TY  - CONF
AU  - Bisenić, Aleksandar
AU  - Tomić, Sergej
AU  - Bekić, Marina
AU  - Pavlović, Luka
AU  - Dinić, Miroslav
AU  - Terzić- Vidojević, Amarela
AU  - Radojević, Dušan
AU  - Soković Bajić, Svetlana
AU  - Mitrović, Hristina
AU  - Jakovljević, Stefan
AU  - Stevanović, Dušan
AU  - Golić, Nataša
AU  - Đokić, Jelena
PY  - 2024
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2374
AB  - Alterations in gut microbiota and deregulation
of the gut immune system are recognized
as important events in autoimmune diseases.
The knowledge about the important role of anaerobic
gut bacteria that produce short-chain
fatty acids (SCFAs), in the regulation of intestinal
barrier and immune response made a way
for the development of microbiota-based interventions.
Our research aimed to isolate the
strains with the potential to produce SCFAs,
from healthy volunteer fecal material, and to
test their effects on IL-8 production in the culture
of intestinal epithelial cells (Caco2) as an in
vitro system imitating initial intestinal inflammation,
the effects on the expression of neuronal
activity-regulated genes of Caenorhabditis
elegans, and the effect on the development
of experimental autoimmune encephalomyelitis
(EAE), a mouse model of multiple  sclerosis.
Three isolated butyric acid (BA)-producing
strains, and three acetic acid (AA)-producing
strains diminished the production of IL-8 in Caco-
2 cells treated with IL-1β/TNF-α. Further, all
BA-producing strains stimulated the expression
of important neuro-related genes in C. elegans.
Based on the strongest effects in these
assays an isolate identified as Faecalimonas sp.
NGB245 strain was further tested in EAE model.
The oral treatment of EAE-induced mice with
this strain for 16h per day for 15 days resulted
in alleviated daily clinical scores, maximal
clinical scores, and the duration of the illness
in comparison to the effect of media used for
strain cultivation. These results point to the potential
of NGB245 to modify the gut-brain axis
opening the field for future development of microbiota-
based therapy for the diseases associated
with immune response dysfunctions.
PB  - Serbian Society for Microbiology
C3  - XIII Congress of microbiologists of Serbia: From biotechnology to human and planetary health
T1  - SHORT-CHAIN FATTY ACID-PRODUCING FAECALIMONAS SP. NGB245 STRAIN REGULATES THE EXPRESSION OF NEURONAL ACTIVITY-REGULATED GENES AND ATTENUATES THE SYMPTOMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
EP  - 116
SP  - 116
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2374
ER  - 

@conference{
author = "Bisenić, Aleksandar and Tomić, Sergej and Bekić, Marina and Pavlović, Luka and Dinić, Miroslav and Terzić- Vidojević, Amarela and Radojević, Dušan and Soković Bajić, Svetlana and Mitrović, Hristina and Jakovljević, Stefan and Stevanović, Dušan and Golić, Nataša and Đokić, Jelena",
year = "2024",
abstract = "Alterations in gut microbiota and deregulation
of the gut immune system are recognized
as important events in autoimmune diseases.
The knowledge about the important role of anaerobic
gut bacteria that produce short-chain
fatty acids (SCFAs), in the regulation of intestinal
barrier and immune response made a way
for the development of microbiota-based interventions.
Our research aimed to isolate the
strains with the potential to produce SCFAs,
from healthy volunteer fecal material, and to
test their effects on IL-8 production in the culture
of intestinal epithelial cells (Caco2) as an in
vitro system imitating initial intestinal inflammation,
the effects on the expression of neuronal
activity-regulated genes of Caenorhabditis
elegans, and the effect on the development
of experimental autoimmune encephalomyelitis
(EAE), a mouse model of multiple  sclerosis.
Three isolated butyric acid (BA)-producing
strains, and three acetic acid (AA)-producing
strains diminished the production of IL-8 in Caco-
2 cells treated with IL-1β/TNF-α. Further, all
BA-producing strains stimulated the expression
of important neuro-related genes in C. elegans.
Based on the strongest effects in these
assays an isolate identified as Faecalimonas sp.
NGB245 strain was further tested in EAE model.
The oral treatment of EAE-induced mice with
this strain for 16h per day for 15 days resulted
in alleviated daily clinical scores, maximal
clinical scores, and the duration of the illness
in comparison to the effect of media used for
strain cultivation. These results point to the potential
of NGB245 to modify the gut-brain axis
opening the field for future development of microbiota-
based therapy for the diseases associated
with immune response dysfunctions.",
publisher = "Serbian Society for Microbiology",
journal = "XIII Congress of microbiologists of Serbia: From biotechnology to human and planetary health",
title = "SHORT-CHAIN FATTY ACID-PRODUCING FAECALIMONAS SP. NGB245 STRAIN REGULATES THE EXPRESSION OF NEURONAL ACTIVITY-REGULATED GENES AND ATTENUATES THE SYMPTOMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS",
pages = "116-116",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2374"
}

Bisenić, A., Tomić, S., Bekić, M., Pavlović, L., Dinić, M., Terzić- Vidojević, A., Radojević, D., Soković Bajić, S., Mitrović, H., Jakovljević, S., Stevanović, D., Golić, N.,& Đokić, J.. (2024). SHORT-CHAIN FATTY ACID-PRODUCING FAECALIMONAS SP. NGB245 STRAIN REGULATES THE EXPRESSION OF NEURONAL ACTIVITY-REGULATED GENES AND ATTENUATES THE SYMPTOMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. in XIII Congress of microbiologists of Serbia: From biotechnology to human and planetary health
Serbian Society for Microbiology., 116-116.
https://hdl.handle.net/21.15107/rcub_imagine_2374

Bisenić A, Tomić S, Bekić M, Pavlović L, Dinić M, Terzić- Vidojević A, Radojević D, Soković Bajić S, Mitrović H, Jakovljević S, Stevanović D, Golić N, Đokić J. SHORT-CHAIN FATTY ACID-PRODUCING FAECALIMONAS SP. NGB245 STRAIN REGULATES THE EXPRESSION OF NEURONAL ACTIVITY-REGULATED GENES AND ATTENUATES THE SYMPTOMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. in XIII Congress of microbiologists of Serbia: From biotechnology to human and planetary health. 2024;:116-116.
https://hdl.handle.net/21.15107/rcub_imagine_2374 .

