TY  - CONF
AU  - Mićanović, Dragica
AU  - Stegnjaić, Goran
AU  - Nikolovski, Neda
AU  - Momčilović, Miljana
AU  - Foresti, Roberta
AU  - Motterlini, Roberto
AU  - Miljković, Đorđe
AU  - Saksida, Tamara
PY  - 2023
UR  - https://benbedphar.org/wp-content/uploads/2023/10/abstract_book_Graz_final.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6473
AB  - Type 1 diabetes (T1D) is an autoimmune disease that leads to the death of insulin-producing
pancreatic β-cells. The autoimmune response in T1D becomes chronic as a consequence of
regulatory mechanisms unable to counteract this disease. In this study, we evaluated the
anti-diabetic potential of a new hybrid compound (HYCO-3) consisting of a CO-releasing
molecule conjugated to a fumaric ester derivative that is known to activate the Nrf2 and
increase the expression of the CO-producing enzyme heme oxygenase-1. T1D was induced
in C57BL/6 mice treated intraperitoneally for 5 consecutive days with multiple low doses of
streptozotocin (40 mg/kg BW). HYCO-3 (25 mg/kg BW daily) was administered by oral
gavage while the control group received the vehicle (DMSO/sesame oil) for 14 days, starting
on the first day of streptozotocin treatment. To evaluate the development of T1D, glycaemia
and body mass were measured weekly. At the end of the experiment the pancreas was
collected and histochemical analyses for insulin expression were performed. Insulitis, the
infiltration of immune cells in the pancreas, was also assessed. We found that treatment
with HYCO-3 lowered blood glucose levels compared to the control group in association
with a lower insulitis grade and a higher expression of insulin in pancreatic islets.
Furthermore, to assess the effect of HYCO-3 on antigen specific response, cells from the
draining pancreatic lymph nodes of diabetic animals were stimulated with insulin and
HYCO-3 to assess the production of pro-inflammatory markers in cell supernatants. HYCO-
3 was able to down-regulate the production of IL-17 in the cultures where antigen specific
response was induced with insulin.
Overall, our results show that HYCO-3 ameliorated T1D in C57BL/6 mice by inhibiting the
recruitment of immune cells into the pancreas. These results warrant future investigation of
cellular and molecular mechanisms by which HYCO-3 acts on immune cells that are of
importance in the pathogenesis of T1D.
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  - HYCO-3, an Nrf2 activator that simultaneously releases carbon monoxide (CO), ameliorates type 1 diabetes in a mouse model
SP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6473
ER  - 

@conference{
author = "Mićanović, Dragica and Stegnjaić, Goran and Nikolovski, Neda and Momčilović, Miljana and Foresti, Roberta and Motterlini, Roberto and Miljković, Đorđe and Saksida, Tamara",
year = "2023",
abstract = "Type 1 diabetes (T1D) is an autoimmune disease that leads to the death of insulin-producing
pancreatic β-cells. The autoimmune response in T1D becomes chronic as a consequence of
regulatory mechanisms unable to counteract this disease. In this study, we evaluated the
anti-diabetic potential of a new hybrid compound (HYCO-3) consisting of a CO-releasing
molecule conjugated to a fumaric ester derivative that is known to activate the Nrf2 and
increase the expression of the CO-producing enzyme heme oxygenase-1. T1D was induced
in C57BL/6 mice treated intraperitoneally for 5 consecutive days with multiple low doses of
streptozotocin (40 mg/kg BW). HYCO-3 (25 mg/kg BW daily) was administered by oral
gavage while the control group received the vehicle (DMSO/sesame oil) for 14 days, starting
on the first day of streptozotocin treatment. To evaluate the development of T1D, glycaemia
and body mass were measured weekly. At the end of the experiment the pancreas was
collected and histochemical analyses for insulin expression were performed. Insulitis, the
infiltration of immune cells in the pancreas, was also assessed. We found that treatment
with HYCO-3 lowered blood glucose levels compared to the control group in association
with a lower insulitis grade and a higher expression of insulin in pancreatic islets.
Furthermore, to assess the effect of HYCO-3 on antigen specific response, cells from the
draining pancreatic lymph nodes of diabetic animals were stimulated with insulin and
HYCO-3 to assess the production of pro-inflammatory markers in cell supernatants. HYCO-
3 was able to down-regulate the production of IL-17 in the cultures where antigen specific
response was induced with insulin.
Overall, our results show that HYCO-3 ameliorated T1D in C57BL/6 mice by inhibiting the
recruitment of immune cells into the pancreas. These results warrant future investigation of
cellular and molecular mechanisms by which HYCO-3 acts on immune cells that are of
importance in the pathogenesis of T1D.",
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 = "HYCO-3, an Nrf2 activator that simultaneously releases carbon monoxide (CO), ameliorates type 1 diabetes in a mouse model",
pages = "46",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6473"
}

Mićanović, D., Stegnjaić, G., Nikolovski, N., Momčilović, M., Foresti, R., Motterlini, R., Miljković, Đ.,& Saksida, T.. (2023). HYCO-3, an Nrf2 activator that simultaneously releases carbon monoxide (CO), ameliorates type 1 diabetes in a mouse model. 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., 46.
https://hdl.handle.net/21.15107/rcub_ibiss_6473

Mićanović D, Stegnjaić G, Nikolovski N, Momčilović M, Foresti R, Motterlini R, Miljković Đ, Saksida T. HYCO-3, an Nrf2 activator that simultaneously releases carbon monoxide (CO), ameliorates type 1 diabetes in a mouse model. 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;:46.
https://hdl.handle.net/21.15107/rcub_ibiss_6473 .

