - Утицај повећаног уноса глукозе на молекуларнe механизмe редокс-регулације у јетри пацова различите старосне доби
T1  - Uticaj povećanog unosa glukoze na molekularne mehanizme redoks-regulacije u jetri pacova različite starosne dobi
VL  - пп 297
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5194
ER  - 

@conference{
author = "Ivanović, Anđelija and Martinović, Vesna and Stančić, Ana and Otašević, Vesna and Savić, Nevena and Đurašević, Siniša and Grigorov, Ilijana",
year = "2022",
abstract = "Повећан унос хранљивих материја са високим садржајем енергије сматра се новим еволутивним изазовом. Иако се ћелијски и молекуларни ефекти хранљивих материја интензивно испитују, недовољно је сазнања која се тичу утицаја прекомерно унетих шећера на активност молекула укључених у регулаторне процесе.1,2 Међу недовољно испитаним деловањем је молекуларни аспект укључивања глукозе у одржавање редокс равнотеже у ћелијама, са аспекта деловања редокс осетљивих регулаторних протеина активираних посредством АТP-а. Стога је циљ ове студије био да се у јетри пацова старости 3(3М), 8(8М) и 16(16М) месеци испитају старосно-зависни ефекти осмонедељне исхране са 20% и 60% раствором декстрозе на експресију и активност редокс-сензитивног фактора транскрипције Nrf2 одговорног за иницирање антиоксидативног одговора (АОО) преко модулације експресије/активности антиоксидативних ензима глутатион пероксидазе (GPx), хем-оксигеназе (HO1), каталазе (CAT) и глутатион С-трансферазе (GST). Повећање количине унете глукозе довело је до повећања нивоа ATP-a у јетри 3М и 8М пацова и смањења увећаног ATP нивоа код 16М. Сразмерно унетој количини глукозе, нивоу ATP-a, eкспресији GLUT2 и ATP-зависног P2X7 рецептора, сваку старосну групу карактерише селективна модулација активности GPx, CAT и GST, активација Nrf2 и експресија HO-1 и CAT. Резултати указују на специфичности коришћеног Wistar Hannover соја у старосно-зависном АОО и на активну улогу Nrf2 у адаптацији на глукозом измењен оксидативни статус у јетри., Povećan unos hranljivih materija sa visokim sadržajem energije smatra se novim evolutivnim izazovom. Iako se ćelijski i molekularni efekti hranljivih materija intenzivno ispituju, nedovoljno je saznanja koja se tiču uticaja prekomerno unetih šećera na aktivnost molekula uključenih u regulatorne procese.1,2 Među nedovoljno ispitanim delovanjem je molekularni aspekt uključivanja glukoze u održavanje redoks ravnoteže u ćelijama, sa aspekta delovanja redoks osetljivih regulatornih proteina aktiviranih posredstvom ATP-a. Stoga je cilj ove studije bio da se u jetri pacova starosti 3(3M), 8(8M) i 16(16M) meseci ispitaju starosno-zavisni efekti osmonedeljne ishrane sa 20% i 60% rastvorom dekstroze na ekspresiju i aktivnost redoks-senzitivnog faktora transkripcije Nrf2 odgovornog za iniciranje antioksidativnog odgovora (AOO) preko modulacije ekspresije/aktivnosti antioksidativnih enzima glutation peroksidaze (GPx), hem-oksigenaze (HO1), katalaze (CAT) i glutation S-transferaze (GST). Povećanje količine unete glukoze dovelo je do povećanja nivoa ATP-a u jetri 3M i 8M pacova i smanjenja uvećanog ATP nivoa kod 16M. Srazmerno unetoj količini glukoze, nivou ATP-a, ekspresiji GLUT2 i ATP-zavisnog P2X7 receptora, svaku starosnu grupu karakteriše selektivna modulacija aktivnosti GPx, CAT i GST, aktivacija Nrf2 i ekspresija HO-1 i CAT. Rezultati ukazuju na specifičnosti korišćenog Wistar Hannover soja u starosno-zavisnom AOO i na aktivnu ulogu Nrf2 u adaptaciji na glukozom izmenjen oksidativni status u jetri.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia",
title = "Утицај повећаног уноса глукозе на молекуларнe механизмe редокс-регулације у јетри пацова различите старосне доби, Uticaj povećanog unosa glukoze na molekularne mehanizme redoks-regulacije u jetri pacova različite starosne dobi",
volume = "пп 297",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5194"
}