Bisenić, Aleksandar, Tomić, Sergej, Bekić, Marina, Pavlović, Luka, Dinić, Miroslav, Terzić- Vidojević, Amarela, Radojević, Dušan, Soković Bajić, Svetlana, Mitrović, Hristina, Jakovljević, Stefan, Stevanović, Dušan, Golić, Nataša, Đokić, Jelena, "SHORT-CHAIN FATTY ACID-PRODUCING FAECALIMONAS SP. NGB245 STRAIN REGULATES THE EXPRESSION OF NEURONAL ACTIVITY-REGULATED GENES AND ATTENUATES THE SYMPTOMS OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS" in XIII Congress of microbiologists of Serbia: From biotechnology to human and planetary health (2024):116-116,
https://hdl.handle.net/21.15107/rcub_imagine_2374 .

TY  - JOUR
AU  - Milanović, Marijana
AU  - Bekić, Marina
AU  - Đokić, Jelena
AU  - Vučević, Dragana
AU  - Čolić, Miodrag
AU  - Tomić, Sergej
PY  - 2024
UR  - https://www.ijbs.com/v20p1064.htm
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2313
AB  - Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs’ capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.
PB  - Ivyspring International
T2  - International Journal of Biological Sciences
T2  - International Journal of Biological Sciences
T1  - Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response
EP  - 1087
IS  - 3
SP  - 1064
VL  - 20
DO  - 10.7150/ijbs.91109
ER  - 

@article{
author = "Milanović, Marijana and Bekić, Marina and Đokić, Jelena and Vučević, Dragana and Čolić, Miodrag and Tomić, Sergej",
year = "2024",
abstract = "Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs’ capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.",
publisher = "Ivyspring International",
journal = "International Journal of Biological Sciences, International Journal of Biological Sciences",
title = "Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response",
pages = "1087-1064",
number = "3",
volume = "20",
doi = "10.7150/ijbs.91109"
}

Milanović, M., Bekić, M., Đokić, J., Vučević, D., Čolić, M.,& Tomić, S.. (2024). Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. in International Journal of Biological Sciences
Ivyspring International., 20(3), 1064-1087.
https://doi.org/10.7150/ijbs.91109

Milanović M, Bekić M, Đokić J, Vučević D, Čolić M, Tomić S. Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. in International Journal of Biological Sciences. 2024;20(3):1064-1087.
doi:10.7150/ijbs.91109 .

Milanović, Marijana, Bekić, Marina, Đokić, Jelena, Vučević, Dragana, Čolić, Miodrag, Tomić, Sergej, "Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response" in International Journal of Biological Sciences, 20, no. 3 (2024):1064-1087,
https://doi.org/10.7150/ijbs.91109 . .

TY  - JOUR
AU  - Drakul, Marija
AU  - Tomić, Sergej
AU  - Bekić, Marina
AU  - Mihajlović, Dušan
AU  - Vasiljević, Miloš
AU  - Rakočević, Sara
AU  - Đokić, Jelena
AU  - Popović, Nikola
AU  - Bokonjić, Dejan
AU  - Čolić, Miodrag
PY  - 2023
UR  - https://www.mdpi.com/1422-0067/24/23/16829
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2220
AB  - Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T2  - International Journal of Molecular Sciences
T1  - Sitagliptin Induces Tolerogenic Human Dendritic Cells
IS  - 23
SP  - 16829
VL  - 24
DO  - 10.3390/ijms242316829
ER  - 

@article{
author = "Drakul, Marija and Tomić, Sergej and Bekić, Marina and Mihajlović, Dušan and Vasiljević, Miloš and Rakočević, Sara and Đokić, Jelena and Popović, Nikola and Bokonjić, Dejan and Čolić, Miodrag",
year = "2023",
abstract = "Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences, International Journal of Molecular Sciences",
title = "Sitagliptin Induces Tolerogenic Human Dendritic Cells",
number = "23",
pages = "16829",
volume = "24",
doi = "10.3390/ijms242316829"
}

Drakul, M., Tomić, S., Bekić, M., Mihajlović, D., Vasiljević, M., Rakočević, S., Đokić, J., Popović, N., Bokonjić, D.,& Čolić, M.. (2023). Sitagliptin Induces Tolerogenic Human Dendritic Cells. in International Journal of Molecular Sciences
MDPI., 24(23), 16829.
https://doi.org/10.3390/ijms242316829

Drakul M, Tomić S, Bekić M, Mihajlović D, Vasiljević M, Rakočević S, Đokić J, Popović N, Bokonjić D, Čolić M. Sitagliptin Induces Tolerogenic Human Dendritic Cells. in International Journal of Molecular Sciences. 2023;24(23):16829.
doi:10.3390/ijms242316829 .

Drakul, Marija, Tomić, Sergej, Bekić, Marina, Mihajlović, Dušan, Vasiljević, Miloš, Rakočević, Sara, Đokić, Jelena, Popović, Nikola, Bokonjić, Dejan, Čolić, Miodrag, "Sitagliptin Induces Tolerogenic Human Dendritic Cells" in International Journal of Molecular Sciences, 24, no. 23 (2023):16829,
https://doi.org/10.3390/ijms242316829 . .

TY  - JOUR
AU  - Čolić, Miodrag
AU  - Miljuš, Nataša
AU  - Đokić, Jelena
AU  - Bekić, Marina
AU  - Krivokuća, Aleksandra
AU  - Tomić, Sergej
AU  - Radojević, Dušan
AU  - Radanović, Marina
AU  - Eraković, Mile
AU  - Ismaili, Bashkim
AU  - Škrbić, Ranko
PY  - 2023
UR  - https://www.mdpi.com/1422-0067/24/20/15407
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2167
AB  - Pomegranate has shown a favorable effect on gingivitis/periodontitis, but the mechanisms involved are poorly understood. The aim of this study was to test the effect of pomegranate peel extract (PoPEx) on gingiva-derived mesenchymal stromal cells (GMSCs) under physiological and inflammatory conditions. GMSC lines from healthy (H) and periodontitis (P) gingiva (n = 3 of each) were established. The lines were treated with two non-toxic concentrations of PoPEX (low—10; high—40 µg/mL), with or without additional lipopolysaccharide (LPS) stimulation. Twenty-four genes in GMSCs involved in different functions were examined using real-time polymerase chain reaction (RT-PCR). PoPEx (mostly at higher concentrations) inhibited the basal expression of IL-6, MCP-1, GRO-α, RANTES, IP-10, HIF-1α, SDF-1, and HGF but increased the expression of IL-8, TLR3, TGF-β, TGF-β/LAP ratio, IDO-1, and IGFB4 genes in H-GMSCs. PoPEx increased IL-6, RANTES, MMP3, and BMP2 but inhibited TLR2 and GRO-α gene expression in P-GMSCs. LPS upregulated genes for proinflammatory cytokines and chemokines, tissue regeneration/repair (MMP3, IGFBP4, HGF), and immunomodulation (IP-10, RANTES, IDO-1, TLR3, COX-2), more strongly in P-GMSCs. PoPEx also potentiated most genes’ expression in LPS-stimulated P-GMSCs, including upregulation of osteoblastic genes (RUNX2, BMP2, COL1A1, and OPG), simultaneously inhibiting cell proliferation. In conclusion, the modulatory effects of PoPEx on gene expression in GMSCs are complex and dependent on applied concentrations, GMSC type, and LPS stimulation. Generally, the effect is more pronounced in inflammation-simulating conditions.
T2  - International Journal of Molecular Sciences
T2  - International Journal of Molecular Sciences
T1  - Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions
IS  - 20
SP  - 15407
VL  - 24
DO  - 10.3390/ijms242015407
ER  - 

