TY  - JOUR
AU  - Božić, Iva
AU  - Lavrnja, Irena
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6369
AB  - Thiamine, also known as vitamin B1, is an essential nutrient that plays a crucial role in energy
metabolism and overall health. It is a water-soluble vitamin that plays an important role in the
conversion of carbohydrates into energy in the body. Thiamine is essential for the proper functioning of the nervous system, heart and muscles. Thiamine deficiency is a life-threatening disease
that leads to various disorders and lesions in the nerves and brain, at least in vertebrates. Several
thiamine precursors with higher bioavailability have been developed to compensate for thiamine
deficiency, including benfotiamine. Benfotiamine is more bioavailable and has higher tissue
penetration than thiamine. Studies have shown its antioxidant and anti-inflammatory potential in
activated immune and glial cells. It also improves complications observed in type 2 diabetes and
has beneficial effects in mouse models of neurodegenerative disease. Benfotiamine represents an
off-the-shelf agent used to support nerve health, promote healthy aging and support glucose
metabolism. Accordingly, the present review aimed to provide an overview of the neuroprotective
effects of thiamine/benfotiamine in the context of inflammation and oxidative stress.
PB  - Elsevier
T2  - Heliyon
T1  - Thiamine and benfotiamine: Focus on their therapeutic potential
IS  - 11
VL  - 9
DO  - 10.1016/j.heliyon.2023.e21839
SP  - e21839
ER  - 

@article{
author = "Božić, Iva and Lavrnja, Irena",
year = "2023",
abstract = "Thiamine, also known as vitamin B1, is an essential nutrient that plays a crucial role in energy
metabolism and overall health. It is a water-soluble vitamin that plays an important role in the
conversion of carbohydrates into energy in the body. Thiamine is essential for the proper functioning of the nervous system, heart and muscles. Thiamine deficiency is a life-threatening disease
that leads to various disorders and lesions in the nerves and brain, at least in vertebrates. Several
thiamine precursors with higher bioavailability have been developed to compensate for thiamine
deficiency, including benfotiamine. Benfotiamine is more bioavailable and has higher tissue
penetration than thiamine. Studies have shown its antioxidant and anti-inflammatory potential in
activated immune and glial cells. It also improves complications observed in type 2 diabetes and
has beneficial effects in mouse models of neurodegenerative disease. Benfotiamine represents an
off-the-shelf agent used to support nerve health, promote healthy aging and support glucose
metabolism. Accordingly, the present review aimed to provide an overview of the neuroprotective
effects of thiamine/benfotiamine in the context of inflammation and oxidative stress.",
publisher = "Elsevier",
journal = "Heliyon",
title = "Thiamine and benfotiamine: Focus on their therapeutic potential",
number = "11",
volume = "9",
doi = "10.1016/j.heliyon.2023.e21839",
pages = "e21839"
}

Božić, I.,& Lavrnja, I.. (2023). Thiamine and benfotiamine: Focus on their therapeutic potential. in Heliyon
Elsevier., 9(11), e21839.
https://doi.org/10.1016/j.heliyon.2023.e21839

Božić I, Lavrnja I. Thiamine and benfotiamine: Focus on their therapeutic potential. in Heliyon. 2023;9(11):e21839.
doi:10.1016/j.heliyon.2023.e21839 .

Božić, Iva, Lavrnja, Irena, "Thiamine and benfotiamine: Focus on their therapeutic potential" in Heliyon, 9, no. 11 (2023):e21839,
https://doi.org/10.1016/j.heliyon.2023.e21839 . .

TY  - CONF
AU  - Milošević, Katarina
AU  - Milošević, Ana
AU  - Živković, Anica
AU  - Stevanović, Ivana
AU  - Laketa, Danijela
AU  - Božić, Iva
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5875
AB  - Oxidative burst is a component of neuroinflammation whereby microglia-generated reactive oxygen species (ROS) either target pathogens or act as secondary messengers for microglial activation. In response to increased ROS during microglial activation, cytoprotective mechanisms are initiated primarily via Nrf2 activation and HO-1 expression. Agmatine is known to exert neuroprotective effect in vivo due to Nrf2 induction. While agmatine has been shown to activate the Nrf2/HO-1 signaling and protect macrophages from Lps-induced inflammation in vitro, its interaction with this pathway in activated microglia remains unexplored. Therefore, we sought to examine the potential of 100 μM agmatine as a pretreatment of Lps to activate Nrf2 in BV-2 microglia. In addition to cell viability, we analyzed the nuclear level of Nrf2 by Western blot and the expression of Hmox1 by PCR, as well as the protein level of HO-1. We also measured indicators of prooxidant and antioxidant activity: 4-HNE and total glutathione, respectively. Agmatine induces oxidative stress in non-stimulated microglia, as confirmed by the increase in the lipid peroxidation marker — 4-HNE, while cell viability stays preserved. Moreover, agmatine alone causes delayed Nrf2 nuclear overexpression and an increase in total glutathione content, eventually leading to an adaptive stress response. On the other hand, in Lps-stimulated microglia, agmatine prevents lipid peroxidation, readily upregulates the nuclear protein levels of Nrf2, which increases gene and protein expression of HO-1, and maintains delayed Nrf2 nuclear overexpression, resulting in increased total glutathione content associated with cytoprotection. Overall, we interpret agmatine-induced oxidative stress in non-activated microglia as triggering the adaptive response via Nrf2 and total glutathione, enabling them to cope with subsequent stressors, ie, Lps.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia
SP  - 106
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5875
ER  - 

@conference{
author = "Milošević, Katarina and Milošević, Ana and Živković, Anica and Stevanović, Ivana and Laketa, Danijela and Božić, Iva and Janjić, Marija and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2023",
abstract = "Oxidative burst is a component of neuroinflammation whereby microglia-generated reactive oxygen species (ROS) either target pathogens or act as secondary messengers for microglial activation. In response to increased ROS during microglial activation, cytoprotective mechanisms are initiated primarily via Nrf2 activation and HO-1 expression. Agmatine is known to exert neuroprotective effect in vivo due to Nrf2 induction. While agmatine has been shown to activate the Nrf2/HO-1 signaling and protect macrophages from Lps-induced inflammation in vitro, its interaction with this pathway in activated microglia remains unexplored. Therefore, we sought to examine the potential of 100 μM agmatine as a pretreatment of Lps to activate Nrf2 in BV-2 microglia. In addition to cell viability, we analyzed the nuclear level of Nrf2 by Western blot and the expression of Hmox1 by PCR, as well as the protein level of HO-1. We also measured indicators of prooxidant and antioxidant activity: 4-HNE and total glutathione, respectively. Agmatine induces oxidative stress in non-stimulated microglia, as confirmed by the increase in the lipid peroxidation marker — 4-HNE, while cell viability stays preserved. Moreover, agmatine alone causes delayed Nrf2 nuclear overexpression and an increase in total glutathione content, eventually leading to an adaptive stress response. On the other hand, in Lps-stimulated microglia, agmatine prevents lipid peroxidation, readily upregulates the nuclear protein levels of Nrf2, which increases gene and protein expression of HO-1, and maintains delayed Nrf2 nuclear overexpression, resulting in increased total glutathione content associated with cytoprotection. Overall, we interpret agmatine-induced oxidative stress in non-activated microglia as triggering the adaptive response via Nrf2 and total glutathione, enabling them to cope with subsequent stressors, ie, Lps.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia",
pages = "106",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5875"
}

Milošević, K., Milošević, A., Živković, A., Stevanović, I., Laketa, D., Božić, I., Janjić, M., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2023). Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 106.
https://hdl.handle.net/21.15107/rcub_ibiss_5875

Milošević K, Milošević A, Živković A, Stevanović I, Laketa D, Božić I, Janjić M, Bjelobaba I, Lavrnja I, Savić D. Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:106.
https://hdl.handle.net/21.15107/rcub_ibiss_5875 .

Milošević, Katarina, Milošević, Ana, Živković, Anica, Stevanović, Ivana, Laketa, Danijela, Božić, Iva, Janjić, Marija, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):106,
https://hdl.handle.net/21.15107/rcub_ibiss_5875 .

TY  - CONF
AU  - Živković, Anica
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Milošević, Katarina
AU  - Božić, Iva
AU  - Trifunović, Svetlana
AU  - Savić, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5859
AB  - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous
system (CNS) that leads to severe neurological deficits. In past decades, numerous
studies have observed that anterior pituitary hormones play a pivotal role in regulation
of physiological immune response, as well as development and course of autoimmune
diseases.
Specifically, growth hormone (GH) and prolactin (PRL), peptide hormones
synthesized and secreted by the anterior pituitary, have been implicated in regulating
the immune system. Growth hormone secretion is positively regulated by the
hypothalamic growth hormone-releasing hormone (GHRH), while somatostatin (SST)
inhibits the release of GH.
Previous studies demonstrated that GHRH and GH are implicated in development of
experimental autoimmune encephalomyelitis (EAE), a representative animal model of
MS. Significantly higher PRL serum levels in MS patients were also reported.
We investigated spatiotemporal differences in GH and PRL levels in pituitaries from
EAE animals. Using immunolabeling and stereological methods we evaluated changes
in volume density of GH- and PRL-positive cells in pituitary gland of animals with
EAE compared to healthy controls. As we determined that there is no change in cell
volume density, we checked if there are any changes in gene expression of PRL, GH,
as well as GHRH and SST. Growth hormone and prolactin protein expression was
also measured in anterior pituitary. Our results show that, in addition to GH- and
PRL-positive cells volume density, there are no significant changes in gene and
protein expression in anterior pituitary during EAE.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats
SP  - 105
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5859
ER  - 

@conference{
author = "Živković, Anica and Milošević, Ana and Janjić, Marija and Milošević, Katarina and Božić, Iva and Trifunović, Svetlana and Savić, Danijela and Bjelobaba, Ivana and Lavrnja, Irena",
year = "2023",
abstract = "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous
system (CNS) that leads to severe neurological deficits. In past decades, numerous
studies have observed that anterior pituitary hormones play a pivotal role in regulation
of physiological immune response, as well as development and course of autoimmune
diseases.
Specifically, growth hormone (GH) and prolactin (PRL), peptide hormones
synthesized and secreted by the anterior pituitary, have been implicated in regulating
the immune system. Growth hormone secretion is positively regulated by the
hypothalamic growth hormone-releasing hormone (GHRH), while somatostatin (SST)
inhibits the release of GH.
Previous studies demonstrated that GHRH and GH are implicated in development of
experimental autoimmune encephalomyelitis (EAE), a representative animal model of
MS. Significantly higher PRL serum levels in MS patients were also reported.
We investigated spatiotemporal differences in GH and PRL levels in pituitaries from
EAE animals. Using immunolabeling and stereological methods we evaluated changes
in volume density of GH- and PRL-positive cells in pituitary gland of animals with
EAE compared to healthy controls. As we determined that there is no change in cell
volume density, we checked if there are any changes in gene expression of PRL, GH,
as well as GHRH and SST. Growth hormone and prolactin protein expression was
also measured in anterior pituitary. Our results show that, in addition to GH- and
PRL-positive cells volume density, there are no significant changes in gene and
protein expression in anterior pituitary during EAE.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats",
pages = "105",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5859"
}

Živković, A., Milošević, A., Janjić, M., Milošević, K., Božić, I., Trifunović, S., Savić, D., Bjelobaba, I.,& Lavrnja, I.. (2023). Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 105.
https://hdl.handle.net/21.15107/rcub_ibiss_5859

Živković A, Milošević A, Janjić M, Milošević K, Božić I, Trifunović S, Savić D, Bjelobaba I, Lavrnja I. Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:105.
https://hdl.handle.net/21.15107/rcub_ibiss_5859 .

Živković, Anica, Milošević, Ana, Janjić, Marija, Milošević, Katarina, Božić, Iva, Trifunović, Svetlana, Savić, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, "Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):105,
https://hdl.handle.net/21.15107/rcub_ibiss_5859 .