Ivanović, A., Martinović, V., Stančić, A., Otašević, V., Savić, N., Đurašević, S.,& Grigorov, I.. (2022). Утицај повећаног уноса глукозе на молекуларнe механизмe редокс-регулације у јетри пацова различите старосне доби. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society., пп 297.
https://hdl.handle.net/21.15107/rcub_ibiss_5194

Ivanović A, Martinović V, Stančić A, Otašević V, Savić N, Đurašević S, Grigorov I. Утицај повећаног уноса глукозе на молекуларнe механизмe редокс-регулације у јетри пацова различите старосне доби. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;пп 297.
https://hdl.handle.net/21.15107/rcub_ibiss_5194 .

Ivanović, Anđelija, Martinović, Vesna, Stančić, Ana, Otašević, Vesna, Savić, Nevena, Đurašević, Siniša, Grigorov, Ilijana, "Утицај повећаног уноса глукозе на молекуларнe механизмe редокс-регулације у јетри пацова различите старосне доби" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia, пп 297 (2022),
https://hdl.handle.net/21.15107/rcub_ibiss_5194 .

TY  - JOUR
AU  - Korać, Aleksandra
AU  - Srdić-Galić, Biljana
AU  - Stančić, Ana
AU  - Otašević, Vesna
AU  - Korać, Bato
AU  - Janković, Aleksandra
PY  - 2021
UR  - https://doi.org/10.5114/aoms/92118
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4197
AB  - Introduction: Metabolic syndrome arises from abnormal adipose function accompanied by insulin resistance. As early factors reflecting/impacting lip-id storage dysfunction of adipose tissues, we sought to determine adipokine levels in subcutaneous and visceral adipose tissues (SAT and VAT). Material and methods: Gene and protein expression levels of leptin, adi-ponectin, and resistin were analysed in SAT and VAT of normal-weight and overweight/obese women, subclassified according to insulin resistance index, triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels into metabolically healthy and "at risk" groups. Results: Compared with normal-weight women, obese women had higher serum leptin levels (p < 0.05), as well as increased leptin gene and protein expression in VAT. Conversely, expression levels of leptin were lower in SAT of obese women, and minor in the SAT of "at risk" groups of women, compared with weight-matched healthy groups. In addition, lower adiponectin levels were detected in SAT of metabolically healthy obese women (p < 0.01), and lower in SAT and VAT (p < 0.05) of "at risk" obese women compared to healthy, obese women. Significant differences in resistin levels were only observed in obese women; resistin gene expression was higher in VAT and SAT of obese, compared to normal-weight women. However, higher gene expression was not consistent with protein expression of resistin. Conclusions: Low adiponectin in both examined adipose tissues and inappropriate leptin expression levels in SAT appear to be important characteristics of obesity-related metabolic syndrome. Intriguingly, this adipokine dysregulation is primary seen in SAT, suggesting that endocrine dysfunction in this abdominal depot may be an early risk sign of metabolic syndrome.
PB  - Termedia Sp. z.o.o.
T2  - Archives of Medical Science
T1  - Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles
IS  - 2
VL  - 17
DO  - 10.5114/aoms/92118
SP  - 323
EP  - 336
ER  - 