@article{
author = "Čolić, Miodrag and Miljuš, Nataša and Đokić, Jelena and Bekić, Marina and Krivokuća, Aleksandra and Tomić, Sergej and Radojević, Dušan and Radanović, Marina and Eraković, Mile and Ismaili, Bashkim and Škrbić, Ranko",
year = "2023",
abstract = "Pomegranate has shown a favorable effect on gingivitis/periodontitis, but the mechanisms involved are poorly understood. The aim of this study was to test the effect of pomegranate peel extract (PoPEx) on gingiva-derived mesenchymal stromal cells (GMSCs) under physiological and inflammatory conditions. GMSC lines from healthy (H) and periodontitis (P) gingiva (n = 3 of each) were established. The lines were treated with two non-toxic concentrations of PoPEX (low—10; high—40 µg/mL), with or without additional lipopolysaccharide (LPS) stimulation. Twenty-four genes in GMSCs involved in different functions were examined using real-time polymerase chain reaction (RT-PCR). PoPEx (mostly at higher concentrations) inhibited the basal expression of IL-6, MCP-1, GRO-α, RANTES, IP-10, HIF-1α, SDF-1, and HGF but increased the expression of IL-8, TLR3, TGF-β, TGF-β/LAP ratio, IDO-1, and IGFB4 genes in H-GMSCs. PoPEx increased IL-6, RANTES, MMP3, and BMP2 but inhibited TLR2 and GRO-α gene expression in P-GMSCs. LPS upregulated genes for proinflammatory cytokines and chemokines, tissue regeneration/repair (MMP3, IGFBP4, HGF), and immunomodulation (IP-10, RANTES, IDO-1, TLR3, COX-2), more strongly in P-GMSCs. PoPEx also potentiated most genes’ expression in LPS-stimulated P-GMSCs, including upregulation of osteoblastic genes (RUNX2, BMP2, COL1A1, and OPG), simultaneously inhibiting cell proliferation. In conclusion, the modulatory effects of PoPEx on gene expression in GMSCs are complex and dependent on applied concentrations, GMSC type, and LPS stimulation. Generally, the effect is more pronounced in inflammation-simulating conditions.",
journal = "International Journal of Molecular Sciences, International Journal of Molecular Sciences",
title = "Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions",
number = "20",
pages = "15407",
volume = "24",
doi = "10.3390/ijms242015407"
}

Čolić, M., Miljuš, N., Đokić, J., Bekić, M., Krivokuća, A., Tomić, S., Radojević, D., Radanović, M., Eraković, M., Ismaili, B.,& Škrbić, R.. (2023). Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions. in International Journal of Molecular Sciences, 24(20), 15407.
https://doi.org/10.3390/ijms242015407

Čolić M, Miljuš N, Đokić J, Bekić M, Krivokuća A, Tomić S, Radojević D, Radanović M, Eraković M, Ismaili B, Škrbić R. Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions. in International Journal of Molecular Sciences. 2023;24(20):15407.
doi:10.3390/ijms242015407 .

Čolić, Miodrag, Miljuš, Nataša, Đokić, Jelena, Bekić, Marina, Krivokuća, Aleksandra, Tomić, Sergej, Radojević, Dušan, Radanović, Marina, Eraković, Mile, Ismaili, Bashkim, Škrbić, Ranko, "Pomegranate Peel Extract Differently Modulates Gene Expression in Gingiva-Derived Mesenchymal Stromal Cells under Physiological and Inflammatory Conditions" in International Journal of Molecular Sciences, 24, no. 20 (2023):15407,
https://doi.org/10.3390/ijms242015407 . .

TY  - CONF
AU  - Bekić, Marina
AU  - Đokić, Jelena
AU  - Radojević, Dušan
AU  - Vučević, Dragana
AU  - Vasilev, Saša
AU  - Tomić, Sergej
PY  - 2023
UR  - https://belbi.bg.ac.rs/
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2042
AB  - Although genetic predisposition to Multiple Sclerosis (MS) may play an essential role in disease
development, myeloid cell overactivation and gut microbiota dysbiosis are key contributors to MS
pathogenesis. Myeloid-Derived Suppressor Cells (MDSC)s are immature myeloid cells with strong
immunosuppressive functions which can be exploited in the treatment of autoimmune diseases.
Considering the limited data on MDSCs application in MS therapy and their poorly studied effects
on the gut microbiota, we have investigated the therapeutic potential of mice MDSC differentiated
according to the standard protocol (MDSC) and modified with the addition of prostaglandin (PG)
E2 (MDSC-PGE2) to ameliorate experimental autoimmune encephalomyelitis (EAE) induced with
MOG35-55/CFA/PtX in C57BL/6 mice. Additionally, we analyzed the changes in gut microbiota
features in control and MDSC-treated animals by using a shotgun metagenomics approach. In
mice, PGE2-activated MDSC significantly inhibited the onset and clinical course of EAE. This effect
correlated with increased IL-10, TGF-β, IL-4 production, and Arginase-1 level in MDSC-PGE2,
as well as with reduced leukocyte infiltrates in the spinal cord. MDSC-PGE2 protective effect is
also reflected in the maintenance of gut microbiota composition based on Kraken2/Bracken2
and LEfSe analysis. We observed an increase of MS-associated species Romboutsia ilealis in
the control EAE group, while in both MDSC treatments the increase in relative abundances of
Muribaculum gordoncarteri and Duncaniella dubiosis, associated with immunoregulatory properties,
was observed. Microbial metabolic pathways profiling using Humann3 pipeline also reveals the
increase in pathways involved in the production of potentially immunoregulatory metabolites
in the MDSC-PGE2 group. In conclusion, we pointed to the significant association between the
efficacy of MDSC-PGE2 treatment and gut microbiota features which can be further exploited in
order to improve MDSC-based EAE therapy.
PB  - Belgrade : Institute of molecular genetics and genetic engineering
C3  - 4th Belgrade Bioinformatics Conference
T1  - Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation
EP  - 97
SP  - 97
VL  - 4
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2042
ER  - 