TY  - CONF
AU  - Milošević, Ana
AU  - Milošević, Katarina
AU  - Nikolić, Ljiljana
AU  - Bogdanović Pristov, Jelena
AU  - Božić, Iva
AU  - Živković, Anica
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5836
AB  - Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that controls
mammalian reproduction by acting on its receptor (GnRHR) expressed on pituitary
gonadotrope cells. While GnRHR signaling in gonadotropes is well described,
knowledge of GnRHR activation-related events at extrapituitary sites including
neurons is limited. It was proposed that GnRH analogs (GnRHa) induce distinct
changes in hippocampal gene expression, emotional processes, and cognitive
functions.
To explore neuronal GnRHR signaling we used the human neuroblastoma cell line
SH-SY5Y. Further, we explored the regional expression of Gnrhr in rat brain and
investigated the expression of several relevant genes in the hippocampus and preoptic
area of peripubertal male rats treated with GnRHa.
GNRHR is expressed in SH-SY5Y cell line, but its expression does not change after
adding GnRHa in the incubation media. Electrophysiological recordings confirmed
that GnRHa induced membrane depolarization but could not evoke action potentials.
In the rat brain, Gnrhr expression could be detected in the hippocampus, amygdala,
and hypothalamus, including the preoptic area. Prolonged treatment of peripubertal
rats with GnRHa had no effect on the expression of genes in the hippocampus
previously shown to be affected in the sheep model of delayed puberty.
These results imply that neuronal GnRHR is either differently coupled (not coupled
with Gq/11 protein), or that its membrane density is too low to induce transcriptional
events. More investigation is needed to elucidate the role(s) of GnRH-GnRHR
signaling in the brain.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - GnRHR signaling in neuronal cells: in vitro and in vivo data
SP  - 53
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5836
ER  - 

@conference{
author = "Milošević, Ana and Milošević, Katarina and Nikolić, Ljiljana and Bogdanović Pristov, Jelena and Božić, Iva and Živković, Anica and Lavrnja, Irena and Savić, Danijela and Janjić, Marija and Bjelobaba, Ivana",
year = "2023",
abstract = "Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that controls
mammalian reproduction by acting on its receptor (GnRHR) expressed on pituitary
gonadotrope cells. While GnRHR signaling in gonadotropes is well described,
knowledge of GnRHR activation-related events at extrapituitary sites including
neurons is limited. It was proposed that GnRH analogs (GnRHa) induce distinct
changes in hippocampal gene expression, emotional processes, and cognitive
functions.
To explore neuronal GnRHR signaling we used the human neuroblastoma cell line
SH-SY5Y. Further, we explored the regional expression of Gnrhr in rat brain and
investigated the expression of several relevant genes in the hippocampus and preoptic
area of peripubertal male rats treated with GnRHa.
GNRHR is expressed in SH-SY5Y cell line, but its expression does not change after
adding GnRHa in the incubation media. Electrophysiological recordings confirmed
that GnRHa induced membrane depolarization but could not evoke action potentials.
In the rat brain, Gnrhr expression could be detected in the hippocampus, amygdala,
and hypothalamus, including the preoptic area. Prolonged treatment of peripubertal
rats with GnRHa had no effect on the expression of genes in the hippocampus
previously shown to be affected in the sheep model of delayed puberty.
These results imply that neuronal GnRHR is either differently coupled (not coupled
with Gq/11 protein), or that its membrane density is too low to induce transcriptional
events. More investigation is needed to elucidate the role(s) of GnRH-GnRHR
signaling in the brain.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "GnRHR signaling in neuronal cells: in vitro and in vivo data",
pages = "53",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5836"
}

Milošević, A., Milošević, K., Nikolić, L., Bogdanović Pristov, J., Božić, I., Živković, A., Lavrnja, I., Savić, D., Janjić, M.,& Bjelobaba, I.. (2023). GnRHR signaling in neuronal cells: in vitro and in vivo data. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 53.
https://hdl.handle.net/21.15107/rcub_ibiss_5836

Milošević A, Milošević K, Nikolić L, Bogdanović Pristov J, Božić I, Živković A, Lavrnja I, Savić D, Janjić M, Bjelobaba I. GnRHR signaling in neuronal cells: in vitro and in vivo data. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:53.
https://hdl.handle.net/21.15107/rcub_ibiss_5836 .

Milošević, Ana, Milošević, Katarina, Nikolić, Ljiljana, Bogdanović Pristov, Jelena, Božić, Iva, Živković, Anica, Lavrnja, Irena, Savić, Danijela, Janjić, Marija, Bjelobaba, Ivana, "GnRHR signaling in neuronal cells: in vitro and in vivo data" in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):53,
https://hdl.handle.net/21.15107/rcub_ibiss_5836 .

TY  - JOUR
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2022
UR  - https://www.mdpi.com/1422-0067/23/7/3561
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC8998340
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4948
AB  - Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.
PB  - Basel: MDPI
T2  - International Journal of Molecular Sciences
T1  - Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.
IS  - 7
VL  - 23
DO  - 10.3390/ijms23073561
SP  - 3561
ER  - 

@article{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2022",
abstract = "Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.",
publisher = "Basel: MDPI",
journal = "International Journal of Molecular Sciences",
title = "Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.",
number = "7",
volume = "23",
doi = "10.3390/ijms23073561",
pages = "3561"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Janjić, M., Laketa, D., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2022). Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.. in International Journal of Molecular Sciences
Basel: MDPI., 23(7), 3561.
https://doi.org/10.3390/ijms23073561

Milošević K, Stevanović I, Božić I, Milošević A, Janjić M, Laketa D, Bjelobaba I, Lavrnja I, Savić D. Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.. in International Journal of Molecular Sciences. 2022;23(7):3561.
doi:10.3390/ijms23073561 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response." in International Journal of Molecular Sciences, 23, no. 7 (2022):3561,
https://doi.org/10.3390/ijms23073561 . .

TY  - CONF
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5749
AB  - Prekomerna neuroinflamacija i mikroglijska aktivacija su uključene u patologiju mnogih neurodegenerativnih bolesti i mogu se simulirati u in vitro sistemu mikroglijskih ćelija primenom bakterijskog lipolisaharida (engl. Lipopolisaharide, LPS). Naša studija imala je za cilj da proceni efekte  pretretmana agmatinom na LPS-om izazvani oksidativni stres u BV-2 mišjoj mikroglijskoj ćelijskoj liniji. Pokazano je da u LPS-om stimulisanoj mikrogliji agmatin smanjuje enzimsku aktivnost iNOS i ksantin oksidaze (engl. Xanthine oxidase, XO), kao i nivo O2−, zaustavlja lipidnu peroksidaciju, povećava količinu ukupnog glutationa i omogućava da se delimično očuva aktivnost glutation reduktaze i katalaze, čime redukuje azotni i oksidativni stres. Agmatin utiče i na dva glavna signalna puta (NF-kB i Nrf2) uključena u inflamaciju, odnosno, antioksidativnu zaštitu, smanjujući tako nivo iNOS i COX-2, kao i oslobađanje TNF, IL-1β i IL-6. Istovremeno povećava se nivo ARG1, CD206 i HO-1, iz čega proizilazi da u uslovima inflamacije agmatin moduliše aktivaciju mikroglije u pravcu antiinflamacijskog fenotipa. Pokazali smo i da sam agmatin kod BV-2 ćelija dovodi do porasta nivoa krajnjih produkata lipidne peroksidacije, ali i ukupnog glutationa, aktivnosti glutation peroksidaze i aktivacije Nrf2 puta. Ovi rezultati podržavaju hipotezu da su agmatinom izazvani oksidativni stres i adaptivni odgovor, koji prethode stimulaciji LPS-om, odgovorni za efekte agmatina u aktiviranoj mikrogliji.
AB  - Прекомерена неуроинфламација и микроглијска активација су укључене у
патологију многих неуродегенеративних болести и могу се симулирати у in vitro
систему микроглијских ћелија применом бактеријског липолисахарида (енгл.
Lipopolisaharide, LPS). Наша студија имала је за циљ да процени ефекте
претретмана агматином на LPS-ом изазвани оксидативни стрес у BV-2 мишјој
микроглијској ћелијској линији. Показано је да у LPS-ом стимулисаној микроглији
агматин смањује ензимску активност iNOS и ксантин оксидазе (енгл. Xanthine
oxidase, XO), као и ниво O2−, зауставља липидну пероксидацију, повећава количину
укупног глутатиона и омогућава да се делимично очува активност глутатион
редуктазе и каталазе, чиме редукује азотни и оксидативни стрес. Агматин утиче и
на два главна сигнална пута (NF-kB и Nrf2) укључена у инфламацију, односно,
антиоксидативну заштиту, смањујући тако ниво iNOS и COX-2, као и ослобађање
TNF, IL-1β и IL-6. Истовремено повећава се ниво ARG1, CD206 и HO-1, из чега
произилази да у условима инфламације агматин модулише активацију микроглије
у правцу антиинфламацијског фенотипа. Показали смо и да сам агматин код BV-2
ћелија доводи до пораста нивоа крајњих продуката липидне пероксидације, али и
укупног глутатиона, активности глутатион пероксидазе и активације Nrf2 пута.
Ови резултати подржавају хипотезу да су агматином изазвани оксидативни стрес и
адаптивни одговор, који претходе стимулацији LPS-ом, одговорни за ефекте
агматина у активираној микроглији.
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  - Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom
T1  - Утицај агматина на оксидативни и инфламацијски одговор микроглијских ћелија активираних бактеријским липополисахаридом
SP  - 290
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5749
ER  - 

@conference{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2022",
abstract = "Prekomerna neuroinflamacija i mikroglijska aktivacija su uključene u patologiju mnogih neurodegenerativnih bolesti i mogu se simulirati u in vitro sistemu mikroglijskih ćelija primenom bakterijskog lipolisaharida (engl. Lipopolisaharide, LPS). Naša studija imala je za cilj da proceni efekte  pretretmana agmatinom na LPS-om izazvani oksidativni stres u BV-2 mišjoj mikroglijskoj ćelijskoj liniji. Pokazano je da u LPS-om stimulisanoj mikrogliji agmatin smanjuje enzimsku aktivnost iNOS i ksantin oksidaze (engl. Xanthine oxidase, XO), kao i nivo O2−, zaustavlja lipidnu peroksidaciju, povećava količinu ukupnog glutationa i omogućava da se delimično očuva aktivnost glutation reduktaze i katalaze, čime redukuje azotni i oksidativni stres. Agmatin utiče i na dva glavna signalna puta (NF-kB i Nrf2) uključena u inflamaciju, odnosno, antioksidativnu zaštitu, smanjujući tako nivo iNOS i COX-2, kao i oslobađanje TNF, IL-1β i IL-6. Istovremeno povećava se nivo ARG1, CD206 i HO-1, iz čega proizilazi da u uslovima inflamacije agmatin moduliše aktivaciju mikroglije u pravcu antiinflamacijskog fenotipa. Pokazali smo i da sam agmatin kod BV-2 ćelija dovodi do porasta nivoa krajnjih produkata lipidne peroksidacije, ali i ukupnog glutationa, aktivnosti glutation peroksidaze i aktivacije Nrf2 puta. Ovi rezultati podržavaju hipotezu da su agmatinom izazvani oksidativni stres i adaptivni odgovor, koji prethode stimulaciji LPS-om, odgovorni za efekte agmatina u aktiviranoj mikrogliji., Прекомерена неуроинфламација и микроглијска активација су укључене у
патологију многих неуродегенеративних болести и могу се симулирати у in vitro
систему микроглијских ћелија применом бактеријског липолисахарида (енгл.
Lipopolisaharide, LPS). Наша студија имала је за циљ да процени ефекте
претретмана агматином на LPS-ом изазвани оксидативни стрес у BV-2 мишјој
микроглијској ћелијској линији. Показано је да у LPS-ом стимулисаној микроглији
агматин смањује ензимску активност iNOS и ксантин оксидазе (енгл. Xanthine
oxidase, XO), као и ниво O2−, зауставља липидну пероксидацију, повећава количину
укупног глутатиона и омогућава да се делимично очува активност глутатион
редуктазе и каталазе, чиме редукује азотни и оксидативни стрес. Агматин утиче и
на два главна сигнална пута (NF-kB и Nrf2) укључена у инфламацију, односно,
антиоксидативну заштиту, смањујући тако ниво iNOS и COX-2, као и ослобађање
TNF, IL-1β и IL-6. Истовремено повећава се ниво ARG1, CD206 и HO-1, из чега
произилази да у условима инфламације агматин модулише активацију микроглије
у правцу антиинфламацијског фенотипа. Показали смо и да сам агматин код BV-2
ћелија доводи до пораста нивоа крајњих продуката липидне пероксидације, али и
укупног глутатиона, активности глутатион пероксидазе и активације Nrf2 пута.
Ови резултати подржавају хипотезу да су агматином изазвани оксидативни стрес и
адаптивни одговор, који претходе стимулацији LPS-ом, одговорни за ефекте
агматина у активираној микроглији.",
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 = "Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom, Утицај агматина на оксидативни и инфламацијски одговор микроглијских ћелија активираних бактеријским липополисахаридом",
pages = "290",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5749"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Janjić, M., Laketa, D., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2022). Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society., 290.
https://hdl.handle.net/21.15107/rcub_ibiss_5749

Milošević K, Stevanović I, Božić I, Milošević A, Janjić M, Laketa D, Bjelobaba I, Lavrnja I, Savić D. Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;:290.
https://hdl.handle.net/21.15107/rcub_ibiss_5749 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia (2022):290,
https://hdl.handle.net/21.15107/rcub_ibiss_5749 .