@article{
author = "Korać, Aleksandra and Srdić-Galić, Biljana and Stančić, Ana and Otašević, Vesna and Korać, Bato and Janković, Aleksandra",
year = "2021",
abstract = "Introduction: Metabolic syndrome arises from abnormal adipose function accompanied by insulin resistance. As early factors reflecting/impacting lip-id storage dysfunction of adipose tissues, we sought to determine adipokine levels in subcutaneous and visceral adipose tissues (SAT and VAT). Material and methods: Gene and protein expression levels of leptin, adi-ponectin, and resistin were analysed in SAT and VAT of normal-weight and overweight/obese women, subclassified according to insulin resistance index, triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels into metabolically healthy and "at risk" groups. Results: Compared with normal-weight women, obese women had higher serum leptin levels (p < 0.05), as well as increased leptin gene and protein expression in VAT. Conversely, expression levels of leptin were lower in SAT of obese women, and minor in the SAT of "at risk" groups of women, compared with weight-matched healthy groups. In addition, lower adiponectin levels were detected in SAT of metabolically healthy obese women (p < 0.01), and lower in SAT and VAT (p < 0.05) of "at risk" obese women compared to healthy, obese women. Significant differences in resistin levels were only observed in obese women; resistin gene expression was higher in VAT and SAT of obese, compared to normal-weight women. However, higher gene expression was not consistent with protein expression of resistin. Conclusions: Low adiponectin in both examined adipose tissues and inappropriate leptin expression levels in SAT appear to be important characteristics of obesity-related metabolic syndrome. Intriguingly, this adipokine dysregulation is primary seen in SAT, suggesting that endocrine dysfunction in this abdominal depot may be an early risk sign of metabolic syndrome.",
publisher = "Termedia Sp. z.o.o.",
journal = "Archives of Medical Science",
title = "Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles",
number = "2",
volume = "17",
doi = "10.5114/aoms/92118",
pages = "323-336"
}

Korać, A., Srdić-Galić, B., Stančić, A., Otašević, V., Korać, B.,& Janković, A.. (2021). Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles. in Archives of Medical Science
Termedia Sp. z.o.o.., 17(2), 323-336.
https://doi.org/10.5114/aoms/92118

Korać A, Srdić-Galić B, Stančić A, Otašević V, Korać B, Janković A. Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles. in Archives of Medical Science. 2021;17(2):323-336.
doi:10.5114/aoms/92118 .

Korać, Aleksandra, Srdić-Galić, Biljana, Stančić, Ana, Otašević, Vesna, Korać, Bato, Janković, Aleksandra, "Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles" in Archives of Medical Science, 17, no. 2 (2021):323-336,
https://doi.org/10.5114/aoms/92118 . .

TY  - JOUR
AU  - Otašević, Vesna
AU  - Vučetić, M.
AU  - Grigorov, Ilijana
AU  - Martinović, Vesna
AU  - Stančić, Ana
PY  - 2021
UR  - https://www.hindawi.com/journals/omcl/2021/5537330/
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4417
AB  - Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
T2  - Oxidative Medicine and Cellular Longevity
T1  - Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria
VL  - 2021
DO  - 10.1155/2021/5537330
SP  - 1
EP  - 16
ER  - 

@article{
author = "Otašević, Vesna and Vučetić, M. and Grigorov, Ilijana and Martinović, Vesna and Stančić, Ana",
year = "2021",
abstract = "Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.",
journal = "Oxidative Medicine and Cellular Longevity",
title = "Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria",
volume = "2021",
doi = "10.1155/2021/5537330",
pages = "1-16"
}

Otašević, V., Vučetić, M., Grigorov, I., Martinović, V.,& Stančić, A.. (2021). Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria. in Oxidative Medicine and Cellular Longevity, 2021, 1-16.
https://doi.org/10.1155/2021/5537330

Otašević V, Vučetić M, Grigorov I, Martinović V, Stančić A. Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria. in Oxidative Medicine and Cellular Longevity. 2021;2021:1-16.
doi:10.1155/2021/5537330 .

Otašević, Vesna, Vučetić, M., Grigorov, Ilijana, Martinović, Vesna, Stančić, Ana, "Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria" in Oxidative Medicine and Cellular Longevity, 2021 (2021):1-16,
https://doi.org/10.1155/2021/5537330 . .