@conference{
author = "Bekić, Marina and Đokić, Jelena and Radojević, Dušan and Vučević, Dragana and Vasilev, Saša and Tomić, Sergej",
year = "2023",
abstract = "Although genetic predisposition to Multiple Sclerosis (MS) may play an essential role in disease
development, myeloid cell overactivation and gut microbiota dysbiosis are key contributors to MS
pathogenesis. Myeloid-Derived Suppressor Cells (MDSC)s are immature myeloid cells with strong
immunosuppressive functions which can be exploited in the treatment of autoimmune diseases.
Considering the limited data on MDSCs application in MS therapy and their poorly studied effects
on the gut microbiota, we have investigated the therapeutic potential of mice MDSC differentiated
according to the standard protocol (MDSC) and modified with the addition of prostaglandin (PG)
E2 (MDSC-PGE2) to ameliorate experimental autoimmune encephalomyelitis (EAE) induced with
MOG35-55/CFA/PtX in C57BL/6 mice. Additionally, we analyzed the changes in gut microbiota
features in control and MDSC-treated animals by using a shotgun metagenomics approach. In
mice, PGE2-activated MDSC significantly inhibited the onset and clinical course of EAE. This effect
correlated with increased IL-10, TGF-β, IL-4 production, and Arginase-1 level in MDSC-PGE2,
as well as with reduced leukocyte infiltrates in the spinal cord. MDSC-PGE2 protective effect is
also reflected in the maintenance of gut microbiota composition based on Kraken2/Bracken2
and LEfSe analysis. We observed an increase of MS-associated species Romboutsia ilealis in
the control EAE group, while in both MDSC treatments the increase in relative abundances of
Muribaculum gordoncarteri and Duncaniella dubiosis, associated with immunoregulatory properties,
was observed. Microbial metabolic pathways profiling using Humann3 pipeline also reveals the
increase in pathways involved in the production of potentially immunoregulatory metabolites
in the MDSC-PGE2 group. In conclusion, we pointed to the significant association between the
efficacy of MDSC-PGE2 treatment and gut microbiota features which can be further exploited in
order to improve MDSC-based EAE therapy.",
publisher = "Belgrade : Institute of molecular genetics and genetic engineering",
journal = "4th Belgrade Bioinformatics Conference",
title = "Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation",
pages = "97-97",
volume = "4",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2042"
}

Bekić, M., Đokić, J., Radojević, D., Vučević, D., Vasilev, S.,& Tomić, S.. (2023). Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation. in 4th Belgrade Bioinformatics Conference
Belgrade : Institute of molecular genetics and genetic engineering., 4, 97-97.
https://hdl.handle.net/21.15107/rcub_imagine_2042

Bekić M, Đokić J, Radojević D, Vučević D, Vasilev S, Tomić S. Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation. in 4th Belgrade Bioinformatics Conference. 2023;4:97-97.
https://hdl.handle.net/21.15107/rcub_imagine_2042 .

Bekić, Marina, Đokić, Jelena, Radojević, Dušan, Vučević, Dragana, Vasilev, Saša, Tomić, Sergej, "Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation" in 4th Belgrade Bioinformatics Conference, 4 (2023):97-97,
https://hdl.handle.net/21.15107/rcub_imagine_2042 .

TY  - JOUR
AU  - Radojević, Dušan
AU  - Bekić, Marina
AU  - Gruden-Movsesijan, Alisa
AU  - Ilić, Nataša
AU  - Dinić, Miroslav
AU  - Bisenić, Aleksandar
AU  - Golić, Nataša
AU  - Vucević, Dragana
AU  - Đokić, Jelena
AU  - Tomić, Sergej
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1540
AB  - Over-activated myeloid cells and disturbance in gut microbiota composition are critical factors contributing to the pathogenesis of Multiple Sclerosis (MS). Myeloid-derived suppressor cells (MDSCs) emerged as promising regulators of chronic inflammatory diseases, including autoimmune diseases. However, it remained unclear whether MDSCs display any therapeutic potential in MS, and how this therapy modulates gut microbiota composition. Here, we assessed the potential of in vitro generated bone marrow-derived MDSCs to ameliorate experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats and investigated how their application associates with the changes in gut microbiota composition. MDSCs differentiated with prostaglandin (PG)E2 (MDSC-PGE2) and control MDSCs (differentiated without PGE2) displayed strong immunosuppressive properties in vitro, but only MDSC-PGE2 significantly ameliorated EAE symptoms. This effect correlated with a reduced infiltration of Th17 and IFN-gamma-producing NK cells, and an increased proportion of regulatory T cells in the CNS and spleen. Importantly, both MDSCs and MDSC-PGE2 prevented EAE-induced reduction of gut microbiota diversity, but only MDSC-PGE2 prevented the extensive alterations in gut microbiota composition following their early migration into Payer's patches and mesenteric lymph nodes. This phenomenon was related to the significant enrichment of gut microbial taxa with potential immunoregulatory properties, as well as higher levels of butyrate, propionate, and putrescine in feces. This study provides new insights into the host-microbiota interactions in EAE, suggesting that activated MDSCs could be potentially used as an efficient therapy for acute phases of MS. Considering a significant association between the efficacy of MDSC-PGE2 and gut microbiota composition, our findings also provide a rationale for further exploring the specific microbial metabolites in MS therapy.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Gut Microbes
T1  - Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis
IS  - 1
VL  - 14
DO  - 10.1080/19490976.2022.2127455
ER  - 