TY  - JOUR
AU  - Nikolovski, Neda
AU  - Božić, Iva
AU  - Miljković, Đorđe
AU  - Lavrnja, Irena
PY  - 2021
UR  - https://www.eurekaselect.com/185602/article
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4477
AB  - BACKGROUND Benfotiamine is a synthetic liposoluble derivative of vitamin B1 that has been shown to have anti-inflammatory properties. OBJECTIVE To study the effects of benfotiamine on dendritic cells. METHODS Dendritic cells were obtained from murine bone marrow precursor cells in the presence of GM-CSF. Benfotiamine was applied to the cell culture during the process of bone marrow cell differentiation into dendritic cells. Dendritic cells were stimulated with lipopolysaccharide (LPS) and expression of MHC class II molecules and CD86 was determined by flow cytometry, while levels of tumor necrosis factor (TNF) and interleukin (IL)-1β in cell culture supernatants were measured by ELISA. F-Actin, NF-κB and Nrf2 were visualized by immunofluorescent staining and microscopy. RESULTS Benfotiamine potently reduced LPS-induced expression of MHC class II molecules and CD86, in addition to suppressing the release of pro-inflammatory cytokines TNF and IL-1β. It also prevented LPS-imposed morphological changes of dendritic cells, i.e. enlargement and intensified protrusions. The effects were paralleled with the reduction of NF-κB translocation to the nucleus, but not of Nrf2 activation inhibition. CONCLUSION Having in mind the importance of dendritic cells for the configuration of the immune response, our results imply that benfotiamine has the ability to regulate the immune response through inhibition of inflammatory properties of dendritic cells.
T2  - Endocrine, Metabolic & Immune Disorders - Drug Targets
T1  - Benfotiamine Reduces Dendritic Cell Inflammatory Potency.
IS  - 7
VL  - 21
DO  - 10.2174/1871530320999200905114135
SP  - 1344
EP  - 1351
ER  - 

@article{
author = "Nikolovski, Neda and Božić, Iva and Miljković, Đorđe and Lavrnja, Irena",
year = "2021",
abstract = "BACKGROUND Benfotiamine is a synthetic liposoluble derivative of vitamin B1 that has been shown to have anti-inflammatory properties. OBJECTIVE To study the effects of benfotiamine on dendritic cells. METHODS Dendritic cells were obtained from murine bone marrow precursor cells in the presence of GM-CSF. Benfotiamine was applied to the cell culture during the process of bone marrow cell differentiation into dendritic cells. Dendritic cells were stimulated with lipopolysaccharide (LPS) and expression of MHC class II molecules and CD86 was determined by flow cytometry, while levels of tumor necrosis factor (TNF) and interleukin (IL)-1β in cell culture supernatants were measured by ELISA. F-Actin, NF-κB and Nrf2 were visualized by immunofluorescent staining and microscopy. RESULTS Benfotiamine potently reduced LPS-induced expression of MHC class II molecules and CD86, in addition to suppressing the release of pro-inflammatory cytokines TNF and IL-1β. It also prevented LPS-imposed morphological changes of dendritic cells, i.e. enlargement and intensified protrusions. The effects were paralleled with the reduction of NF-κB translocation to the nucleus, but not of Nrf2 activation inhibition. CONCLUSION Having in mind the importance of dendritic cells for the configuration of the immune response, our results imply that benfotiamine has the ability to regulate the immune response through inhibition of inflammatory properties of dendritic cells.",
journal = "Endocrine, Metabolic & Immune Disorders - Drug Targets",
title = "Benfotiamine Reduces Dendritic Cell Inflammatory Potency.",
number = "7",
volume = "21",
doi = "10.2174/1871530320999200905114135",
pages = "1344-1351"
}

Nikolovski, N., Božić, I., Miljković, Đ.,& Lavrnja, I.. (2021). Benfotiamine Reduces Dendritic Cell Inflammatory Potency.. in Endocrine, Metabolic & Immune Disorders - Drug Targets, 21(7), 1344-1351.
https://doi.org/10.2174/1871530320999200905114135

Nikolovski N, Božić I, Miljković Đ, Lavrnja I. Benfotiamine Reduces Dendritic Cell Inflammatory Potency.. in Endocrine, Metabolic & Immune Disorders - Drug Targets. 2021;21(7):1344-1351.
doi:10.2174/1871530320999200905114135 .

Nikolovski, Neda, Božić, Iva, Miljković, Đorđe, Lavrnja, Irena, "Benfotiamine Reduces Dendritic Cell Inflammatory Potency." in Endocrine, Metabolic & Immune Disorders - Drug Targets, 21, no. 7 (2021):1344-1351,
https://doi.org/10.2174/1871530320999200905114135 . .

TY  - CONF
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Jakovljević, Marija
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Laketa, Danijela
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6003
AB  - Mitochondria play a key role in energy metabolism and regulate some of the principal cellular processes such as the production of ATP and reactive oxygen species, as well as a regulation of apoptotic cell death. Mitochondrial dysfunction and oxidative stress are common threads in most neurodegenerative disorders, which are also accompanied by chronic microglial activation. Agmatine, neuromodulatory polyamine, was shown to exhibit neuroprotective effects in oxidative stress conditions. Therefore, the goal of this study was to determine the ability of agmatine to preserve mitochondrial function and prevent apoptosis during neuroinflammation.
The effects of 100 µM agmatine on cellular energy status and cell death were examined in LPS-stimulated BV2 microglial cell line. To detect changes in mitochondrial membrane potential, TMRE fluorescent assay was performed, while the changes in intracellular ATP concentration were determined by bioluminescent assay, 6h, and 24h after LPS stimulation. The expression of apoptosis regulators Bax and Bcl2 was assessed by Western blot analysis and the Bax/Bcl2 ratio was determined.
Agmatine increases mitochondrial membrane potential, indicating its protective role during mitochondrial insult caused by LPS stimulation. LPS and agmatine administrated separately, increase intracellular ATP levels, however, agmatine treatment followed by LPS stimulation enhances ATP production even further, at both time points. Moreover, agmatine shows an antiapoptotic effect by reduction of Bax/Bcl2 ratio in comparison to LPS stimulation.
We conclude that the results of this study indicate the capacity of agmatine to protect mitochondrial function and suppress apoptosis, which may be beneficial in neurodegenerative disorders and
neuroinflammation.
PB  - Federation of European Neuroscience Societies
C3  - Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
T1  - Agmatine protects mitochondria in LPS-stimulated microglia
SP  - 285
EP  - 286
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6003
ER  - 

@conference{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Jakovljević, Marija and Janjić, Marija and Bjelobaba, Ivana and Laketa, Danijela and Lavrnja, Irena and Savić, Danijela",
year = "2021",
abstract = "Mitochondria play a key role in energy metabolism and regulate some of the principal cellular processes such as the production of ATP and reactive oxygen species, as well as a regulation of apoptotic cell death. Mitochondrial dysfunction and oxidative stress are common threads in most neurodegenerative disorders, which are also accompanied by chronic microglial activation. Agmatine, neuromodulatory polyamine, was shown to exhibit neuroprotective effects in oxidative stress conditions. Therefore, the goal of this study was to determine the ability of agmatine to preserve mitochondrial function and prevent apoptosis during neuroinflammation.
The effects of 100 µM agmatine on cellular energy status and cell death were examined in LPS-stimulated BV2 microglial cell line. To detect changes in mitochondrial membrane potential, TMRE fluorescent assay was performed, while the changes in intracellular ATP concentration were determined by bioluminescent assay, 6h, and 24h after LPS stimulation. The expression of apoptosis regulators Bax and Bcl2 was assessed by Western blot analysis and the Bax/Bcl2 ratio was determined.
Agmatine increases mitochondrial membrane potential, indicating its protective role during mitochondrial insult caused by LPS stimulation. LPS and agmatine administrated separately, increase intracellular ATP levels, however, agmatine treatment followed by LPS stimulation enhances ATP production even further, at both time points. Moreover, agmatine shows an antiapoptotic effect by reduction of Bax/Bcl2 ratio in comparison to LPS stimulation.
We conclude that the results of this study indicate the capacity of agmatine to protect mitochondrial function and suppress apoptosis, which may be beneficial in neurodegenerative disorders and
neuroinflammation.",
publisher = "Federation of European Neuroscience Societies",
journal = "Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland",
title = "Agmatine protects mitochondria in LPS-stimulated microglia",
pages = "285-286",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6003"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Jakovljević, M., Janjić, M., Bjelobaba, I., Laketa, D., Lavrnja, I.,& Savić, D.. (2021). Agmatine protects mitochondria in LPS-stimulated microglia. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
Federation of European Neuroscience Societies., 285-286.
https://hdl.handle.net/21.15107/rcub_ibiss_6003

Milošević K, Stevanović I, Božić I, Milošević A, Jakovljević M, Janjić M, Bjelobaba I, Laketa D, Lavrnja I, Savić D. Agmatine protects mitochondria in LPS-stimulated microglia. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland. 2021;:285-286.
https://hdl.handle.net/21.15107/rcub_ibiss_6003 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Jakovljević, Marija, Janjić, Marija, Bjelobaba, Ivana, Laketa, Danijela, Lavrnja, Irena, Savić, Danijela, "Agmatine protects mitochondria in LPS-stimulated microglia" in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland (2021):285-286,
https://hdl.handle.net/21.15107/rcub_ibiss_6003 .

TY  - JOUR
AU  - Trifunović, Svetlana
AU  - Stevanović, Ivana
AU  - Milošević, Ana
AU  - Ristić, Nataša
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Jakovljević, Marija
AU  - Milošević, Katarina
AU  - Laketa, Danijela
AU  - Lavrnja, Irena
PY  - 2021
UR  - https://www.frontiersin.org/articles/10.3389/fnins.2021.649485/full
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4436
AB  - Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic-pituitary-adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.
PB  - Lausanne: Frontiers Media SA
T2  - Frontiers in Neuroscience
T1  - The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.
VL  - 15
DO  - 10.3389/fnins.2021.649485
SP  - 649485
ER  - 

@article{
author = "Trifunović, Svetlana and Stevanović, Ivana and Milošević, Ana and Ristić, Nataša and Janjić, Marija and Bjelobaba, Ivana and Savić, Danijela and Božić, Iva and Jakovljević, Marija and Milošević, Katarina and Laketa, Danijela and Lavrnja, Irena",
year = "2021",
abstract = "Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic-pituitary-adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.",
publisher = "Lausanne: Frontiers Media SA",
journal = "Frontiers in Neuroscience",
title = "The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.",
volume = "15",
doi = "10.3389/fnins.2021.649485",
pages = "649485"
}

Trifunović, S., Stevanović, I., Milošević, A., Ristić, N., Janjić, M., Bjelobaba, I., Savić, D., Božić, I., Jakovljević, M., Milošević, K., Laketa, D.,& Lavrnja, I.. (2021). The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.. in Frontiers in Neuroscience
Lausanne: Frontiers Media SA., 15, 649485.
https://doi.org/10.3389/fnins.2021.649485

Trifunović S, Stevanović I, Milošević A, Ristić N, Janjić M, Bjelobaba I, Savić D, Božić I, Jakovljević M, Milošević K, Laketa D, Lavrnja I. The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.. in Frontiers in Neuroscience. 2021;15:649485.
doi:10.3389/fnins.2021.649485 .