TY  - CONF
AU  - Stančić, Ana
AU  - Saksida, Tamara
AU  - Markelić, Milica
AU  - Vučetić, Milica
AU  - Grigorov, Ilijana
AU  - Martinović, Vesna
AU  - Ivanović, Anđelija
AU  - Veličković, Ksenija
AU  - Otašević, Vesna
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4899
AB  - Diabetes is a complex metabolic disorder which incidence rises in the epidemic fashion, suggesting the urgent need for new therapies. Its main pathological hallmark is loss of functional β-cells, and to date, several types of β-cell death have been described – necrosis, apoptosis, and autophagy. However, the role of ferroptosis in reducing β-cell population in diabetes remains elusive. In this study we aimed to examine whether and how this type of cell death is implicated in regulation of β-cell destiny in diabetes. For that purpose, Rin-5F insulin-producing pancreatic cells were treated with diabetes-mimicking factors – high glucose (HG) and H2O2, as well with commonly used diabetogenic agent streptozotocin (STZ). Results showed that HG, H2O2 and STZ induce the death of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron; inactivation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and decrease in glutathione peroxidase 4 expression. This is consistent with the effect of the treatment with RSL-3, a well-known inducer of ferroptosis. Ferrostatin-1, a ferroptosis inhibitor, diminished above-stated effects and rescued cells from death. Our data revealed that β-cells underwent ferroptotic cell death under diabetogenic conditions. Results also implicate HG and H2O2 as contributing factors to ferroptosis of β-cells and suggest the novel mechanism of STZ diabetogenic action. Furthermore, the results shed a new light on antidiabetic strategy based on Nrf2 activation, putting it into the anti-ferroptotic context. In close, targeting ferroptosis in diabetes might be a new promising therapeutic approach based on preservation of β-cell population.
PB  - Belgrade: Faculty of Chemistry: Serbian Biochemical Society
C3  - Serbian Biochemical Society Tenth Conference: with international participation: Biochemical Insights into Molecular Mechanisms; 2021 Sep 24; Kragujevac, Serbia
T1  - Ferroptosis as a novel determinant of β-cell death in diabetic conditions
SP  - 146
EP  - 147
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4899
ER  - 

@conference{
author = "Stančić, Ana and Saksida, Tamara and Markelić, Milica and Vučetić, Milica and Grigorov, Ilijana and Martinović, Vesna and Ivanović, Anđelija and Veličković, Ksenija and Otašević, Vesna",
year = "2021",
abstract = "Diabetes is a complex metabolic disorder which incidence rises in the epidemic fashion, suggesting the urgent need for new therapies. Its main pathological hallmark is loss of functional β-cells, and to date, several types of β-cell death have been described – necrosis, apoptosis, and autophagy. However, the role of ferroptosis in reducing β-cell population in diabetes remains elusive. In this study we aimed to examine whether and how this type of cell death is implicated in regulation of β-cell destiny in diabetes. For that purpose, Rin-5F insulin-producing pancreatic cells were treated with diabetes-mimicking factors – high glucose (HG) and H2O2, as well with commonly used diabetogenic agent streptozotocin (STZ). Results showed that HG, H2O2 and STZ induce the death of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron; inactivation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and decrease in glutathione peroxidase 4 expression. This is consistent with the effect of the treatment with RSL-3, a well-known inducer of ferroptosis. Ferrostatin-1, a ferroptosis inhibitor, diminished above-stated effects and rescued cells from death. Our data revealed that β-cells underwent ferroptotic cell death under diabetogenic conditions. Results also implicate HG and H2O2 as contributing factors to ferroptosis of β-cells and suggest the novel mechanism of STZ diabetogenic action. Furthermore, the results shed a new light on antidiabetic strategy based on Nrf2 activation, putting it into the anti-ferroptotic context. In close, targeting ferroptosis in diabetes might be a new promising therapeutic approach based on preservation of β-cell population.",
publisher = "Belgrade: Faculty of Chemistry: Serbian Biochemical Society",
journal = "Serbian Biochemical Society Tenth Conference: with international participation: Biochemical Insights into Molecular Mechanisms; 2021 Sep 24; Kragujevac, Serbia",
title = "Ferroptosis as a novel determinant of β-cell death in diabetic conditions",
pages = "146-147",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4899"
}

Stančić, A., Saksida, T., Markelić, M., Vučetić, M., Grigorov, I., Martinović, V., Ivanović, A., Veličković, K.,& Otašević, V.. (2021). Ferroptosis as a novel determinant of β-cell death in diabetic conditions. in Serbian Biochemical Society Tenth Conference: with international participation: Biochemical Insights into Molecular Mechanisms; 2021 Sep 24; Kragujevac, Serbia
Belgrade: Faculty of Chemistry: Serbian Biochemical Society., 146-147.
https://hdl.handle.net/21.15107/rcub_ibiss_4899

Stančić A, Saksida T, Markelić M, Vučetić M, Grigorov I, Martinović V, Ivanović A, Veličković K, Otašević V. Ferroptosis as a novel determinant of β-cell death in diabetic conditions. in Serbian Biochemical Society Tenth Conference: with international participation: Biochemical Insights into Molecular Mechanisms; 2021 Sep 24; Kragujevac, Serbia. 2021;:146-147.
https://hdl.handle.net/21.15107/rcub_ibiss_4899 .