@article{
author = "Radojević, Dušan and Bekić, Marina and Gruden-Movsesijan, Alisa and Ilić, Nataša and Dinić, Miroslav and Bisenić, Aleksandar and Golić, Nataša and Vucević, Dragana and Đokić, Jelena and Tomić, Sergej",
year = "2022",
abstract = "Over-activated myeloid cells and disturbance in gut microbiota composition are critical factors contributing to the pathogenesis of Multiple Sclerosis (MS). Myeloid-derived suppressor cells (MDSCs) emerged as promising regulators of chronic inflammatory diseases, including autoimmune diseases. However, it remained unclear whether MDSCs display any therapeutic potential in MS, and how this therapy modulates gut microbiota composition. Here, we assessed the potential of in vitro generated bone marrow-derived MDSCs to ameliorate experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats and investigated how their application associates with the changes in gut microbiota composition. MDSCs differentiated with prostaglandin (PG)E2 (MDSC-PGE2) and control MDSCs (differentiated without PGE2) displayed strong immunosuppressive properties in vitro, but only MDSC-PGE2 significantly ameliorated EAE symptoms. This effect correlated with a reduced infiltration of Th17 and IFN-gamma-producing NK cells, and an increased proportion of regulatory T cells in the CNS and spleen. Importantly, both MDSCs and MDSC-PGE2 prevented EAE-induced reduction of gut microbiota diversity, but only MDSC-PGE2 prevented the extensive alterations in gut microbiota composition following their early migration into Payer's patches and mesenteric lymph nodes. This phenomenon was related to the significant enrichment of gut microbial taxa with potential immunoregulatory properties, as well as higher levels of butyrate, propionate, and putrescine in feces. This study provides new insights into the host-microbiota interactions in EAE, suggesting that activated MDSCs could be potentially used as an efficient therapy for acute phases of MS. Considering a significant association between the efficacy of MDSC-PGE2 and gut microbiota composition, our findings also provide a rationale for further exploring the specific microbial metabolites in MS therapy.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Gut Microbes",
title = "Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis",
number = "1",
volume = "14",
doi = "10.1080/19490976.2022.2127455"
}

Radojević, D., Bekić, M., Gruden-Movsesijan, A., Ilić, N., Dinić, M., Bisenić, A., Golić, N., Vucević, D., Đokić, J.,& Tomić, S.. (2022). Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis. in Gut Microbes
Taylor & Francis Inc, Philadelphia., 14(1).
https://doi.org/10.1080/19490976.2022.2127455

Radojević D, Bekić M, Gruden-Movsesijan A, Ilić N, Dinić M, Bisenić A, Golić N, Vucević D, Đokić J, Tomić S. Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis. in Gut Microbes. 2022;14(1).
doi:10.1080/19490976.2022.2127455 .

Radojević, Dušan, Bekić, Marina, Gruden-Movsesijan, Alisa, Ilić, Nataša, Dinić, Miroslav, Bisenić, Aleksandar, Golić, Nataša, Vucević, Dragana, Đokić, Jelena, Tomić, Sergej, "Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis" in Gut Microbes, 14, no. 1 (2022),
https://doi.org/10.1080/19490976.2022.2127455 . .

TY  - JOUR
AU  - Čolić, Miodrag
AU  - Bekić, Marina
AU  - Tomić, Sergej
AU  - Đokić, Jelena
AU  - Radojević, Dušan
AU  - Savikin, Katarina
AU  - Miljus, Nataša
AU  - Marković, Milan
AU  - Skrbić, Ranko
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1605
AB  - Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory properties, but its effect on the adaptive immune system has not been sufficiently investigated. In this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range 6.25-400 mu g/mL) resulted in cytotoxicity at concentrations of 100 mu g/mL and higher, due to the induction of apoptosis and oxidative stress, whereas autophagy was reduced. At non-cytotoxic concentrations, the opposite effect on these processes was observed simultaneously with the inhibition of PHA-induced PBMC proliferation and a significant decrease in the expression of CD4. PoPEx differently modulated the expression of activation markers (CD69, CD25, ICOS) and PD1 (inhibitory marker), depending on the dose and T-cell subsets. PoPEx (starting from 12.5 mu g/mL) suppressed the production of Th1 (IFN-gamma), Th17 (IL-17A, IL-17F, and IL-22), Th9 (IL-9), and proinflammatory cytokines (TNF-alpha and IL-6) in culture supernatants. Lower concentrations upregulated Th2 (IL-5 and IL-13) and Treg (IL-10) responses as well as CD4+CD25hiFoxp3+ cell frequency. Higher concentrations of PoPEx increased the frequency of IL-10- and TGF-beta-producing T-cells (much higher in the CD4+ subset). In conclusion, our study suggested for the first time complex immunoregulatory effects of PoPEx on T cells, which could assist in the suppression of chronic inflammatory and autoimmune diseases.
PB  - MDPI, Basel
T2  - Pharmaceutics
T1  - Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture
IS  - 6
VL  - 14
DO  - 10.3390/pharmaceutics14061140
ER  - 

@article{
author = "Čolić, Miodrag and Bekić, Marina and Tomić, Sergej and Đokić, Jelena and Radojević, Dušan and Savikin, Katarina and Miljus, Nataša and Marković, Milan and Skrbić, Ranko",
year = "2022",
abstract = "Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory properties, but its effect on the adaptive immune system has not been sufficiently investigated. In this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range 6.25-400 mu g/mL) resulted in cytotoxicity at concentrations of 100 mu g/mL and higher, due to the induction of apoptosis and oxidative stress, whereas autophagy was reduced. At non-cytotoxic concentrations, the opposite effect on these processes was observed simultaneously with the inhibition of PHA-induced PBMC proliferation and a significant decrease in the expression of CD4. PoPEx differently modulated the expression of activation markers (CD69, CD25, ICOS) and PD1 (inhibitory marker), depending on the dose and T-cell subsets. PoPEx (starting from 12.5 mu g/mL) suppressed the production of Th1 (IFN-gamma), Th17 (IL-17A, IL-17F, and IL-22), Th9 (IL-9), and proinflammatory cytokines (TNF-alpha and IL-6) in culture supernatants. Lower concentrations upregulated Th2 (IL-5 and IL-13) and Treg (IL-10) responses as well as CD4+CD25hiFoxp3+ cell frequency. Higher concentrations of PoPEx increased the frequency of IL-10- and TGF-beta-producing T-cells (much higher in the CD4+ subset). In conclusion, our study suggested for the first time complex immunoregulatory effects of PoPEx on T cells, which could assist in the suppression of chronic inflammatory and autoimmune diseases.",
publisher = "MDPI, Basel",
journal = "Pharmaceutics",
title = "Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture",
number = "6",
volume = "14",
doi = "10.3390/pharmaceutics14061140"
}

Čolić, M., Bekić, M., Tomić, S., Đokić, J., Radojević, D., Savikin, K., Miljus, N., Marković, M.,& Skrbić, R.. (2022). Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture. in Pharmaceutics
MDPI, Basel., 14(6).
https://doi.org/10.3390/pharmaceutics14061140

Čolić M, Bekić M, Tomić S, Đokić J, Radojević D, Savikin K, Miljus N, Marković M, Skrbić R. Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture. in Pharmaceutics. 2022;14(6).
doi:10.3390/pharmaceutics14061140 .

Čolić, Miodrag, Bekić, Marina, Tomić, Sergej, Đokić, Jelena, Radojević, Dušan, Savikin, Katarina, Miljus, Nataša, Marković, Milan, Skrbić, Ranko, "Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture" in Pharmaceutics, 14, no. 6 (2022),
https://doi.org/10.3390/pharmaceutics14061140 . .