Trifunović, Svetlana, Stevanović, Ivana, Milošević, Ana, Ristić, Nataša, Janjić, Marija, Bjelobaba, Ivana, Savić, Danijela, Božić, Iva, Jakovljević, Marija, Milošević, Katarina, Laketa, Danijela, Lavrnja, Irena, "The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators." in Frontiers in Neuroscience, 15 (2021):649485,
https://doi.org/10.3389/fnins.2021.649485 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Božić, Iva
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Stojilković, Stanko S.
AU  - Janjić, Marija
PY  - 2021
UR  - https://doi.org/10.1038/s41598-021-88305-5
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4248
AB  - Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood testosterone levels, which was also observed in male rats during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To better understand the causes of decreased testosterone production during EAE, we investigated the expression status of genes and proteins associated with steroidogenesis in the testes. No changes in the number of interstitial cells were observed in EAE animals, but the expression of the insulin-like 3 gene was reduced at the peak of the disease, implying that the Leydig cell functional capacity was affected. Consistent with this finding, the expression of most steroidogenic enzyme genes and proteins was reduced during EAE, including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation were observed. Recovery of steroidogenesis was observed after injection of hCG, the placental gonadotropin, or buserelin acetate, a gonadotropin-releasing hormone analogue, at the peak of EAE. Together, our results are consistent with the hypothesis that impaired testicular steroidogenesis originates upstream of the testes and that low serum LH is the main cause of decreased testosterone levels during EAE.
PB  - Springer Science and Business Media LLC
T2  - Scientific Reports
T1  - Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats
IS  - 1
VL  - 11
DO  - 10.1038/s41598-021-88305-5
SP  - 8996
ER  - 

@article{
author = "Milošević, Ana and Bjelobaba, Ivana and Božić, Iva and Lavrnja, Irena and Savić, Danijela and Milošević, Katarina and Jakovljević, Marija and Stojilković, Stanko S. and Janjić, Marija",
year = "2021",
abstract = "Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood testosterone levels, which was also observed in male rats during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To better understand the causes of decreased testosterone production during EAE, we investigated the expression status of genes and proteins associated with steroidogenesis in the testes. No changes in the number of interstitial cells were observed in EAE animals, but the expression of the insulin-like 3 gene was reduced at the peak of the disease, implying that the Leydig cell functional capacity was affected. Consistent with this finding, the expression of most steroidogenic enzyme genes and proteins was reduced during EAE, including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation were observed. Recovery of steroidogenesis was observed after injection of hCG, the placental gonadotropin, or buserelin acetate, a gonadotropin-releasing hormone analogue, at the peak of EAE. Together, our results are consistent with the hypothesis that impaired testicular steroidogenesis originates upstream of the testes and that low serum LH is the main cause of decreased testosterone levels during EAE.",
publisher = "Springer Science and Business Media LLC",
journal = "Scientific Reports",
title = "Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats",
number = "1",
volume = "11",
doi = "10.1038/s41598-021-88305-5",
pages = "8996"
}

Milošević, A., Bjelobaba, I., Božić, I., Lavrnja, I., Savić, D., Milošević, K., Jakovljević, M., Stojilković, S. S.,& Janjić, M.. (2021). Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats. in Scientific Reports
Springer Science and Business Media LLC., 11(1), 8996.
https://doi.org/10.1038/s41598-021-88305-5

Milošević A, Bjelobaba I, Božić I, Lavrnja I, Savić D, Milošević K, Jakovljević M, Stojilković SS, Janjić M. Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats. in Scientific Reports. 2021;11(1):8996.
doi:10.1038/s41598-021-88305-5 .

Milošević, Ana, Bjelobaba, Ivana, Božić, Iva, Lavrnja, Irena, Savić, Danijela, Milošević, Katarina, Jakovljević, Marija, Stojilković, Stanko S., Janjić, Marija, "Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats" in Scientific Reports, 11, no. 1 (2021):8996,
https://doi.org/10.1038/s41598-021-88305-5 . .

TY  - JOUR
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Lavrnja, Irena
PY  - 2021
UR  - http://www.ncbi.nlm.nih.gov/pubmed/33226087
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4404
AB  - Astrocytes, the most abundant glial cells in the central nervous system (CNS), have numerous integral roles in all CNS functions. They are essential for synaptic transmission and support neurons by providing metabolic substrates, secreting growth factors and regulating extracellular concentrations of ions and neurotransmitters. Astrocytes respond to CNS insults through reactive astrogliosis, in which they go through many functional and molecular changes. In neuroinflammatory conditions reactive astrocytes exert both beneficial and detrimental functions, depending on the context and heterogeneity of astrocytic populations. In this review we profile astrocytic diversity in the context of neuroinflammation; with a specific focus on multiple sclerosis (MS) and its best-described animal model experimental autoimmune encephalomyelitis (EAE). We characterize two main subtypes, protoplasmic and fibrous astrocytes and describe the role of intermediate filaments in the physiology and pathology of these cells. Additionally, we outline a variety of markers that are emerging as important in investigating astrocytic biology in both physiological conditions and neuroinflammation.
T2  - Histology and Histopathology
T1  - Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation
IS  - 3
VL  - 36
DO  - 10.14670/HH-18-284
SP  - 267
EP  - 290
ER  - 

@article{
author = "Božić, Iva and Savić, Danijela and Lavrnja, Irena",
year = "2021",
abstract = "Astrocytes, the most abundant glial cells in the central nervous system (CNS), have numerous integral roles in all CNS functions. They are essential for synaptic transmission and support neurons by providing metabolic substrates, secreting growth factors and regulating extracellular concentrations of ions and neurotransmitters. Astrocytes respond to CNS insults through reactive astrogliosis, in which they go through many functional and molecular changes. In neuroinflammatory conditions reactive astrocytes exert both beneficial and detrimental functions, depending on the context and heterogeneity of astrocytic populations. In this review we profile astrocytic diversity in the context of neuroinflammation; with a specific focus on multiple sclerosis (MS) and its best-described animal model experimental autoimmune encephalomyelitis (EAE). We characterize two main subtypes, protoplasmic and fibrous astrocytes and describe the role of intermediate filaments in the physiology and pathology of these cells. Additionally, we outline a variety of markers that are emerging as important in investigating astrocytic biology in both physiological conditions and neuroinflammation.",
journal = "Histology and Histopathology",
title = "Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation",
number = "3",
volume = "36",
doi = "10.14670/HH-18-284",
pages = "267-290"
}

Božić, I., Savić, D.,& Lavrnja, I.. (2021). Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation. in Histology and Histopathology, 36(3), 267-290.
https://doi.org/10.14670/HH-18-284

Božić I, Savić D, Lavrnja I. Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation. in Histology and Histopathology. 2021;36(3):267-290.
doi:10.14670/HH-18-284 .

Božić, Iva, Savić, Danijela, Lavrnja, Irena, "Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation" in Histology and Histopathology, 36, no. 3 (2021):267-290,
https://doi.org/10.14670/HH-18-284 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Peković, Sanja
AU  - Stojilkovic, Stanko S.
AU  - Bjelobaba, Ivana
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32592862
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6149
AB  - Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.
PB  - Elsevier BV
PB  - Elsevier
T2  - Brain, Behavior, and Immunity
T1  - The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.
VL  - 89
DO  - 10.1016/j.bbi.2020.06.025
SP  - 233
EP  - 244
ER  - 

@article{
author = "Milošević, Ana and Janjić, Marija and Lavrnja, Irena and Savić, Danijela and Božić, Iva and Milošević, Katarina and Jakovljević, Marija and Peković, Sanja and Stojilkovic, Stanko S. and Bjelobaba, Ivana",
year = "2020",
abstract = "Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.",
publisher = "Elsevier BV, Elsevier",
journal = "Brain, Behavior, and Immunity",
title = "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.",
volume = "89",
doi = "10.1016/j.bbi.2020.06.025",
pages = "233-244"
}

Milošević, A., Janjić, M., Lavrnja, I., Savić, D., Božić, I., Milošević, K., Jakovljević, M., Peković, S., Stojilkovic, S. S.,& Bjelobaba, I.. (2020). The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity
Elsevier BV., 89, 233-244.
https://doi.org/10.1016/j.bbi.2020.06.025

Milošević A, Janjić M, Lavrnja I, Savić D, Božić I, Milošević K, Jakovljević M, Peković S, Stojilkovic SS, Bjelobaba I. The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity. 2020;89:233-244.
doi:10.1016/j.bbi.2020.06.025 .

Milošević, Ana, Janjić, Marija, Lavrnja, Irena, Savić, Danijela, Božić, Iva, Milošević, Katarina, Jakovljević, Marija, Peković, Sanja, Stojilkovic, Stanko S., Bjelobaba, Ivana, "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis." in Brain, Behavior, and Immunity, 89 (2020):233-244,
https://doi.org/10.1016/j.bbi.2020.06.025 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Peković, Sanja
AU  - Stojilkovic, Stanko S.
AU  - Bjelobaba, Ivana
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32592862
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3762
AB  - Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.
PB  - Elsevier BV
T2  - Brain, Behavior, and Immunity
T1  - The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.
VL  - 89
DO  - 10.1016/j.bbi.2020.06.025
SP  - DOI:10.1016/j.bbi.2020.06.025
EP  - 244
ER  - 

@article{
author = "Milošević, Ana and Janjić, Marija and Lavrnja, Irena and Savić, Danijela and Božić, Iva and Milošević, Katarina and Jakovljević, Marija and Peković, Sanja and Stojilkovic, Stanko S. and Bjelobaba, Ivana",
year = "2020",
abstract = "Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.",
publisher = "Elsevier BV",
journal = "Brain, Behavior, and Immunity",
title = "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.",
volume = "89",
doi = "10.1016/j.bbi.2020.06.025",
pages = "DOI:10.1016/j.bbi.2020.06.025-244"
}

Milošević, A., Janjić, M., Lavrnja, I., Savić, D., Božić, I., Milošević, K., Jakovljević, M., Peković, S., Stojilkovic, S. S.,& Bjelobaba, I.. (2020). The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity
Elsevier BV., 89, DOI:10.1016/j.bbi.2020.06.025-244.
https://doi.org/10.1016/j.bbi.2020.06.025

Milošević A, Janjić M, Lavrnja I, Savić D, Božić I, Milošević K, Jakovljević M, Peković S, Stojilkovic SS, Bjelobaba I. The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity. 2020;89:DOI:10.1016/j.bbi.2020.06.025-244.
doi:10.1016/j.bbi.2020.06.025 .

Milošević, Ana, Janjić, Marija, Lavrnja, Irena, Savić, Danijela, Božić, Iva, Milošević, Katarina, Jakovljević, Marija, Peković, Sanja, Stojilkovic, Stanko S., Bjelobaba, Ivana, "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis." in Brain, Behavior, and Immunity, 89 (2020):DOI:10.1016/j.bbi.2020.06.025-244,
https://doi.org/10.1016/j.bbi.2020.06.025 . .

TY  - CONF
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Janjić, Marija
AU  - Savić, Danijela
AU  - Laketa, Danijela
AU  - Jakovljević, Marija
AU  - Milošević, Ana
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6006
AB  - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, neurodegeneration and gliosis. It is considered as a perplexing multifactorial disease in which the neuroendocrine system plays an important role. Growth hormone (GH) is synthesized and secreted by the somatotroph cells of the anterior pituitary. GH secretion is positively regulated by the hypothalamic factor GHRH and exerts its effects through interaction with the GH receptor (GHR), a member of the class I cytokine receptor family. It was demonstrated that neurons and astrocytes also produce GH and that GHR is widely expressed in the CNS. Nonetheless, it is not known whether expression pattern of GHR changes in the CNS during MS. We investigated GHR expression in the spinal cord during the course of experimental autoimmune encephalomyelitis (EAE), animal model of MS that is broadly used. Our results show that GHR is diminished on mRNA and protein level during EAE. Double immunofluorescence studies demonstrated that GHR is expressed in different cell types in the spinal cord in physiological conditions, including astrocytes and microglia. This expression pattern does not change extensively after the onset of EAE. However, at the peak of disease GHR is absent from astrocytes in the white and grey matter, but still present in microglia, although to a lesser degree. At the end of disease, when the animals have recovered, GHR expression is similar to control conditions. Our results point to complex involvement of GHR in the pathology of EAE.
PB  - Belgrade : Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis
EP  - 212
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6006
ER  - 

@conference{
author = "Božić, Iva and Milošević, Katarina and Janjić, Marija and Savić, Danijela and Laketa, Danijela and Jakovljević, Marija and Milošević, Ana and Peković, Sanja and Lavrnja, Irena",
year = "2019",
abstract = "Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, neurodegeneration and gliosis. It is considered as a perplexing multifactorial disease in which the neuroendocrine system plays an important role. Growth hormone (GH) is synthesized and secreted by the somatotroph cells of the anterior pituitary. GH secretion is positively regulated by the hypothalamic factor GHRH and exerts its effects through interaction with the GH receptor (GHR), a member of the class I cytokine receptor family. It was demonstrated that neurons and astrocytes also produce GH and that GHR is widely expressed in the CNS. Nonetheless, it is not known whether expression pattern of GHR changes in the CNS during MS. We investigated GHR expression in the spinal cord during the course of experimental autoimmune encephalomyelitis (EAE), animal model of MS that is broadly used. Our results show that GHR is diminished on mRNA and protein level during EAE. Double immunofluorescence studies demonstrated that GHR is expressed in different cell types in the spinal cord in physiological conditions, including astrocytes and microglia. This expression pattern does not change extensively after the onset of EAE. However, at the peak of disease GHR is absent from astrocytes in the white and grey matter, but still present in microglia, although to a lesser degree. At the end of disease, when the animals have recovered, GHR expression is similar to control conditions. Our results point to complex involvement of GHR in the pathology of EAE.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis",
pages = "212",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6006"
}

Božić, I., Milošević, K., Janjić, M., Savić, D., Laketa, D., Jakovljević, M., Milošević, A., Peković, S.,& Lavrnja, I.. (2019). Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade : Serbian Neuroscience Society..
https://hdl.handle.net/21.15107/rcub_ibiss_6006

Božić I, Milošević K, Janjić M, Savić D, Laketa D, Jakovljević M, Milošević A, Peković S, Lavrnja I. Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:null-212.
https://hdl.handle.net/21.15107/rcub_ibiss_6006 .

