TY  - CONF
AU  - Jonić, Natalija
AU  - Koprivica, Ivan
AU  - Chatzigiannis, Christos
AU  - Tsiailanis, Antonis
AU  - Kyrkou, Stavroula
AU  - Tzakos, Eleftherios Paraskevas
AU  - Pavić, Aleksandar
AU  - Dimitrijević, Mirjana
AU  - Jovanović, Anđelina
AU  - Jovanović, Milan B.
AU  - Marinho, Sergio
AU  - Castro-Almeida, Ines
AU  - Otašević, Vesna
AU  - Moura-Alves, Pedro
AU  - Tzakos, Andreas
AU  - Stojanović, Ivana D.
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/7017
AB  - Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by an imbalance between pathogenic CD4+ and
CD8+ lymphocytes on one side and regulatory T cells (Treg) on the other. Activating Treg and/or tolerogenic dendritic
cells (tolDC) through various methods has shown benefits in animal models of T1D. Both cell types express high levels
of the aryl hydrocarbon receptor (AHR), and AHR activation is typically associated with enhanced tolDC and Treg
functionality. In this study, the novel fluorescent indole-containing compound AGT-5 was investigated for its potential
to act as an AHR ligand and modulate immune cells both in vitro and in vivo. Through in silico docking analysis, AGT-
5 demonstrated the ability to bind AHR, and its agonistic effects were confirmed using the reporter Caco-2 cell line.
Additionally, due to its fluorescent properties, AGT-5 was visualized in macrophages in vitro and in the small intestine
lamina propria ex vivo after oral administration using confocal microscopy. AGT-5 exhibited no toxicity towards murine
macrophages and human tonsillar cells. Moreover, tests on zebrafish embryos revealed no nephrotoxicity, hepatotoxicity,
or cardiotoxicity. Utilizing an ADME virtual platform it was confirmed that AGT-5 possesses drug-like characteristics.
Subsequently, AGT-5 was orally administered to C57BL/6 mice that had received low doses of streptozotocin to induce
T1D. Treatment with AGT-5 commencing from the first day of T1D induction and lasting for 20 days effectively
prevented immune cell infiltration into the pancreas, preserved insulin production, and halted the progression of T1D.
AGT-5 achieved this by promoting tolDC and Treg activity along the gut-pancreatic lymph node-pancreas axis.
Mechanistically, AGT-5 upregulated indoleamine 2,3-dioxygenase 1 in tolDC and enhanced ATP-degrading enzyme
expression on Treg, thereby promoting immunosuppressive action. The positive outcomes seen in T1D animals suggest
that AGT-5 holds promise for a potential treatment for inflammatory conditions that can benefit from stimulation of the
regulatory arm of the immune response.
PB  - John Wiley and Sons
C3  - 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
T1  - A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells
IS  - 54
DO  - 10.1002/eji.202470200
SP  - 372
EP  - 373
ER  - 