TY  - CHAP
AU  - Đorić, Ilona
AU  - Išić Denčić, Tijana
AU  - Šelemetjev, Sonja Šelemetjev
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1814
AB  - Tumorska mikrosredina predstavlja specifično okruženje sastavljeno od okoloćelijskog matriksa
i nemalignih elemenata kao što su krvni sudovi, fibroblasti i makrofagi. Ona se aktivno stvara
od strane malignih ćelija i ima uticaj na njihovo ponašanje. Tumorski okoloćelijski matriks ima znatno
izmenjene biofizičke i biohemijske osobine u odnosu na netumorsko tkivo, što posledično
uzrokuje promene u ćelijskoj signalizaciji. Recipročna interakcija između tumorske ćelije i njenog
okruženja je ključna za nastanak i progresiju maligniteta, orkestrirajući sve faze malignog procesa:
epitelo-mezenhimsku tranziciju, održavanje besmrtnosti maligne ćelije, neoangiogenezu, izbegavanje
imunskog odgovora, formiranje metastaza i rezistenciju na hemoterapeutike. U ovom poglavlju
daćemo pregled najvažnijih karakteristika tumorskog okruženja, i osvrnućemo se na najnovija
saznanja o njihovom uticaju na malignu progresiju.
AB  - The tumor microenvironment is a specific surrounding composed of extracellular matrix and
non-malignant elements such as blood vessles, fibroblasts and macrophages. It is actively generated
by malignant cells and has an influence on their behavior. The tumor extracellular matrix acquires altered
biochemical and biophysical properties compared to healthy tissue, with many repercussions
on cellular signaling. The mutual interaction between the tumor cell and its surroundings is crucial for
the onset and progression of malignant tumors, orcestrating all phases of the malignant process: epithelial-
mesenchimal transition, maintenance of cellular immortality, angiogenesis, avoidance of immune
survailance, formation of metastases, and resistance to therapeutics. In this chapter, we will review
the most important features of the tumor microenvironment and revise the most recent understandings
on its influence on malignant progression.
PB  - Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo
T2  - Trendovi u molekularnoj Biologiji
T1  - Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta
T1  - Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta
EP  - 89
IS  - 2
SP  - 75
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1814
ER  - 

@inbook{
author = "Đorić, Ilona and Išić Denčić, Tijana and Šelemetjev, Sonja Šelemetjev",
year = "2022",
abstract = "Tumorska mikrosredina predstavlja specifično okruženje sastavljeno od okoloćelijskog matriksa
i nemalignih elemenata kao što su krvni sudovi, fibroblasti i makrofagi. Ona se aktivno stvara
od strane malignih ćelija i ima uticaj na njihovo ponašanje. Tumorski okoloćelijski matriks ima znatno
izmenjene biofizičke i biohemijske osobine u odnosu na netumorsko tkivo, što posledično
uzrokuje promene u ćelijskoj signalizaciji. Recipročna interakcija između tumorske ćelije i njenog
okruženja je ključna za nastanak i progresiju maligniteta, orkestrirajući sve faze malignog procesa:
epitelo-mezenhimsku tranziciju, održavanje besmrtnosti maligne ćelije, neoangiogenezu, izbegavanje
imunskog odgovora, formiranje metastaza i rezistenciju na hemoterapeutike. U ovom poglavlju
daćemo pregled najvažnijih karakteristika tumorskog okruženja, i osvrnućemo se na najnovija
saznanja o njihovom uticaju na malignu progresiju., The tumor microenvironment is a specific surrounding composed of extracellular matrix and
non-malignant elements such as blood vessles, fibroblasts and macrophages. It is actively generated
by malignant cells and has an influence on their behavior. The tumor extracellular matrix acquires altered
biochemical and biophysical properties compared to healthy tissue, with many repercussions
on cellular signaling. The mutual interaction between the tumor cell and its surroundings is crucial for
the onset and progression of malignant tumors, orcestrating all phases of the malignant process: epithelial-
mesenchimal transition, maintenance of cellular immortality, angiogenesis, avoidance of immune
survailance, formation of metastases, and resistance to therapeutics. In this chapter, we will review
the most important features of the tumor microenvironment and revise the most recent understandings
on its influence on malignant progression.",
publisher = "Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo",
journal = "Trendovi u molekularnoj Biologiji",
booktitle = "Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta, Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta",
pages = "89-75",
number = "2",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1814"
}

Đorić, I., Išić Denčić, T.,& Šelemetjev, S. Š.. (2022). Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta. in Trendovi u molekularnoj Biologiji
Beograd : Institut za molekularnu genetiku i genetičko inženjerstvo.(2), 75-89.
https://hdl.handle.net/21.15107/rcub_imagine_1814

Đorić I, Išić Denčić T, Šelemetjev SŠ. Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta. in Trendovi u molekularnoj Biologiji. 2022;(2):75-89.
https://hdl.handle.net/21.15107/rcub_imagine_1814 .

Đorić, Ilona, Išić Denčić, Tijana, Šelemetjev, Sonja Šelemetjev, "Uticaj tumorske mikrosredine na razvoj i progresiju maligniteta" in Trendovi u molekularnoj Biologiji, no. 2 (2022):75-89,
https://hdl.handle.net/21.15107/rcub_imagine_1814 .

TY  - JOUR
AU  - Tertel, Tobias
AU  - Tomić, Sergej
AU  - Đokić, Jelena
AU  - Radojević, Dušan
AU  - Stevanović, Dejan
AU  - Ilić, Nataša
AU  - Giebel, Bernd
AU  - Kosanović, Maja
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1517
AB  - COVID-19 is characterized by a wide spectrum of disease severity, whose indicators and underlying mechanisms need to be identified. The role of extracellular vesicles (EVs) in COVID-19 and their biomarker potential, however, remains largely unknown. Aiming to identify specific EV signatures of patients with mild compared to severe COVID-19, we characterized the EV composition of 20 mild and 26 severe COVID-19 patients along with 16 sex and age-matched healthy donors with a panel of eight different antibodies by imaging flow cytometry (IFCM). We correlated the obtained data with 37 clinical, prerecorded biochemical and immunological parameters. Severe patients' sera contained increased amounts of CD13(+) and CD82(+) EVs, which positively correlated with IL-6-producing and circulating myeloid-derived suppressor cells (MDSCs) and with the serum concentration of proinflammatory cytokines, respectively. Sera of mild COVID-19 patients contained more HLA-ABC(+) EVs than sera of the healthy donors and more CD24(+) EVs than severe COVID-19 patients. Their increased abundance negatively correlated with disease severity and accumulation of MDSCs, being considered as key drivers of immunopathogenesis in COVID-19. Altogether, our results support the potential of serum EVs as powerful biomarkers for COVID-19 severity and pave the way for future investigations aiming to unravel the role of EVs in COVID-19 progression.
PB  - Hoboken : Wiley
T2  - Journal of Extracellular Vesicles
T1  - Serum-derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID-19 patients
IS  - 8
VL  - 11
DO  - 10.1002/jev2.12257
ER  - 