Božić, Iva, Milošević, Katarina, Janjić, Marija, Savić, Danijela, Laketa, Danijela, Jakovljević, Marija, Milošević, Ana, Peković, Sanja, Lavrnja, Irena, "Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019),
https://hdl.handle.net/21.15107/rcub_ibiss_6006 .

TY  - CONF
AU  - Milošević, Katarina
AU  - Lavrnja, Irena
AU  - Janjić, Marija
AU  - Božić, Iva
AU  - Laketa, Danijela
AU  - Dacić, Sanja
AU  - Peković, Sanja
AU  - Savić, Danijela
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6004
AB  - Traumatic brain injury triggers neuroinflammatory response mediated by distinct populations of myeloid cells, including central nervous system (CNS) resident macrophages - microglia. Depending on the time upon insult this response may either contribute to restorative effects or hinder CNS repair.
Therefore, the focus of this study was on determining temporal course in gene expression profiles of markers specific to the mononuclear phagocyte system (MPS).
We have used the model of cortical stab injury which was performed on 3-months-old male Wistar rats. All animals were divided into 3 experimental groups: control, sham and lesion group and sacrificed at 1, 2, 3 and 7 days post-injury. After brain isolation, mRNA was extracted from cortical pieces around the center of lesion (the same tissue part was used for sham and control groups). The gene expression was analyzed by real-time PCR.
The mRNA levels of Itgam, Aif-1, Cd68 and Cx3Cr1, which are surface markers of MPS, were increased in first two days after brain injury, and then all, except Cd68, showed declining trend compared to control group. Furthermore, we analyzed expression of Arg-1, Il-6 and Tnf-alpha genes, which could be indicators of pro- or anti-inflammatory milieu. All of them increased significantly in the first two days post-injury, and then returned to control level, with the most prominent changes detected in Arg-1 mRNA level.
This study indicates enhanced MPS response in the acute phase after cortical stab injury. Further studies are required to determine which populations of CNS myeloid cells predominate in specific time point upon injury.
PB  - Belgrade : Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Mononuclear Phagocyte System In Traumatic Brain Injury
SP  - 503
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6004
ER  - 

@conference{
author = "Milošević, Katarina and Lavrnja, Irena and Janjić, Marija and Božić, Iva and Laketa, Danijela and Dacić, Sanja and Peković, Sanja and Savić, Danijela",
year = "2019",
abstract = "Traumatic brain injury triggers neuroinflammatory response mediated by distinct populations of myeloid cells, including central nervous system (CNS) resident macrophages - microglia. Depending on the time upon insult this response may either contribute to restorative effects or hinder CNS repair.
Therefore, the focus of this study was on determining temporal course in gene expression profiles of markers specific to the mononuclear phagocyte system (MPS).
We have used the model of cortical stab injury which was performed on 3-months-old male Wistar rats. All animals were divided into 3 experimental groups: control, sham and lesion group and sacrificed at 1, 2, 3 and 7 days post-injury. After brain isolation, mRNA was extracted from cortical pieces around the center of lesion (the same tissue part was used for sham and control groups). The gene expression was analyzed by real-time PCR.
The mRNA levels of Itgam, Aif-1, Cd68 and Cx3Cr1, which are surface markers of MPS, were increased in first two days after brain injury, and then all, except Cd68, showed declining trend compared to control group. Furthermore, we analyzed expression of Arg-1, Il-6 and Tnf-alpha genes, which could be indicators of pro- or anti-inflammatory milieu. All of them increased significantly in the first two days post-injury, and then returned to control level, with the most prominent changes detected in Arg-1 mRNA level.
This study indicates enhanced MPS response in the acute phase after cortical stab injury. Further studies are required to determine which populations of CNS myeloid cells predominate in specific time point upon injury.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Mononuclear Phagocyte System In Traumatic Brain Injury",
pages = "503",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6004"
}

Milošević, K., Lavrnja, I., Janjić, M., Božić, I., Laketa, D., Dacić, S., Peković, S.,& Savić, D.. (2019). Mononuclear Phagocyte System In Traumatic Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade : Serbian Neuroscience Society., 503.
https://hdl.handle.net/21.15107/rcub_ibiss_6004

Milošević K, Lavrnja I, Janjić M, Božić I, Laketa D, Dacić S, Peković S, Savić D. Mononuclear Phagocyte System In Traumatic Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:503.
https://hdl.handle.net/21.15107/rcub_ibiss_6004 .

Milošević, Katarina, Lavrnja, Irena, Janjić, Marija, Božić, Iva, Laketa, Danijela, Dacić, Sanja, Peković, Sanja, Savić, Danijela, "Mononuclear Phagocyte System In Traumatic Brain Injury" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):503,
https://hdl.handle.net/21.15107/rcub_ibiss_6004 .

TY  - JOUR
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Milošević, Katarina
AU  - Bjelobaba, Ivana
AU  - Jakovljević, Marija
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5874
AB  - Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.
PB  - New York: Springer
T2  - Neurochemical Research
T1  - The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis
IS  - 12
VL  - 44
DO  - 10.1007/s11064-019-02892-4
SP  - 2733
EP  - 2745
ER  - 

@article{
author = "Božić, Iva and Savić, Danijela and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Milošević, Katarina and Bjelobaba, Ivana and Jakovljević, Marija and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2019",
abstract = "Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.",
publisher = "New York: Springer",
journal = "Neurochemical Research",
title = "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis",
number = "12",
volume = "44",
doi = "10.1007/s11064-019-02892-4",
pages = "2733-2745"
}

Božić, I., Savić, D., Milošević, A., Janjić, M., Laketa, D., Milošević, K., Bjelobaba, I., Jakovljević, M., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2019). The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research
New York: Springer., 44(12), 2733-2745.
https://doi.org/10.1007/s11064-019-02892-4

Božić I, Savić D, Milošević A, Janjić M, Laketa D, Milošević K, Bjelobaba I, Jakovljević M, Nedeljković N, Peković S, Lavrnja I. The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research. 2019;44(12):2733-2745.
doi:10.1007/s11064-019-02892-4 .

Božić, Iva, Savić, Danijela, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Milošević, Katarina, Bjelobaba, Ivana, Jakovljević, Marija, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis" in Neurochemical Research, 44, no. 12 (2019):2733-2745,
https://doi.org/10.1007/s11064-019-02892-4 . .

TY  - CONF
AU  - Božić, Iva
AU  - Nikolovski, Neda
AU  - Lazarević, Milica
AU  - Miljković, Đorđe
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6062
AB  - Dendritic cells (DC) are professional antigen presenting cells that have an important role in inducing the immune response. Under normal conditions, DC reside in peripheral tissues in an immature state. However, they undergo a series of maturation steps in response to inflammatory stimuli. During maturation, DC up-regulate major histocompatibility complex (MHC) class II molecules and co-stimulatory molecules (CD40, CD80, CD86) for antigen presentation and increasingly secrete cytokines. Tolerogenic DC (tolDC) have immunoregulatory properties and are characterized by low expression of MHC class II and co-stimulatory molecules, with limited production of proinflammatory cytokines. TolDC-based immunotherapy is a promising perspective in the treatment of autoimmune diseases. Benfotiamine (S-benzoylthiamine-O-monophosphate) is an S-acyl derivative of vitamin B1 with anti-inflammatory and anti-oxidative properties. Here, we explored the potential of benfotiamine to induce tolerogenic phenotype of DC. DC were cultivated from progenitor bone marrow cells isolated from the femur of C57BL/6 mice. The cells were cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (20 ng/mL) with 100 ng/mL lipopolysaccharide added for the last 24 h of cultivation for maturation. Treatment with benfotiamine (100 μM) was performed on days 0, 2, 4 and 6. FACS analysis showed that benfotiamine applied during differentiation of DC suppressed the expression of MHC class II and CD86, while it did not affect the expression of CD40. The secretion of proinflammatory cytokines TNF, IL-1β, and IL-6 was also decreased. Morphological analysis showed that DC treated with benfotiamine were similar in shape and size to immature DC, despite the maturation stimulus that they were exposed to. The effects of benfotiamine are associated with its suppression of NF-κB translocation to the nucleus. Together, these results show that benfotiamine has the potential to direct DC toward tolDC. Studies on the application of benfotiamine-treated DC in animal models of autoimmunity are warranted.
PB  - Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade
C3  - Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
T1  - Benfotiamine directs dendritic cells toward a tolerogenic phenotype
SP  - 7
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6062
ER  - 

@conference{
author = "Božić, Iva and Nikolovski, Neda and Lazarević, Milica and Miljković, Đorđe and Lavrnja, Irena",
year = "2019",
abstract = "Dendritic cells (DC) are professional antigen presenting cells that have an important role in inducing the immune response. Under normal conditions, DC reside in peripheral tissues in an immature state. However, they undergo a series of maturation steps in response to inflammatory stimuli. During maturation, DC up-regulate major histocompatibility complex (MHC) class II molecules and co-stimulatory molecules (CD40, CD80, CD86) for antigen presentation and increasingly secrete cytokines. Tolerogenic DC (tolDC) have immunoregulatory properties and are characterized by low expression of MHC class II and co-stimulatory molecules, with limited production of proinflammatory cytokines. TolDC-based immunotherapy is a promising perspective in the treatment of autoimmune diseases. Benfotiamine (S-benzoylthiamine-O-monophosphate) is an S-acyl derivative of vitamin B1 with anti-inflammatory and anti-oxidative properties. Here, we explored the potential of benfotiamine to induce tolerogenic phenotype of DC. DC were cultivated from progenitor bone marrow cells isolated from the femur of C57BL/6 mice. The cells were cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (20 ng/mL) with 100 ng/mL lipopolysaccharide added for the last 24 h of cultivation for maturation. Treatment with benfotiamine (100 μM) was performed on days 0, 2, 4 and 6. FACS analysis showed that benfotiamine applied during differentiation of DC suppressed the expression of MHC class II and CD86, while it did not affect the expression of CD40. The secretion of proinflammatory cytokines TNF, IL-1β, and IL-6 was also decreased. Morphological analysis showed that DC treated with benfotiamine were similar in shape and size to immature DC, despite the maturation stimulus that they were exposed to. The effects of benfotiamine are associated with its suppression of NF-κB translocation to the nucleus. Together, these results show that benfotiamine has the potential to direct DC toward tolDC. Studies on the application of benfotiamine-treated DC in animal models of autoimmunity are warranted.",
publisher = "Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade",
journal = "Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia",
title = "Benfotiamine directs dendritic cells toward a tolerogenic phenotype",
pages = "7",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6062"
}

Božić, I., Nikolovski, N., Lazarević, M., Miljković, Đ.,& Lavrnja, I.. (2019). Benfotiamine directs dendritic cells toward a tolerogenic phenotype. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
Belgrade: Institute for Biological Research "Siniša Stanković"– National Institute of Republic of Serbia, University of Belgrade., 7.
https://hdl.handle.net/21.15107/rcub_ibiss_6062

Božić I, Nikolovski N, Lazarević M, Miljković Đ, Lavrnja I. Benfotiamine directs dendritic cells toward a tolerogenic phenotype. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia. 2019;:7.
https://hdl.handle.net/21.15107/rcub_ibiss_6062 .

Božić, Iva, Nikolovski, Neda, Lazarević, Milica, Miljković, Đorđe, Lavrnja, Irena, "Benfotiamine directs dendritic cells toward a tolerogenic phenotype" in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia (2019):7,
https://hdl.handle.net/21.15107/rcub_ibiss_6062 .