@conference{
author = "Jonić, Natalija and Koprivica, Ivan and Chatzigiannis, Christos and Tsiailanis, Antonis and Kyrkou, Stavroula and Tzakos, Eleftherios Paraskevas and Pavić, Aleksandar and Dimitrijević, Mirjana and Jovanović, Anđelina and Jovanović, Milan B. and Marinho, Sergio and Castro-Almeida, Ines and Otašević, Vesna and Moura-Alves, Pedro and Tzakos, Andreas and Stojanović, Ivana D.",
year = "2024",
abstract = "Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by an imbalance between pathogenic CD4+ and
CD8+ lymphocytes on one side and regulatory T cells (Treg) on the other. Activating Treg and/or tolerogenic dendritic
cells (tolDC) through various methods has shown benefits in animal models of T1D. Both cell types express high levels
of the aryl hydrocarbon receptor (AHR), and AHR activation is typically associated with enhanced tolDC and Treg
functionality. In this study, the novel fluorescent indole-containing compound AGT-5 was investigated for its potential
to act as an AHR ligand and modulate immune cells both in vitro and in vivo. Through in silico docking analysis, AGT-
5 demonstrated the ability to bind AHR, and its agonistic effects were confirmed using the reporter Caco-2 cell line.
Additionally, due to its fluorescent properties, AGT-5 was visualized in macrophages in vitro and in the small intestine
lamina propria ex vivo after oral administration using confocal microscopy. AGT-5 exhibited no toxicity towards murine
macrophages and human tonsillar cells. Moreover, tests on zebrafish embryos revealed no nephrotoxicity, hepatotoxicity,
or cardiotoxicity. Utilizing an ADME virtual platform it was confirmed that AGT-5 possesses drug-like characteristics.
Subsequently, AGT-5 was orally administered to C57BL/6 mice that had received low doses of streptozotocin to induce
T1D. Treatment with AGT-5 commencing from the first day of T1D induction and lasting for 20 days effectively
prevented immune cell infiltration into the pancreas, preserved insulin production, and halted the progression of T1D.
AGT-5 achieved this by promoting tolDC and Treg activity along the gut-pancreatic lymph node-pancreas axis.
Mechanistically, AGT-5 upregulated indoleamine 2,3-dioxygenase 1 in tolDC and enhanced ATP-degrading enzyme
expression on Treg, thereby promoting immunosuppressive action. The positive outcomes seen in T1D animals suggest
that AGT-5 holds promise for a potential treatment for inflammatory conditions that can benefit from stimulation of the
regulatory arm of the immune response.",
publisher = "John Wiley and Sons",
journal = "7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland",
title = "A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells",
number = "54",
doi = "10.1002/eji.202470200",
pages = "372-373"
}

Jonić, N., Koprivica, I., Chatzigiannis, C., Tsiailanis, A., Kyrkou, S., Tzakos, E. P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Marinho, S., Castro-Almeida, I., Otašević, V., Moura-Alves, P., Tzakos, A.,& Stojanović, I. D.. (2024). A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland
John Wiley and Sons.(54), 372-373.
https://doi.org/10.1002/eji.202470200

Jonić N, Koprivica I, Chatzigiannis C, Tsiailanis A, Kyrkou S, Tzakos EP, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Marinho S, Castro-Almeida I, Otašević V, Moura-Alves P, Tzakos A, Stojanović ID. A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells. in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland. 2024;(54):372-373.
doi:10.1002/eji.202470200 .

Jonić, Natalija, Koprivica, Ivan, Chatzigiannis, Christos, Tsiailanis, Antonis, Kyrkou, Stavroula, Tzakos, Eleftherios Paraskevas, Pavić, Aleksandar, Dimitrijević, Mirjana, Jovanović, Anđelina, Jovanović, Milan B., Marinho, Sergio, Castro-Almeida, Ines, Otašević, Vesna, Moura-Alves, Pedro, Tzakos, Andreas, Stojanović, Ivana D., "A novel aryl hydrocarbon receptor ligand inhibits the development of Type 1 diabetes by enhancing the function of tolerogenic dendritic cells and regulatory T cells" in 7th European Congress of Immunology: ECI 2024; 2024 Sep 1-4; Dublin, Ireland, no. 54 (2024):372-373,
https://doi.org/10.1002/eji.202470200 . .