@article{
author = "Tertel, Tobias and Tomić, Sergej and Đokić, Jelena and Radojević, Dušan and Stevanović, Dejan and Ilić, Nataša and Giebel, Bernd and Kosanović, Maja",
year = "2022",
abstract = "COVID-19 is characterized by a wide spectrum of disease severity, whose indicators and underlying mechanisms need to be identified. The role of extracellular vesicles (EVs) in COVID-19 and their biomarker potential, however, remains largely unknown. Aiming to identify specific EV signatures of patients with mild compared to severe COVID-19, we characterized the EV composition of 20 mild and 26 severe COVID-19 patients along with 16 sex and age-matched healthy donors with a panel of eight different antibodies by imaging flow cytometry (IFCM). We correlated the obtained data with 37 clinical, prerecorded biochemical and immunological parameters. Severe patients' sera contained increased amounts of CD13(+) and CD82(+) EVs, which positively correlated with IL-6-producing and circulating myeloid-derived suppressor cells (MDSCs) and with the serum concentration of proinflammatory cytokines, respectively. Sera of mild COVID-19 patients contained more HLA-ABC(+) EVs than sera of the healthy donors and more CD24(+) EVs than severe COVID-19 patients. Their increased abundance negatively correlated with disease severity and accumulation of MDSCs, being considered as key drivers of immunopathogenesis in COVID-19. Altogether, our results support the potential of serum EVs as powerful biomarkers for COVID-19 severity and pave the way for future investigations aiming to unravel the role of EVs in COVID-19 progression.",
publisher = "Hoboken : Wiley",
journal = "Journal of Extracellular Vesicles",
title = "Serum-derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID-19 patients",
number = "8",
volume = "11",
doi = "10.1002/jev2.12257"
}

Tertel, T., Tomić, S., Đokić, J., Radojević, D., Stevanović, D., Ilić, N., Giebel, B.,& Kosanović, M.. (2022). Serum-derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID-19 patients. in Journal of Extracellular Vesicles
Hoboken : Wiley., 11(8).
https://doi.org/10.1002/jev2.12257

Tertel T, Tomić S, Đokić J, Radojević D, Stevanović D, Ilić N, Giebel B, Kosanović M. Serum-derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID-19 patients. in Journal of Extracellular Vesicles. 2022;11(8).
doi:10.1002/jev2.12257 .

Tertel, Tobias, Tomić, Sergej, Đokić, Jelena, Radojević, Dušan, Stevanović, Dejan, Ilić, Nataša, Giebel, Bernd, Kosanović, Maja, "Serum-derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID-19 patients" in Journal of Extracellular Vesicles, 11, no. 8 (2022),
https://doi.org/10.1002/jev2.12257 . .

TY  - JOUR
AU  - Bekić, Marina
AU  - Radanović, Marina
AU  - Đokić, Jelena
AU  - Tomić, Sergej
AU  - Eraković, Mile
AU  - Radojević, Dušan
AU  - Duka, Milos
AU  - Marković, Dejan
AU  - Marković, Milan
AU  - Ismaili, Bashkim
AU  - Bokonjić, Dejan
AU  - Čolić, Miodrag
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1558
AB  - Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-alpha, RANTES, TLR-2, HIF-1 alpha, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-alpha were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-beta, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment.
PB  - MDPI, Basel
T2  - International Journal of Molecular Sciences
T1  - Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis
IS  - 7
VL  - 23
DO  - 10.3390/ijms23073510
ER  - 

@article{
author = "Bekić, Marina and Radanović, Marina and Đokić, Jelena and Tomić, Sergej and Eraković, Mile and Radojević, Dušan and Duka, Milos and Marković, Dejan and Marković, Milan and Ismaili, Bashkim and Bokonjić, Dejan and Čolić, Miodrag",
year = "2022",
abstract = "Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-alpha, RANTES, TLR-2, HIF-1 alpha, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-alpha were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-beta, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment.",
publisher = "MDPI, Basel",
journal = "International Journal of Molecular Sciences",
title = "Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis",
number = "7",
volume = "23",
doi = "10.3390/ijms23073510"
}

Bekić, M., Radanović, M., Đokić, J., Tomić, S., Eraković, M., Radojević, D., Duka, M., Marković, D., Marković, M., Ismaili, B., Bokonjić, D.,& Čolić, M.. (2022). Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis. in International Journal of Molecular Sciences
MDPI, Basel., 23(7).
https://doi.org/10.3390/ijms23073510

Bekić M, Radanović M, Đokić J, Tomić S, Eraković M, Radojević D, Duka M, Marković D, Marković M, Ismaili B, Bokonjić D, Čolić M. Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis. in International Journal of Molecular Sciences. 2022;23(7).
doi:10.3390/ijms23073510 .

Bekić, Marina, Radanović, Marina, Đokić, Jelena, Tomić, Sergej, Eraković, Mile, Radojević, Dušan, Duka, Milos, Marković, Dejan, Marković, Milan, Ismaili, Bashkim, Bokonjić, Dejan, Čolić, Miodrag, "Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis" in International Journal of Molecular Sciences, 23, no. 7 (2022),
https://doi.org/10.3390/ijms23073510 . .