TY  - CONF
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5982
AB  - Considering neuroinflammatory paradigm, increased extracellular levels of ATP have adverse effects, while adenosine is predominantly anti-inflammatory. In the CNS, NTPDase1/CD39 is the main enzyme that initiates the degradation pathway of extracellular ATP to adenosine. The aim of the study was to explore the activation state of the cells that express NTPDase1/CD39 – microglia and macrophages, during experimental autoimmune encephalomyelitis (EAE). Acute monophasic EAE was induced in female Dark Agouti rats. Animals were sacrificed at the disease onset (Eo), peak (Ep) and end (Ee). The lumbosacral parts of spinal cords were isolated for gene (qRT-PCR and in situ hybridization) and protein expression analysis (Western Blot, immunofluorescence and flow cytometry). Activation state of microglia/macrophages was assessed by colocalization analysis of NTPDase1/Iba1 and NTPDase1/CD68 with iNOS or Arg1 as specific markers of pro- and antiinflammatory state, respectively. During EAE, NTPDase1/CD39 was significantly increased both at mRNA and protein level at Ep. Immunofluorescence combined with flow cytometry showed that reactive microglia and mononuclear infiltrates accounted for the most of the observed increase. Both Iba1 and CD68 microglia/macrophage markers showed higher co-occurrence with iNOS at Eo and Arg1 at Ep, suggesting prevalence of M1-like at Eo and M2-like at Ep. In addition, NTPDase1 showed about three-times higher colocalization with Arg1 compared to iNOS at Ep, suggesting its higher association with M2-like activation state of microglia/ macrophages. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward anti-inflammatory phenotype in EAE.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages
SP  - 492
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5982
ER  - 

@conference{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Milošević, Ana and Bjelobaba, Ivana and Savić, Danijela and Peković, Sanja and Nedeljković, Nadežda and Laketa, Danijela",
year = "2019",
abstract = "Considering neuroinflammatory paradigm, increased extracellular levels of ATP have adverse effects, while adenosine is predominantly anti-inflammatory. In the CNS, NTPDase1/CD39 is the main enzyme that initiates the degradation pathway of extracellular ATP to adenosine. The aim of the study was to explore the activation state of the cells that express NTPDase1/CD39 – microglia and macrophages, during experimental autoimmune encephalomyelitis (EAE). Acute monophasic EAE was induced in female Dark Agouti rats. Animals were sacrificed at the disease onset (Eo), peak (Ep) and end (Ee). The lumbosacral parts of spinal cords were isolated for gene (qRT-PCR and in situ hybridization) and protein expression analysis (Western Blot, immunofluorescence and flow cytometry). Activation state of microglia/macrophages was assessed by colocalization analysis of NTPDase1/Iba1 and NTPDase1/CD68 with iNOS or Arg1 as specific markers of pro- and antiinflammatory state, respectively. During EAE, NTPDase1/CD39 was significantly increased both at mRNA and protein level at Ep. Immunofluorescence combined with flow cytometry showed that reactive microglia and mononuclear infiltrates accounted for the most of the observed increase. Both Iba1 and CD68 microglia/macrophage markers showed higher co-occurrence with iNOS at Eo and Arg1 at Ep, suggesting prevalence of M1-like at Eo and M2-like at Ep. In addition, NTPDase1 showed about three-times higher colocalization with Arg1 compared to iNOS at Ep, suggesting its higher association with M2-like activation state of microglia/ macrophages. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward anti-inflammatory phenotype in EAE.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages",
pages = "492",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5982"
}

Jakovljević, M., Lavrnja, I., Božić, I., Milošević, A., Bjelobaba, I., Savić, D., Peković, S., Nedeljković, N.,& Laketa, D.. (2019). NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 492.
https://hdl.handle.net/21.15107/rcub_ibiss_5982

Jakovljević M, Lavrnja I, Božić I, Milošević A, Bjelobaba I, Savić D, Peković S, Nedeljković N, Laketa D. NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:492.
https://hdl.handle.net/21.15107/rcub_ibiss_5982 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Milošević, Ana, Bjelobaba, Ivana, Savić, Danijela, Peković, Sanja, Nedeljković, Nadežda, Laketa, Danijela, "NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):492,
https://hdl.handle.net/21.15107/rcub_ibiss_5982 .

TY  - JOUR
AU  - Dacić, Sanja
AU  - Božić, Iva
AU  - Jeremić, Rada
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Rakić, Ljubisav
AU  - Stojiljković, Mirjana
AU  - Peković, Sanja
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5989
AB  - Aims: Traumatic brain injury (TBI) causes disruption in homeostasis of calcium ions (Ca2+), important second messenger considered as the major culprit of secondary injury and TBI-induced neuronal damage and death. Ca2+ entry into the cells occurs via various types of voltage-dependent calcium channels (VDCCs). The aim of this study was to evaluate the involvement of Ca2+ entry via L-type CaV1.2 VDCCs in the processes of neuroinflammation and regeneration after brain injury. Methods: TBI was performed on male Wistar rats by sensorimotor cortex ablation (SCA) at the following coordinates: 2 mm anterior and 4 mm posterior to bregma, and 4 mm lateral from the midline. Temporal and cellular pattern of CaV1.2 expression was followed at different time points post-injury (2, 7, 14, 30 dpi) using double immunofluorescence staining with specific markers. Results: Upregulation of CaV1.2 expression was detected on reactive astrocytes and astrocytic processes that form glial scar around the lesion site, on subset of proinflammatory microglia/macrophages and neutrophils surrounding the lesion cavity. Interestingly, presence of CaV1.2+ cells was detected in the migratory pathway, consisted of DCX+ progenitors, extending from subventricular zone up to the lesion site. Furthermore, CaV1.2+/DCX+ newborn neurons were detected in subgranular layer of hippocampal dentate gyrus. Conclusions: We concluded that L-type CaV1.2 calcium channel has an important role in the regulation of processes of neuroinflammation, neuroregeneration and neurogenesis, pointing to the complexity of intercellular regulation of Ca2+ homeostasis after brain injury. Consequently, modulation of CaV1.2 channels expression may be potential target for the treatment of brain injury.
PB  - Belgrade: Serbian Neuroscience Society
T2  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - L-type Calcium Channels Involvement in the Regulation of Neuroinflammation and Neuroregeneration After Brain Injury
SP  - 487
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5989
ER  - 

@article{
author = "Dacić, Sanja and Božić, Iva and Jeremić, Rada and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela and Rakić, Ljubisav and Stojiljković, Mirjana and Peković, Sanja",
year = "2019",
abstract = "Aims: Traumatic brain injury (TBI) causes disruption in homeostasis of calcium ions (Ca2+), important second messenger considered as the major culprit of secondary injury and TBI-induced neuronal damage and death. Ca2+ entry into the cells occurs via various types of voltage-dependent calcium channels (VDCCs). The aim of this study was to evaluate the involvement of Ca2+ entry via L-type CaV1.2 VDCCs in the processes of neuroinflammation and regeneration after brain injury. Methods: TBI was performed on male Wistar rats by sensorimotor cortex ablation (SCA) at the following coordinates: 2 mm anterior and 4 mm posterior to bregma, and 4 mm lateral from the midline. Temporal and cellular pattern of CaV1.2 expression was followed at different time points post-injury (2, 7, 14, 30 dpi) using double immunofluorescence staining with specific markers. Results: Upregulation of CaV1.2 expression was detected on reactive astrocytes and astrocytic processes that form glial scar around the lesion site, on subset of proinflammatory microglia/macrophages and neutrophils surrounding the lesion cavity. Interestingly, presence of CaV1.2+ cells was detected in the migratory pathway, consisted of DCX+ progenitors, extending from subventricular zone up to the lesion site. Furthermore, CaV1.2+/DCX+ newborn neurons were detected in subgranular layer of hippocampal dentate gyrus. Conclusions: We concluded that L-type CaV1.2 calcium channel has an important role in the regulation of processes of neuroinflammation, neuroregeneration and neurogenesis, pointing to the complexity of intercellular regulation of Ca2+ homeostasis after brain injury. Consequently, modulation of CaV1.2 channels expression may be potential target for the treatment of brain injury.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "L-type Calcium Channels Involvement in the Regulation of Neuroinflammation and Neuroregeneration After Brain Injury",
pages = "487",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5989"
}

Dacić, S., Božić, I., Jeremić, R., Bjelobaba, I., Lavrnja, I., Savić, D., Rakić, L., Stojiljković, M.,& Peković, S.. (2019). L-type Calcium Channels Involvement in the Regulation of Neuroinflammation and Neuroregeneration After Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 487.
https://hdl.handle.net/21.15107/rcub_ibiss_5989

Dacić S, Božić I, Jeremić R, Bjelobaba I, Lavrnja I, Savić D, Rakić L, Stojiljković M, Peković S. L-type Calcium Channels Involvement in the Regulation of Neuroinflammation and Neuroregeneration After Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:487.
https://hdl.handle.net/21.15107/rcub_ibiss_5989 .

Dacić, Sanja, Božić, Iva, Jeremić, Rada, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, Rakić, Ljubisav, Stojiljković, Mirjana, Peković, Sanja, "L-type Calcium Channels Involvement in the Regulation of Neuroinflammation and Neuroregeneration After Brain Injury" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):487,
https://hdl.handle.net/21.15107/rcub_ibiss_5989 .

TY  - CONF
AU  - Laketa, Danijela
AU  - Jakovljević, Marija
AU  - Božić, Iva
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Lavrnja, Irena
PY  - 2019
UR  - https://biore.bio.bg.ac.rs/handle/123456789/2265
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5893
AB  - Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) is the main ATP- and ADPdegrading
enzyme in extracellular fluid of the central nervous system. In the hydrolysis cascade
NTPDase1 removes ATP and ADP and produces AMP, which is hydrolysed by ecto-5'-nucleotidase to
adenosine. During neuroinflammation, increased extracellular ATP levels exert proinflammatory effects
at microglia as resident immune cells, while adenosine effects are antiinflammatory. Literature data
indicate involvement of purinergic signaling in experimental autoimmune encephalomyelitis (EAE), while
decreased number of NTPDase1/CD39+ regulatory T-cells was evidenced in multiple sclerosis.
Downregulation of NTPDase1 expression was observed in proinflammatory activation phenotype of
macrophages. However, data on the role of NTPDase1 on glial cells in neuroinflammation are still
scarce. We have shown increase in ATP-, ADP- and AMP-hydrolysis, together with upregulated mRNA
and protein expression of NTPDase1 in lumbar spinal cord, correlated to the disease course during EAE.
In this study we aimed to explore contribution of particular cell subsets to the observed changes in
NTPDase1 expression.
Acute monophasic EAE was induced in female rats of Dark Agouti strain by active immunization with a
mixture of spinal cord homogenate in complete Freund’s adjuvant. Immunized animals were sacrificed at
the onset, peak and end of symptoms, while naïve animals were used as control. Significant increase of
NTPDase1 immunofluorescence in lumbar spinal cord cross-sections was related to prominent infiltrates
at the peak of EAE and increased expression of NTPDase1 among isolated mononuclear cells. Analysis
of triple-labeled Arginase1/NTPDase1/Iba1 and iNOS/NTPDase1/Iba1 immunofluorescent micrographs
showed prevalent contribution of Arginase1+ microglia in comparison to iNOS+ microglia in NTPDase1
immunofluorescence, at the peak of EAE. Further studies are needed to reveal possible association of
NTPDase1 with antiinflammatory phenotype in microglia.
PB  - German Neuroscience Society
C3  - Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany
T1  - Microglia-related increase in NTPDase1 expression during EAE
SP  - T12-5B
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5893
ER  - 

@conference{
author = "Laketa, Danijela and Jakovljević, Marija and Božić, Iva and Bjelobaba, Ivana and Savić, Danijela and Peković, Sanja and Nedeljković, Nadežda and Lavrnja, Irena",
year = "2019",
abstract = "Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) is the main ATP- and ADPdegrading
enzyme in extracellular fluid of the central nervous system. In the hydrolysis cascade
NTPDase1 removes ATP and ADP and produces AMP, which is hydrolysed by ecto-5'-nucleotidase to
adenosine. During neuroinflammation, increased extracellular ATP levels exert proinflammatory effects
at microglia as resident immune cells, while adenosine effects are antiinflammatory. Literature data
indicate involvement of purinergic signaling in experimental autoimmune encephalomyelitis (EAE), while
decreased number of NTPDase1/CD39+ regulatory T-cells was evidenced in multiple sclerosis.
Downregulation of NTPDase1 expression was observed in proinflammatory activation phenotype of
macrophages. However, data on the role of NTPDase1 on glial cells in neuroinflammation are still
scarce. We have shown increase in ATP-, ADP- and AMP-hydrolysis, together with upregulated mRNA
and protein expression of NTPDase1 in lumbar spinal cord, correlated to the disease course during EAE.
In this study we aimed to explore contribution of particular cell subsets to the observed changes in
NTPDase1 expression.
Acute monophasic EAE was induced in female rats of Dark Agouti strain by active immunization with a
mixture of spinal cord homogenate in complete Freund’s adjuvant. Immunized animals were sacrificed at
the onset, peak and end of symptoms, while naïve animals were used as control. Significant increase of
NTPDase1 immunofluorescence in lumbar spinal cord cross-sections was related to prominent infiltrates
at the peak of EAE and increased expression of NTPDase1 among isolated mononuclear cells. Analysis
of triple-labeled Arginase1/NTPDase1/Iba1 and iNOS/NTPDase1/Iba1 immunofluorescent micrographs
showed prevalent contribution of Arginase1+ microglia in comparison to iNOS+ microglia in NTPDase1
immunofluorescence, at the peak of EAE. Further studies are needed to reveal possible association of
NTPDase1 with antiinflammatory phenotype in microglia.",
publisher = "German Neuroscience Society",
journal = "Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany",
title = "Microglia-related increase in NTPDase1 expression during EAE",
pages = "T12-5B",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5893"
}

Laketa, D., Jakovljević, M., Božić, I., Bjelobaba, I., Savić, D., Peković, S., Nedeljković, N.,& Lavrnja, I.. (2019). Microglia-related increase in NTPDase1 expression during EAE. in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany
German Neuroscience Society., T12-5B.
https://hdl.handle.net/21.15107/rcub_ibiss_5893

Laketa D, Jakovljević M, Božić I, Bjelobaba I, Savić D, Peković S, Nedeljković N, Lavrnja I. Microglia-related increase in NTPDase1 expression during EAE. in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany. 2019;:T12-5B.
https://hdl.handle.net/21.15107/rcub_ibiss_5893 .