Mićanović, Dragica, Stegnjaić, Goran, Nikolovski, Neda, Momčilović, Miljana, Foresti, Roberta, Motterlini, Roberto, Miljković, Đorđe, Saksida, Tamara, "HYCO-3, an Nrf2 activator that simultaneously releases carbon monoxide (CO), ameliorates type 1 diabetes in a mouse model" 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):46,
https://hdl.handle.net/21.15107/rcub_ibiss_6473 .

TY  - CONF
AU  - Stegnjaić, Goran
AU  - Mićanović, Dragica
AU  - Nikolovski, Neda
AU  - Momčilović, Miljana
AU  - Saksida, Tamara
AU  - Foresti, Roberta
AU  - Motterlini, Roberto
AU  - Miljković, Đorđe
PY  - 2023
UR  - https://benbedphar.org/wp-content/uploads/2023/10/abstract_book_Graz_final.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6476
AB  - HYCOs are a novel class of hybrid compounds consisting of fumaric esters conjugated to
carbon monoxide-releasing molecules (CO-RMs). They were designed based on the
consideration that fumaric esters are known to activate the transcription factor Nrf2 and that
CO possesses potent anti-inflammatory properties. The dual action of these hybrids has
shown promising therapeutic effects. in animal models of psoriasis and multiple sclerosis.
We have recently started with the group of Drs Motterlini and Foresti in France a
collaborative research project relevant to the BenBedPhar COST Action, focusing on the
immunomodulatory effects of HYCOs. These effects were examined in vitro in cultures of
myeloid-derived cells (macrophages and dendritic cells), lymph node cells, immune cells
isolated from the inflamed central nervous system, and microglia. By assessing the
production of immunoactive molecules, including nitric oxide, reactive oxygen species and
cytokines, we provide evidence that HYCOs display immunomodulatory effects in all cell
populations examined in vitro. Moreover, we were able to demonstrate that HYCOs are
efficient in ameliorating type 1 diabetes in an animal model of this autoimmune disease. Our
results indicate that HYCOs are Nrf2 activators with promising immunomodulatory
therapeutic properties.
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  - Immunomodulatory properties of HYCOs, NRF2 activators that simultaneously release carbon monoxide (CO) to cells and tissues
SP  - 21
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6476
ER  - 

@conference{
author = "Stegnjaić, Goran and Mićanović, Dragica and Nikolovski, Neda and Momčilović, Miljana and Saksida, Tamara and Foresti, Roberta and Motterlini, Roberto and Miljković, Đorđe",
year = "2023",
abstract = "HYCOs are a novel class of hybrid compounds consisting of fumaric esters conjugated to
carbon monoxide-releasing molecules (CO-RMs). They were designed based on the
consideration that fumaric esters are known to activate the transcription factor Nrf2 and that
CO possesses potent anti-inflammatory properties. The dual action of these hybrids has
shown promising therapeutic effects. in animal models of psoriasis and multiple sclerosis.
We have recently started with the group of Drs Motterlini and Foresti in France a
collaborative research project relevant to the BenBedPhar COST Action, focusing on the
immunomodulatory effects of HYCOs. These effects were examined in vitro in cultures of
myeloid-derived cells (macrophages and dendritic cells), lymph node cells, immune cells
isolated from the inflamed central nervous system, and microglia. By assessing the
production of immunoactive molecules, including nitric oxide, reactive oxygen species and
cytokines, we provide evidence that HYCOs display immunomodulatory effects in all cell
populations examined in vitro. Moreover, we were able to demonstrate that HYCOs are
efficient in ameliorating type 1 diabetes in an animal model of this autoimmune disease. Our
results indicate that HYCOs are Nrf2 activators with promising immunomodulatory
therapeutic properties.",
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 = "Immunomodulatory properties of HYCOs, NRF2 activators that simultaneously release carbon monoxide (CO) to cells and tissues",
pages = "21",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6476"
}

Stegnjaić, G., Mićanović, D., Nikolovski, N., Momčilović, M., Saksida, T., Foresti, R., Motterlini, R.,& Miljković, Đ.. (2023). Immunomodulatory properties of HYCOs, NRF2 activators that simultaneously release carbon monoxide (CO) to cells and tissues. 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., 21.
https://hdl.handle.net/21.15107/rcub_ibiss_6476

Stegnjaić G, Mićanović D, Nikolovski N, Momčilović M, Saksida T, Foresti R, Motterlini R, Miljković Đ. Immunomodulatory properties of HYCOs, NRF2 activators that simultaneously release carbon monoxide (CO) to cells and tissues. 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;:21.
https://hdl.handle.net/21.15107/rcub_ibiss_6476 .

Stegnjaić, Goran, Mićanović, Dragica, Nikolovski, Neda, Momčilović, Miljana, Saksida, Tamara, Foresti, Roberta, Motterlini, Roberto, Miljković, Đorđe, "Immunomodulatory properties of HYCOs, NRF2 activators that simultaneously release carbon monoxide (CO) to cells and tissues" 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):21,
https://hdl.handle.net/21.15107/rcub_ibiss_6476 .