TY  - JOUR
AU  - Radojević, Dušan
AU  - Tomić, Sergej
AU  - Mihajlović, Dusan
AU  - Tolinački, Maja
AU  - Pavlović, Bojan
AU  - Vucević, Dragana
AU  - Bojić, Svetlana
AU  - Golić, Nataša
AU  - Čolić, Miodrag
AU  - Đokić, Jelena
PY  - 2021
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1475
AB  - Although promising for active immunization in cancer patients, dendritic cells (DCs) vaccines generated in vitro display high inter-individual variability in their immunogenicity, which mostly limits their therapeutic efficacy. Gut microbiota composition is a key emerging factor affecting individuals' immune responses, but it is unknown how it affects the variability of donors' precursor cells to differentiate into immunogenic DCs in vitro. By analyzing gut microbiota composition in 14 healthy donors, along with the phenotype and cytokines production by monocyte-derived DCs, we found significant correlations between immunogenic properties of DC and microbiota composition. Namely, donors who had higher alpha-diversity of gut microbiota and higher abundance of short-chain fatty acid (SCFAs) and SCFA-producing bacteria in feces, displayed lower expression of CD1a on immature (im)DC and higher expression of ILT-3, costimulatory molecules (CD86, CD40) proinflammatory cytokines (TNF-alpha, IL-6, IL-8) and IL-12p70/IL-10 ratio, all of which correlated with their lower maturation potential and immunogenicity upon stimulation with LPS/IFN gamma, a well-known Th1 polarizing cocktail. In contrast, imDCs generated from donors with lower alpha-diversity and higher abundance of Bifidobacterium and Collinsella in feces displayed higher CD1a expression and higher potential to up-regulate CD86 and CD40, increase TNF-alpha, IL-6, IL-8 production, and IL-12p70/IL-10 ratio upon stimulation. These results emphasize the important role of gut microbiota on the capacity of donor precursor cells to differentiate into immunogenic DCs suitable for cancer therapy, which could be harnessed for improving the actual and future DC-based cancer therapies.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Gut Microbes
T1  - Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro
IS  - 1
VL  - 13
DO  - 10.1080/19490976.2021.1921927
ER  - 

@article{
author = "Radojević, Dušan and Tomić, Sergej and Mihajlović, Dusan and Tolinački, Maja and Pavlović, Bojan and Vucević, Dragana and Bojić, Svetlana and Golić, Nataša and Čolić, Miodrag and Đokić, Jelena",
year = "2021",
abstract = "Although promising for active immunization in cancer patients, dendritic cells (DCs) vaccines generated in vitro display high inter-individual variability in their immunogenicity, which mostly limits their therapeutic efficacy. Gut microbiota composition is a key emerging factor affecting individuals' immune responses, but it is unknown how it affects the variability of donors' precursor cells to differentiate into immunogenic DCs in vitro. By analyzing gut microbiota composition in 14 healthy donors, along with the phenotype and cytokines production by monocyte-derived DCs, we found significant correlations between immunogenic properties of DC and microbiota composition. Namely, donors who had higher alpha-diversity of gut microbiota and higher abundance of short-chain fatty acid (SCFAs) and SCFA-producing bacteria in feces, displayed lower expression of CD1a on immature (im)DC and higher expression of ILT-3, costimulatory molecules (CD86, CD40) proinflammatory cytokines (TNF-alpha, IL-6, IL-8) and IL-12p70/IL-10 ratio, all of which correlated with their lower maturation potential and immunogenicity upon stimulation with LPS/IFN gamma, a well-known Th1 polarizing cocktail. In contrast, imDCs generated from donors with lower alpha-diversity and higher abundance of Bifidobacterium and Collinsella in feces displayed higher CD1a expression and higher potential to up-regulate CD86 and CD40, increase TNF-alpha, IL-6, IL-8 production, and IL-12p70/IL-10 ratio upon stimulation. These results emphasize the important role of gut microbiota on the capacity of donor precursor cells to differentiate into immunogenic DCs suitable for cancer therapy, which could be harnessed for improving the actual and future DC-based cancer therapies.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Gut Microbes",
title = "Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro",
number = "1",
volume = "13",
doi = "10.1080/19490976.2021.1921927"
}

Radojević, D., Tomić, S., Mihajlović, D., Tolinački, M., Pavlović, B., Vucević, D., Bojić, S., Golić, N., Čolić, M.,& Đokić, J.. (2021). Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro. in Gut Microbes
Taylor & Francis Inc, Philadelphia., 13(1).
https://doi.org/10.1080/19490976.2021.1921927

Radojević D, Tomić S, Mihajlović D, Tolinački M, Pavlović B, Vucević D, Bojić S, Golić N, Čolić M, Đokić J. Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro. in Gut Microbes. 2021;13(1).
doi:10.1080/19490976.2021.1921927 .

Radojević, Dušan, Tomić, Sergej, Mihajlović, Dusan, Tolinački, Maja, Pavlović, Bojan, Vucević, Dragana, Bojić, Svetlana, Golić, Nataša, Čolić, Miodrag, Đokić, Jelena, "Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro" in Gut Microbes, 13, no. 1 (2021),
https://doi.org/10.1080/19490976.2021.1921927 . .

TY  - JOUR
AU  - Tomić, Sergej
AU  - Đokić, Jelena
AU  - Stevanović, Dejan
AU  - Ilić, Nataša
AU  - Gruden-Movsesijan, Alisa
AU  - Dinić, Miroslav
AU  - Radojević, Dušan
AU  - Bekić, Marina
AU  - Mitrović, Nebojša
AU  - Tomasević, Ratko
AU  - Mikić, Dragan
AU  - Stojanović, Dragos
AU  - Čolić, Miodrag
PY  - 2021
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1446
AB  - Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed similar to 140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with similar to 30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-gamma production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Immunology
T1  - Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients
VL  - 12
DO  - 10.3389/fimmu.2021.614599
ER  - 

@article{
author = "Tomić, Sergej and Đokić, Jelena and Stevanović, Dejan and Ilić, Nataša and Gruden-Movsesijan, Alisa and Dinić, Miroslav and Radojević, Dušan and Bekić, Marina and Mitrović, Nebojša and Tomasević, Ratko and Mikić, Dragan and Stojanović, Dragos and Čolić, Miodrag",
year = "2021",
abstract = "Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed similar to 140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with similar to 30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-gamma production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Immunology",
title = "Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients",
volume = "12",
doi = "10.3389/fimmu.2021.614599"
}

Tomić, S., Đokić, J., Stevanović, D., Ilić, N., Gruden-Movsesijan, A., Dinić, M., Radojević, D., Bekić, M., Mitrović, N., Tomasević, R., Mikić, D., Stojanović, D.,& Čolić, M.. (2021). Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients. in Frontiers in Immunology
Frontiers Media Sa, Lausanne., 12.
https://doi.org/10.3389/fimmu.2021.614599

Tomić S, Đokić J, Stevanović D, Ilić N, Gruden-Movsesijan A, Dinić M, Radojević D, Bekić M, Mitrović N, Tomasević R, Mikić D, Stojanović D, Čolić M. Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients. in Frontiers in Immunology. 2021;12.
doi:10.3389/fimmu.2021.614599 .

Tomić, Sergej, Đokić, Jelena, Stevanović, Dejan, Ilić, Nataša, Gruden-Movsesijan, Alisa, Dinić, Miroslav, Radojević, Dušan, Bekić, Marina, Mitrović, Nebojša, Tomasević, Ratko, Mikić, Dragan, Stojanović, Dragos, Čolić, Miodrag, "Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients" in Frontiers in Immunology, 12 (2021),
https://doi.org/10.3389/fimmu.2021.614599 . .