Laketa, Danijela, Jakovljević, Marija, Božić, Iva, Bjelobaba, Ivana, Savić, Danijela, Peković, Sanja, Nedeljković, Nadežda, Lavrnja, Irena, "Microglia-related increase in NTPDase1 expression during EAE" in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany (2019):T12-5B,
https://hdl.handle.net/21.15107/rcub_ibiss_5893 .

TY  - JOUR
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Sévigny, Jean
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2019
UR  - https://www.frontiersin.org/article/10.3389/fnins.2019.00410/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6498900
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3434
AB  - Purinergic signaling is critically involved in neuroinflammation associated with multiple sclerosis (MS) and its major inflammatory animal model, experimental autoimmune encephalomyelitis (EAE). Herein, we explored the expression of ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) in the spinal cord, at the onset (Eo), peak (Ep), and end (Ee) of EAE. Several-fold increase in mRNA and in NTPDase1 protein levels were observed at Eo and Ep. In situ hybridization combined with fluorescent immunohistochemistry showed that reactive microglia and infiltrated mononuclear cells mostly accounted for the observed increase. Colocalization analysis revealed that up to 80% of Iba1 immunoreactivity and ∼50% of CD68 immunoreactivity was colocalized with NTPDase1, while flow cytometric analysis revealed that ∼70% of mononuclear infiltrates were NTPDase1+ at Ep. Given the main role of NTPDase1 to degrade proinflammatory ATP, we hypothesized that the observed up-regulation of NTPDase1 may be associated with the transition between proinflammatory M1-like to neuroprotective M2-like phenotype of microglia/macrophages during EAE. Functional phenotype of reactive microglia/macrophages that overexpress NTPDase1 was assessed by multi-image colocalization analysis using iNOS and Arg1 as selective markers for M1 and M2 reactive states, respectively. At the peak of EAE NTPDase1 immunoreactivity showed much higher co-occurrence with Arg1 immunoreactivity in microglia and macrophages, compared to iNOS, implying its stronger association with M2-like reactive phenotype. Additionally, in ∼80% of CD68 positive cells NTPDase1 was coexpressed with Arg1 compared to negligible fraction coexpresing iNOS and ∼15% coexpresing both markers, additionally indicating prevalent association of NTPDase1 with M2-like microglial/macrophages phenotype at Ep. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward antiinflammatory phenotype in EAE.
T2  - Frontiers in Neuroscience
T1  - Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.
VL  - 13
DO  - 10.3389/fnins.2019.00410
SP  - 410
ER  - 

@article{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Milošević, Ana and Bjelobaba, Ivana and Savić, Danijela and Sévigny, Jean and Peković, Sanja and Nedeljković, Nadežda and Laketa, Danijela",
year = "2019",
abstract = "Purinergic signaling is critically involved in neuroinflammation associated with multiple sclerosis (MS) and its major inflammatory animal model, experimental autoimmune encephalomyelitis (EAE). Herein, we explored the expression of ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) in the spinal cord, at the onset (Eo), peak (Ep), and end (Ee) of EAE. Several-fold increase in mRNA and in NTPDase1 protein levels were observed at Eo and Ep. In situ hybridization combined with fluorescent immunohistochemistry showed that reactive microglia and infiltrated mononuclear cells mostly accounted for the observed increase. Colocalization analysis revealed that up to 80% of Iba1 immunoreactivity and ∼50% of CD68 immunoreactivity was colocalized with NTPDase1, while flow cytometric analysis revealed that ∼70% of mononuclear infiltrates were NTPDase1+ at Ep. Given the main role of NTPDase1 to degrade proinflammatory ATP, we hypothesized that the observed up-regulation of NTPDase1 may be associated with the transition between proinflammatory M1-like to neuroprotective M2-like phenotype of microglia/macrophages during EAE. Functional phenotype of reactive microglia/macrophages that overexpress NTPDase1 was assessed by multi-image colocalization analysis using iNOS and Arg1 as selective markers for M1 and M2 reactive states, respectively. At the peak of EAE NTPDase1 immunoreactivity showed much higher co-occurrence with Arg1 immunoreactivity in microglia and macrophages, compared to iNOS, implying its stronger association with M2-like reactive phenotype. Additionally, in ∼80% of CD68 positive cells NTPDase1 was coexpressed with Arg1 compared to negligible fraction coexpresing iNOS and ∼15% coexpresing both markers, additionally indicating prevalent association of NTPDase1 with M2-like microglial/macrophages phenotype at Ep. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward antiinflammatory phenotype in EAE.",
journal = "Frontiers in Neuroscience",
title = "Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.",
volume = "13",
doi = "10.3389/fnins.2019.00410",
pages = "410"
}

Jakovljević, M., Lavrnja, I., Božić, I., Milošević, A., Bjelobaba, I., Savić, D., Sévigny, J., Peković, S., Nedeljković, N.,& Laketa, D.. (2019). Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.. in Frontiers in Neuroscience, 13, 410.
https://doi.org/10.3389/fnins.2019.00410

Jakovljević M, Lavrnja I, Božić I, Milošević A, Bjelobaba I, Savić D, Sévigny J, Peković S, Nedeljković N, Laketa D. Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.. in Frontiers in Neuroscience. 2019;13:410.
doi:10.3389/fnins.2019.00410 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Milošević, Ana, Bjelobaba, Ivana, Savić, Danijela, Sévigny, Jean, Peković, Sanja, Nedeljković, Nadežda, Laketa, Danijela, "Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE." in Frontiers in Neuroscience, 13 (2019):410,
https://doi.org/10.3389/fnins.2019.00410 . .

TY  - JOUR
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Laketa, Danijela
AU  - Adžić, Marija
AU  - Jakovljević, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2018
UR  - http://link.springer.com/10.1007/s11064-018-2509-8
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3027
AB  - Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.
T2  - Neurochemical Research
T1  - Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.
IS  - 5
VL  - 43
DO  - 10.1007/s11064-018-2509-8
SP  - 1020
EP  - 1034
ER  - 

@article{
author = "Božić, Iva and Milošević, Katarina and Laketa, Danijela and Adžić, Marija and Jakovljević, Marija and Bjelobaba, Ivana and Savić, Danijela and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2018",
abstract = "Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.",
journal = "Neurochemical Research",
title = "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.",
number = "5",
volume = "43",
doi = "10.1007/s11064-018-2509-8",
pages = "1020-1034"
}

Božić, I., Milošević, K., Laketa, D., Adžić, M., Jakovljević, M., Bjelobaba, I., Savić, D., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2018). Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research, 43(5), 1020-1034.
https://doi.org/10.1007/s11064-018-2509-8

Božić I, Milošević K, Laketa D, Adžić M, Jakovljević M, Bjelobaba I, Savić D, Nedeljković N, Peković S, Lavrnja I. Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research. 2018;43(5):1020-1034.
doi:10.1007/s11064-018-2509-8 .

Božić, Iva, Milošević, Katarina, Laketa, Danijela, Adžić, Marija, Jakovljević, Marija, Bjelobaba, Ivana, Savić, Danijela, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis." in Neurochemical Research, 43, no. 5 (2018):1020-1034,
https://doi.org/10.1007/s11064-018-2509-8 . .

TY  - CONF
AU  - Savić, Danijela
AU  - Lavrnja, Irena
AU  - Bjelobaba, Ivana
AU  - Dacić, Sanja
AU  - Laketa, Danijela
AU  - Božić, Iva
AU  - Jakovljević, Marija
AU  - Nedeljković, Nadežda
AU  - Rakić, Ljubisav
AU  - Peković, Sanja
PY  - 2018
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5888
AB  - Ribavirin je purinski nukleozidni analog, otkriven pre više decenija i odobren kao lek protiv virusa hepatitisa C. Sa otkrićem direktnih antivirusnih agenasa, nastupila je revolucija u lečenju hepatitisa C, a terapijska uloga ribavirina je marginalizovana. Međutim, ribavirin ima širok spektar dejstva što je otvorilo mogućnost da se ovaj lek preusmeri ka tretmanu drugih oboljenja. Naime, osim što deluje antivirusno (inhibicija virusne RNK polimeraze i izazivanje letalne mutageneze) ribavirin je i inhibitor eukariotskog faktora za inicijaciju translacije e4E, što je zaslužno za njegov anti-tumorski efekat, pokazan u leukemiji i na ćelijama glioma. Njegova druga opšte poznata unutarćelijska meta jeste enzim inozin-5’-monofosfat dehidrogenaza (IMPDH), koji predstavlja ključni faktor u de novo sintezi guaninskih nukleotida. Ćelije koje se isključivo na ovaj način snabdevaju purinskim nukleotidima, kao što su aktivirani limfociti i neke proliferišuće ćelije, izuzetno su senzitivne na delovanje ribavirina. Inhibicija IMPDH odgovorna je za imunosupresivno i imunomodulatorno dejstvo ribavirina, pokazano u in vitro i in vivo modelima neuroinflamacije. Dakle, iako ribavirin gubi centralnu ulogu koju je imao u terapiji infekcije virusom hepatitisa C, njegova multipotentna priroda koja se ogleda u različitim mehanizmima delovanja, predstavlja potencijal za preusmeravanje ka novim terapijskim indikacijama, kao što su kancer ili multipla skleroza.
PB  - Belgrade: Serbian Biological Society
C3  - Drugi kongres biologa Srbije; 2018 Sep 25-30; Kladovo, Srbija
T1  - Preusmeravanje antivirusnog leka ribavirina ka novim terapijskim indikacijama: primer multiple skleroze i neoplastičnih transformacija
SP  - 146
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5888
ER  - 

@conference{
author = "Savić, Danijela and Lavrnja, Irena and Bjelobaba, Ivana and Dacić, Sanja and Laketa, Danijela and Božić, Iva and Jakovljević, Marija and Nedeljković, Nadežda and Rakić, Ljubisav and Peković, Sanja",
year = "2018",
abstract = "Ribavirin je purinski nukleozidni analog, otkriven pre više decenija i odobren kao lek protiv virusa hepatitisa C. Sa otkrićem direktnih antivirusnih agenasa, nastupila je revolucija u lečenju hepatitisa C, a terapijska uloga ribavirina je marginalizovana. Međutim, ribavirin ima širok spektar dejstva što je otvorilo mogućnost da se ovaj lek preusmeri ka tretmanu drugih oboljenja. Naime, osim što deluje antivirusno (inhibicija virusne RNK polimeraze i izazivanje letalne mutageneze) ribavirin je i inhibitor eukariotskog faktora za inicijaciju translacije e4E, što je zaslužno za njegov anti-tumorski efekat, pokazan u leukemiji i na ćelijama glioma. Njegova druga opšte poznata unutarćelijska meta jeste enzim inozin-5’-monofosfat dehidrogenaza (IMPDH), koji predstavlja ključni faktor u de novo sintezi guaninskih nukleotida. Ćelije koje se isključivo na ovaj način snabdevaju purinskim nukleotidima, kao što su aktivirani limfociti i neke proliferišuće ćelije, izuzetno su senzitivne na delovanje ribavirina. Inhibicija IMPDH odgovorna je za imunosupresivno i imunomodulatorno dejstvo ribavirina, pokazano u in vitro i in vivo modelima neuroinflamacije. Dakle, iako ribavirin gubi centralnu ulogu koju je imao u terapiji infekcije virusom hepatitisa C, njegova multipotentna priroda koja se ogleda u različitim mehanizmima delovanja, predstavlja potencijal za preusmeravanje ka novim terapijskim indikacijama, kao što su kancer ili multipla skleroza.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Drugi kongres biologa Srbije; 2018 Sep 25-30; Kladovo, Srbija",
title = "Preusmeravanje antivirusnog leka ribavirina ka novim terapijskim indikacijama: primer multiple skleroze i neoplastičnih transformacija",
pages = "146",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5888"
}

Savić, D., Lavrnja, I., Bjelobaba, I., Dacić, S., Laketa, D., Božić, I., Jakovljević, M., Nedeljković, N., Rakić, L.,& Peković, S.. (2018). Preusmeravanje antivirusnog leka ribavirina ka novim terapijskim indikacijama: primer multiple skleroze i neoplastičnih transformacija. in Drugi kongres biologa Srbije; 2018 Sep 25-30; Kladovo, Srbija
Belgrade: Serbian Biological Society., 146.
https://hdl.handle.net/21.15107/rcub_ibiss_5888

Savić D, Lavrnja I, Bjelobaba I, Dacić S, Laketa D, Božić I, Jakovljević M, Nedeljković N, Rakić L, Peković S. Preusmeravanje antivirusnog leka ribavirina ka novim terapijskim indikacijama: primer multiple skleroze i neoplastičnih transformacija. in Drugi kongres biologa Srbije; 2018 Sep 25-30; Kladovo, Srbija. 2018;:146.
https://hdl.handle.net/21.15107/rcub_ibiss_5888 .