Stančić, Ana, Saksida, Tamara, Markelić, Milica, Vučetić, Milica, Grigorov, Ilijana, Martinović, Vesna, Ivanović, Anđelija, Veličković, Ksenija, Otašević, Vesna, "Ferroptosis as a novel determinant of β-cell death in diabetic conditions" in Serbian Biochemical Society Tenth Conference: with international participation: Biochemical Insights into Molecular Mechanisms; 2021 Sep 24; Kragujevac, Serbia (2021):146-147,
https://hdl.handle.net/21.15107/rcub_ibiss_4899 .

TY  - CONF
AU  - Markelić, Milica
AU  - Stančić, Ana
AU  - Saksida, Tamara
AU  - Vučetić, Milica
AU  - Grigorov, Ilijana
AU  - Martinović, Vesna
AU  - Veličković, Ksenija
AU  - Otašević, Vesna
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4897
AB  - Feroptosis is a recently described, programmed form of cell death. It is iron-dependant and characterized by the accumulation of lipid peroxides and reactive species. The main pathological hallmark of diabetes is -cell loss, and so far, several types of -cell death have been described. However, involvement of ferroptosis in -cell loss induced by diabetogenic factors is still unexplored.
The aim of this study was to investigate potential involvement of ferroptosis in the regulation of -cell loss in diabetes.For that purpose Rin-5F pancreatic -cells were treated with well-known diabetes-mimicking agents: high glucose (HG; 25 mM), hydrogen peroxide (H2O2; 75 μM) and streptozotocin (STZ; 10 mM) ) for 12h in the absence or presence of ferrostosis inhibitor, ferrostatin-1 (Fer-1, 1.5 μM). As a positive control, an inducer of ferroptosis RSL3 (3 μM) was used. Cells were prepared for flow citometry (death cell assay propidium iodide (PI) staining; dihydrorhodamine 123 (DHR) reactive oxygen species (ROS) detection) and microscopic analyses (phase contrast analysis of cells viability, morphology and cell confluence; Sudan III detection of neutral lipids and lipofuscin; Prussian blue detection of intracellular iron accumulation; C11-BODIPY detection of lipid peroxides and immunofluorescence detection of phospho-NFE2-related factor 2 (pNrf2)).Our results demonstrated that mimicking diabetic microenvironment by HG, STZ and H2O2 induced ferroptosis of -cells in vitro (Fig. 1), since observed alterations were similar to those induced by RSL3. As we observed microscopically, total cell number decreased, percentage of dead PI+ cells increased and cell changed their morphology from typical to spherical and detached. In addition, increased accumulation of lipid peroxides, ROS, lipids and/or lipofuscin and iron were observed after these treatments. Fer-1 rescued cells from death after all treatments, along with abolishing the effects of those treatments on ROS, lipid peroxides and iron content. Further, Fer-1-induced activation of Nrf2, which is well known as an antioxidant transcriptional factor that regulates level of many of the ferroptosis-related molecules including those involved in metabolism of GSH, iron and lipids. Taken together, our results demonstrated ferroptosis involvement in the -cell loss under diabetogenic conditions, thus proposing it as a new potential target in the diabetes therapy approach.
C3  - MC 2021 goes digital Microscopy Conference Proceedings; 2021 Aug 22-26; Online
T1  - Microscopic study of ferroptotic death of β-cells in diabetogenic conditions in vitro
SP  - 641
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4897
ER  - 