TY  - CONF
AU  - Koprivica, Ivan
AU  - Jonić, Natalija
AU  - Chatzigiannis, Christos
AU  - Tsiailanis, Antonis
AU  - Tzakos, Andreas G
AU  - Stojanović, Ivana D.
PY  - 2023
UR  - https://benbedphar.org/wp-content/uploads/2023/10/abstract_book_Graz_final.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6474
AB  - Aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) are
transcription factors involved in the regulation of drug-metabolizing enzymes. Moreover,
both of them can modulate the immune response. AhR activation can lead to the activation
or inhibition of specific immune cells, especially at barrier tissues such as skin, lungs, gutassociated lymphoid tissue, etc. Nrf2 was also shown to play a role in the anti-inflammatory
process by inhibiting the recruitment of inflammatory cells and regulating anti-inflammatory
gene expression. Nrf2 gene transcription can be directly modulated by AhR activation, as
the Nrf2 promoter possesses three xenobiotic response element-like elements that were
shown to be able to bind AhR in response to a known Ahr agonist TCDD.
In this study, we explored the effect of newly synthetized AhR agonists (indole-based
derivatives) termed C46 and B19 on mouse macrophage differentiation. Peritoneal cells
were incubated with 1.5 µM of AhR ligands for 24 h, after which the proinflammatory M1
(F4/80+CD40+) and anti-inflammatory M2 (F4/80+CD206+) macrophage phenotype was
determined by flow cytometry. The results indicate that both compounds push
macrophages towards a more inflammatory state, as C46 tripled the M1/M2 ratio in culture,
while B19 doubled it, compared to the DMSO (0.005% v/v) control. Additionally, both
mRNA and protein expression of cytochrome P450 1A1 (CYP1A1), commonly used as an
indicator of AhR activation, were also increased by C46 and B19. Finally, western blot
analysis showed that both of the tested AhR ligands downregulated the protein expression
of Nrf2 within the treated cells.
These results suggest that AhR activation and subsequent Nrf2 down-regulation by the
newly synthesized AhR agonists C46 and B19 boosted the proinflammatory phenotype of
mouse peritoneal macrophages.
PB  - BenBedPhar Consortium
C3  - 5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria
T1  - Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands
SP  - 38
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6474
ER  - 

@conference{
author = "Koprivica, Ivan and Jonić, Natalija and Chatzigiannis, Christos and Tsiailanis, Antonis and Tzakos, Andreas G and Stojanović, Ivana D.",
year = "2023",
abstract = "Aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) are
transcription factors involved in the regulation of drug-metabolizing enzymes. Moreover,
both of them can modulate the immune response. AhR activation can lead to the activation
or inhibition of specific immune cells, especially at barrier tissues such as skin, lungs, gutassociated lymphoid tissue, etc. Nrf2 was also shown to play a role in the anti-inflammatory
process by inhibiting the recruitment of inflammatory cells and regulating anti-inflammatory
gene expression. Nrf2 gene transcription can be directly modulated by AhR activation, as
the Nrf2 promoter possesses three xenobiotic response element-like elements that were
shown to be able to bind AhR in response to a known Ahr agonist TCDD.
In this study, we explored the effect of newly synthetized AhR agonists (indole-based
derivatives) termed C46 and B19 on mouse macrophage differentiation. Peritoneal cells
were incubated with 1.5 µM of AhR ligands for 24 h, after which the proinflammatory M1
(F4/80+CD40+) and anti-inflammatory M2 (F4/80+CD206+) macrophage phenotype was
determined by flow cytometry. The results indicate that both compounds push
macrophages towards a more inflammatory state, as C46 tripled the M1/M2 ratio in culture,
while B19 doubled it, compared to the DMSO (0.005% v/v) control. Additionally, both
mRNA and protein expression of cytochrome P450 1A1 (CYP1A1), commonly used as an
indicator of AhR activation, were also increased by C46 and B19. Finally, western blot
analysis showed that both of the tested AhR ligands downregulated the protein expression
of Nrf2 within the treated cells.
These results suggest that AhR activation and subsequent Nrf2 down-regulation by the
newly synthesized AhR agonists C46 and B19 boosted the proinflammatory phenotype of
mouse peritoneal macrophages.",
publisher = "BenBedPhar Consortium",
journal = "5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria",
title = "Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands",
pages = "38",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6474"
}

Koprivica, I., Jonić, N., Chatzigiannis, C., Tsiailanis, A., Tzakos, A. G.,& Stojanović, I. D.. (2023). Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands. in 5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria
BenBedPhar Consortium., 38.
https://hdl.handle.net/21.15107/rcub_ibiss_6474

Koprivica I, Jonić N, Chatzigiannis C, Tsiailanis A, Tzakos AG, Stojanović ID. Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands. in 5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria. 2023;:38.
https://hdl.handle.net/21.15107/rcub_ibiss_6474 .

Koprivica, Ivan, Jonić, Natalija, Chatzigiannis, Christos, Tsiailanis, Antonis, Tzakos, Andreas G, Stojanović, Ivana D., "Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands" in 5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria (2023):38,
https://hdl.handle.net/21.15107/rcub_ibiss_6474 .