Savić, Danijela, Lavrnja, Irena, Bjelobaba, Ivana, Dacić, Sanja, Laketa, Danijela, Božić, Iva, Jakovljević, Marija, Nedeljković, Nadežda, Rakić, Ljubisav, Peković, Sanja, "Preusmeravanje antivirusnog leka ribavirina ka novim terapijskim indikacijama: primer multiple skleroze i neoplastičnih transformacija" in Drugi kongres biologa Srbije; 2018 Sep 25-30; Kladovo, Srbija (2018):146,
https://hdl.handle.net/21.15107/rcub_ibiss_5888 .

TY  - CONF
AU  - Milićević, Katarina
AU  - Milošević, Milena
AU  - Božić, Iva
AU  - Lavrnja, Irena
AU  - Stevanović, Ivana
AU  - Bijelić, Dunja D.
AU  - Živković, Irena
AU  - Stević, Zorica
AU  - Anđus, Pavle R.
PY  - 2017
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5990
AB  - Introduction. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons. Having in mind well documented facts that on one hand, ALS brain is under oxidative stress, and on the other that non-cell autonomous mechanisms involving glial cells contribute to the disease progression, we wanted to examine the effect of humoral factors immunoglobulins G from ALS patients (ALS IgG) on oxidative stress and antioxidative system of BV-2 microglial cell line. Methods. BV-2 cells were treated with ALS and control IgG (0.1 mg/ml). TNF-α release, oxidative stress markers and antioxidative enzymes activities were determined using biochemical assays (24 h treatment), while gene expression was determined using RT-qPCR (4 h treatment). ROS, cytosolic peroxide and pH alteration were evaluated with carboxy-H2DCFDA, HyPer and SypHer, respectively. Results. All tested ALS IgG (compared with control IgG) induced oxidative stress (rise in NO and lipid peroxidation), release of TNF-α and higher antioxidative defense (elevation of Mn- and Cu,Zn-superoxide dismutase, catalase, glutathione reductase with a decrease of glutathione peroxidase and glutathione). IgG from 4/11 ALS patients induced slow exponential rise of HyPer intensity and lower increase of SypHer intensity. None of the control IgG induced changes with neither of the indicators. Acute ROS generation was detected in 1/3 of ALS samples with carboxy-H2DCFDA. Conclusion. Our study demonstrates the potential role of inflammatory humoral factors, ALS IgGs, as triggers (via ROS generation) of the activation in microglia, known to occur in later stages of the disease.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
T1  - Serum IGG fraction from ALS patients alters redox homeostasis in the BV-2 microglial cell line
SP  - 72
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5990
ER  - 

@conference{
author = "Milićević, Katarina and Milošević, Milena and Božić, Iva and Lavrnja, Irena and Stevanović, Ivana and Bijelić, Dunja D. and Živković, Irena and Stević, Zorica and Anđus, Pavle R.",
year = "2017",
abstract = "Introduction. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons. Having in mind well documented facts that on one hand, ALS brain is under oxidative stress, and on the other that non-cell autonomous mechanisms involving glial cells contribute to the disease progression, we wanted to examine the effect of humoral factors immunoglobulins G from ALS patients (ALS IgG) on oxidative stress and antioxidative system of BV-2 microglial cell line. Methods. BV-2 cells were treated with ALS and control IgG (0.1 mg/ml). TNF-α release, oxidative stress markers and antioxidative enzymes activities were determined using biochemical assays (24 h treatment), while gene expression was determined using RT-qPCR (4 h treatment). ROS, cytosolic peroxide and pH alteration were evaluated with carboxy-H2DCFDA, HyPer and SypHer, respectively. Results. All tested ALS IgG (compared with control IgG) induced oxidative stress (rise in NO and lipid peroxidation), release of TNF-α and higher antioxidative defense (elevation of Mn- and Cu,Zn-superoxide dismutase, catalase, glutathione reductase with a decrease of glutathione peroxidase and glutathione). IgG from 4/11 ALS patients induced slow exponential rise of HyPer intensity and lower increase of SypHer intensity. None of the control IgG induced changes with neither of the indicators. Acute ROS generation was detected in 1/3 of ALS samples with carboxy-H2DCFDA. Conclusion. Our study demonstrates the potential role of inflammatory humoral factors, ALS IgGs, as triggers (via ROS generation) of the activation in microglia, known to occur in later stages of the disease.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia",
title = "Serum IGG fraction from ALS patients alters redox homeostasis in the BV-2 microglial cell line",
pages = "72",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5990"
}

Milićević, K., Milošević, M., Božić, I., Lavrnja, I., Stevanović, I., Bijelić, D. D., Živković, I., Stević, Z.,& Anđus, P. R.. (2017). Serum IGG fraction from ALS patients alters redox homeostasis in the BV-2 microglial cell line. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 72.
https://hdl.handle.net/21.15107/rcub_ibiss_5990

Milićević K, Milošević M, Božić I, Lavrnja I, Stevanović I, Bijelić DD, Živković I, Stević Z, Anđus PR. Serum IGG fraction from ALS patients alters redox homeostasis in the BV-2 microglial cell line. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia. 2017;:72.
https://hdl.handle.net/21.15107/rcub_ibiss_5990 .

Milićević, Katarina, Milošević, Milena, Božić, Iva, Lavrnja, Irena, Stevanović, Ivana, Bijelić, Dunja D., Živković, Irena, Stević, Zorica, Anđus, Pavle R., "Serum IGG fraction from ALS patients alters redox homeostasis in the BV-2 microglial cell line" in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia (2017):72,
https://hdl.handle.net/21.15107/rcub_ibiss_5990 .

TY  - CONF
AU  - Laketa, Danijela
AU  - Josipović, Nataša
AU  - Lavrnja, Irena
AU  - Bjelobaba, Ivana
AU  - Jakovljević, Marija
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Dacić, Sanja
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
PY  - 2017
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5988
AB  - Introduction. Ecto-5'–nucleotidase (eN) catalyzes terminal step of extracellular ATP hydrolysis, producing anti-inflammatory adenosine. We reported significantly increased eN activity in lumbar spinal cord during experimental autoimmune encephalomyelitis (EAE), together with increased protein expression connected mainly with reactive astrocytes and appearance of new isoform at ~75kDa at the peak of the disease, besides usual ~71kDa isoform. Since eN is glycoprotein with five potential N-glycosylation sites and 
redicted molecular weight of 57-59 kDa, we hypothesized that occurrence of second isoform during EAE is due to changes in glycosylation pattern, possibly affecting kinetic properties of the enzyme. Methods. Lumbar parts of the spinal cords were obtained from Dark Agouti rats at the onset (Eo), peak (Ep) and the end of symptoms (Er) during EAE and from naïve control animals (C). Results. We here report significant changes of kinetic properties regarding AMP-hydrolysis during EAE, with almost 50% increase of maximal velocity at Ep (92.35±1.86nmolPi/min/mg) and Er (90.68±2.17nmolPi/min/mg), compared to C, whilst Km increased double at Ep (0.041±0.003mmol/l). Enzymatic deglycosylation caused triple decrease of Vmax (33.6±1.8nmolPi/mg/min) at Ep, and double decrease of Km (0.022±0.008mmol/l), whilst immunoblot
probed with anti-eN antibody revealed triple protein band at ~60kDa at all investigated time-points. Conclusion. Our results show that changes of kinetic properties during EAE, at least partially, are governed by modification of glycosylation pattern. Also, appearance of new isoform at the peak of EAE is direct consequence of glycosylation changes. In summary, besides gene and protein expression changes of eN, glycosylation might be additional route of inflammation control conducted by astrocytes.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
T1  - Appearance of second ecto-5'-nucleotidase isoform during experimental autoimmune encephalomyelitis is caused by changes in glycosylation pattern
SP  - 70
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5988
ER  - 

@conference{
author = "Laketa, Danijela and Josipović, Nataša and Lavrnja, Irena and Bjelobaba, Ivana and Jakovljević, Marija and Božić, Iva and Savić, Danijela and Dacić, Sanja and Peković, Sanja and Nedeljković, Nadežda",
year = "2017",
abstract = "Introduction. Ecto-5'–nucleotidase (eN) catalyzes terminal step of extracellular ATP hydrolysis, producing anti-inflammatory adenosine. We reported significantly increased eN activity in lumbar spinal cord during experimental autoimmune encephalomyelitis (EAE), together with increased protein expression connected mainly with reactive astrocytes and appearance of new isoform at ~75kDa at the peak of the disease, besides usual ~71kDa isoform. Since eN is glycoprotein with five potential N-glycosylation sites and 
redicted molecular weight of 57-59 kDa, we hypothesized that occurrence of second isoform during EAE is due to changes in glycosylation pattern, possibly affecting kinetic properties of the enzyme. Methods. Lumbar parts of the spinal cords were obtained from Dark Agouti rats at the onset (Eo), peak (Ep) and the end of symptoms (Er) during EAE and from naïve control animals (C). Results. We here report significant changes of kinetic properties regarding AMP-hydrolysis during EAE, with almost 50% increase of maximal velocity at Ep (92.35±1.86nmolPi/min/mg) and Er (90.68±2.17nmolPi/min/mg), compared to C, whilst Km increased double at Ep (0.041±0.003mmol/l). Enzymatic deglycosylation caused triple decrease of Vmax (33.6±1.8nmolPi/mg/min) at Ep, and double decrease of Km (0.022±0.008mmol/l), whilst immunoblot
probed with anti-eN antibody revealed triple protein band at ~60kDa at all investigated time-points. Conclusion. Our results show that changes of kinetic properties during EAE, at least partially, are governed by modification of glycosylation pattern. Also, appearance of new isoform at the peak of EAE is direct consequence of glycosylation changes. In summary, besides gene and protein expression changes of eN, glycosylation might be additional route of inflammation control conducted by astrocytes.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia",
title = "Appearance of second ecto-5'-nucleotidase isoform during experimental autoimmune encephalomyelitis is caused by changes in glycosylation pattern",
pages = "70",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5988"
}

Laketa, D., Josipović, N., Lavrnja, I., Bjelobaba, I., Jakovljević, M., Božić, I., Savić, D., Dacić, S., Peković, S.,& Nedeljković, N.. (2017). Appearance of second ecto-5'-nucleotidase isoform during experimental autoimmune encephalomyelitis is caused by changes in glycosylation pattern. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 70.
https://hdl.handle.net/21.15107/rcub_ibiss_5988

Laketa D, Josipović N, Lavrnja I, Bjelobaba I, Jakovljević M, Božić I, Savić D, Dacić S, Peković S, Nedeljković N. Appearance of second ecto-5'-nucleotidase isoform during experimental autoimmune encephalomyelitis is caused by changes in glycosylation pattern. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia. 2017;:70.
https://hdl.handle.net/21.15107/rcub_ibiss_5988 .

Laketa, Danijela, Josipović, Nataša, Lavrnja, Irena, Bjelobaba, Ivana, Jakovljević, Marija, Božić, Iva, Savić, Danijela, Dacić, Sanja, Peković, Sanja, Nedeljković, Nadežda, "Appearance of second ecto-5'-nucleotidase isoform during experimental autoimmune encephalomyelitis is caused by changes in glycosylation pattern" in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia (2017):70,
https://hdl.handle.net/21.15107/rcub_ibiss_5988 .