@conference{
author = "Markelić, Milica and Stančić, Ana and Saksida, Tamara and Vučetić, Milica and Grigorov, Ilijana and Martinović, Vesna and Veličković, Ksenija and Otašević, Vesna",
year = "2021",
abstract = "Feroptosis is a recently described, programmed form of cell death. It is iron-dependant and characterized by the accumulation of lipid peroxides and reactive species. The main pathological hallmark of diabetes is -cell loss, and so far, several types of -cell death have been described. However, involvement of ferroptosis in -cell loss induced by diabetogenic factors is still unexplored.
The aim of this study was to investigate potential involvement of ferroptosis in the regulation of -cell loss in diabetes.For that purpose Rin-5F pancreatic -cells were treated with well-known diabetes-mimicking agents: high glucose (HG; 25 mM), hydrogen peroxide (H2O2; 75 μM) and streptozotocin (STZ; 10 mM) ) for 12h in the absence or presence of ferrostosis inhibitor, ferrostatin-1 (Fer-1, 1.5 μM). As a positive control, an inducer of ferroptosis RSL3 (3 μM) was used. Cells were prepared for flow citometry (death cell assay propidium iodide (PI) staining; dihydrorhodamine 123 (DHR) reactive oxygen species (ROS) detection) and microscopic analyses (phase contrast analysis of cells viability, morphology and cell confluence; Sudan III detection of neutral lipids and lipofuscin; Prussian blue detection of intracellular iron accumulation; C11-BODIPY detection of lipid peroxides and immunofluorescence detection of phospho-NFE2-related factor 2 (pNrf2)).Our results demonstrated that mimicking diabetic microenvironment by HG, STZ and H2O2 induced ferroptosis of -cells in vitro (Fig. 1), since observed alterations were similar to those induced by RSL3. As we observed microscopically, total cell number decreased, percentage of dead PI+ cells increased and cell changed their morphology from typical to spherical and detached. In addition, increased accumulation of lipid peroxides, ROS, lipids and/or lipofuscin and iron were observed after these treatments. Fer-1 rescued cells from death after all treatments, along with abolishing the effects of those treatments on ROS, lipid peroxides and iron content. Further, Fer-1-induced activation of Nrf2, which is well known as an antioxidant transcriptional factor that regulates level of many of the ferroptosis-related molecules including those involved in metabolism of GSH, iron and lipids. Taken together, our results demonstrated ferroptosis involvement in the -cell loss under diabetogenic conditions, thus proposing it as a new potential target in the diabetes therapy approach.",
journal = "MC 2021 goes digital Microscopy Conference Proceedings; 2021 Aug 22-26; Online",
title = "Microscopic study of ferroptotic death of β-cells in diabetogenic conditions in vitro",
pages = "641",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4897"
}

Markelić, M., Stančić, A., Saksida, T., Vučetić, M., Grigorov, I., Martinović, V., Veličković, K.,& Otašević, V.. (2021). Microscopic study of ferroptotic death of β-cells in diabetogenic conditions in vitro. in MC 2021 goes digital Microscopy Conference Proceedings; 2021 Aug 22-26; Online, 641.
https://hdl.handle.net/21.15107/rcub_ibiss_4897

Markelić M, Stančić A, Saksida T, Vučetić M, Grigorov I, Martinović V, Veličković K, Otašević V. Microscopic study of ferroptotic death of β-cells in diabetogenic conditions in vitro. in MC 2021 goes digital Microscopy Conference Proceedings; 2021 Aug 22-26; Online. 2021;:641.
https://hdl.handle.net/21.15107/rcub_ibiss_4897 .

Markelić, Milica, Stančić, Ana, Saksida, Tamara, Vučetić, Milica, Grigorov, Ilijana, Martinović, Vesna, Veličković, Ksenija, Otašević, Vesna, "Microscopic study of ferroptotic death of β-cells in diabetogenic conditions in vitro" in MC 2021 goes digital Microscopy Conference Proceedings; 2021 Aug 22-26; Online (2021):641,
https://hdl.handle.net/21.15107/rcub_ibiss_4897 .

TY  - JOUR
AU  - Martinović, Vesna
AU  - Arambašić Jovanović, Jelena
AU  - Bogojević, Desanka
AU  - Ivanović, Anđelija
AU  - Otašević, Vesna
AU  - Stančić, Ana
AU  - Grigorov, Ilijana
PY  - 2020
UR  - http://www.doiserbia.nb.rs/Article.aspx?ID=0354-46642000049M
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4103
UR  - http://www.serbiosoc.org.rs/arch/index.php/abs/article/view/5980
AB  - Haptoglobin (Hp) is a hemoglobin-binding protein that prevents free hemoglobin-induced tissue oxidative damage. In streptozotocin-induced diabetic rats, the initial elevation of Hp expression in the serum and liver tends to decrease with diabetes progression, contributing to increased oxidative stress. Glucose toxicity and diabetic complications are closely related to increased modification of nucleocytoplasmic proteins by O-linked-N-acetylglucosamine (O-GlcNAc). We examined the contribution of O-GlcNAcylation of NF-κB p65 to changes in liver Hp expression in diabetic rats. WGA-affinity chromatography revealed a progressive increase in O-GlcNAcylation in nuclear NF-κB p65 during eight weeks of diabetes. DNA-affinity chromatography followed by immunoblot analysis revealed that decreased Hp expression at 4 and 8 weeks of diabetes was accompanied by the absence of Hp gene hormone-responsive element (HRE) occupancy with NF-κB p65, low occupancy with glucocorticoid receptor (GR), and almost no changes in STAT3 occupancy compared to 2 weeks, when Hp expression was highest. Coimmunoprecipitation experiments indicate that these events were the result of impaired NF-κB p65/STAT3 and GR/STAT3 interactions. Results suggest that the attenuation of Hp expression associated with diabetes was at least in part the result of O-GlcNAcylation of NF-κB p65, which prevents the formation of an effective transcription initiation complex on the Hp gene promoter.
PB  - Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver
T2  - Archives of Biological Sciences
T1  - Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver
IS  - 4
VL  - 72
DO  - 10.2298/ABS200928049M
SP  - 555
EP  - 565
ER  - 

@article{
author = "Martinović, Vesna and Arambašić Jovanović, Jelena and Bogojević, Desanka and Ivanović, Anđelija and Otašević, Vesna and Stančić, Ana and Grigorov, Ilijana",
year = "2020",
abstract = "Haptoglobin (Hp) is a hemoglobin-binding protein that prevents free hemoglobin-induced tissue oxidative damage. In streptozotocin-induced diabetic rats, the initial elevation of Hp expression in the serum and liver tends to decrease with diabetes progression, contributing to increased oxidative stress. Glucose toxicity and diabetic complications are closely related to increased modification of nucleocytoplasmic proteins by O-linked-N-acetylglucosamine (O-GlcNAc). We examined the contribution of O-GlcNAcylation of NF-κB p65 to changes in liver Hp expression in diabetic rats. WGA-affinity chromatography revealed a progressive increase in O-GlcNAcylation in nuclear NF-κB p65 during eight weeks of diabetes. DNA-affinity chromatography followed by immunoblot analysis revealed that decreased Hp expression at 4 and 8 weeks of diabetes was accompanied by the absence of Hp gene hormone-responsive element (HRE) occupancy with NF-κB p65, low occupancy with glucocorticoid receptor (GR), and almost no changes in STAT3 occupancy compared to 2 weeks, when Hp expression was highest. Coimmunoprecipitation experiments indicate that these events were the result of impaired NF-κB p65/STAT3 and GR/STAT3 interactions. Results suggest that the attenuation of Hp expression associated with diabetes was at least in part the result of O-GlcNAcylation of NF-κB p65, which prevents the formation of an effective transcription initiation complex on the Hp gene promoter.",
publisher = "Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver",
journal = "Archives of Biological Sciences",
title = "Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver",
number = "4",
volume = "72",
doi = "10.2298/ABS200928049M",
pages = "555-565"
}

Martinović, V., Arambašić Jovanović, J., Bogojević, D., Ivanović, A., Otašević, V., Stančić, A.,& Grigorov, I.. (2020). Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver. in Archives of Biological Sciences
Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver., 72(4), 555-565.
https://doi.org/10.2298/ABS200928049M

Martinović V, Arambašić Jovanović J, Bogojević D, Ivanović A, Otašević V, Stančić A, Grigorov I. Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver. in Archives of Biological Sciences. 2020;72(4):555-565.
doi:10.2298/ABS200928049M .

Martinović, Vesna, Arambašić Jovanović, Jelena, Bogojević, Desanka, Ivanović, Anđelija, Otašević, Vesna, Stančić, Ana, Grigorov, Ilijana, "Contribution of O-GlcNAc modification of NF-κB p65 in the attenuation of diabetes-induced haptoglobin expression in rat liver" in Archives of Biological Sciences, 72, no. 4 (2020):555-565,
https://doi.org/10.2298/ABS200928049M . .